BACKGROUND: Patients with severe aortic stenosis present frequently (∼50%) with concomitant obstructive coronary artery disease. Current guidelines recommend combined surgical aortic valve replacement (SAVR) and coronary artery bypass grafting (CABG) as the preferred treatment. Transcatheter aortic valve implantation (TAVI) and fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) represent a valid treatment alternative. We aimed to test the non-inferiority of FFR-guided PCI plus TAVI versus SAVR plus CABG in patients with severe aortic stenosis and complex coronary artery disease. METHODS: This international, multicentre, prospective, open-label, non-inferiority, randomised controlled trial was conducted at 18 tertiary medical centres across Europe. Patients (aged ≥70 years) with severe aortic stenosis and complex coronary artery disease, deemed feasible for percutaneous or surgical treatment according to the on-site Heart Team, were randomly assigned (1:1) to FFR-guided PCI plus TAVI or SAVR plus CABG according to a computer-generated sequence with random permuted blocks sizes stratified by site. The primary endpoint was a composite of all-cause mortality, myocardial infarction, disabling stroke, clinically driven target-vessel revascularisation, valve reintervention, and life-threatening or disabling bleeding at 1 year post-treatment. The trial was powered for non-inferiority (with a margin of 15%) and if met, for superiority. The primary and safety analyses were done per an intention-to-treat principle. This trial is registered with ClinicalTrials.gov (NCT03424941) and is closed. FINDINGS: Between May 31, 2018, and June 30, 2023, 172 patients were enrolled, of whom 91 were assigned to the FFR-guided PCI plus TAVI group and 81 to the SAVR plus CABG group. The mean age of patients was 76·5 years (SD 3·9). 118 (69%) of 172 patients were male and 54 (31%) patients were female. FFR-guided PCI plus TAVI resulted in favourable outcomes for the primary endpoint (four [4%] of 91 patients) versus SAVR plus CABG (17 [23%] of 77 patients; risk difference -18·5 [90% CI -27·8 to -9·7]), which was below the 15% prespecified non-inferiority margin (pnon-inferiority<0·001). FFR-guided PCI plus TAVI was superior to SAVR plus CABG (hazard ratio 0·17 [95% CI 0·06-0·51]; psuperiority<0·001), which was driven mainly by all-cause mortality (none [0%] of 91 patients vs seven (10%) of 77 patients; p=0·0025) and life-threatening bleeding (two [2%] vs nine [12%]; p=0·010). INTERPRETATION: The TCW trial is the first trial to compare percutaneous treatment versus surgical treatment in patients with severe aortic stenosis and complex coronary artery disease, showing favourable primary endpoint and mortality outcomes with percutaneous treatment. FUNDING: Isala Heart Centre and Medtronic.

• MeSH
• aortální stenóza * chirurgie   komplikace   MeSH
• chirurgická náhrada chlopně metody   MeSH
• frakční průtoková rezerva myokardu * MeSH
• koronární angioplastika * metody   MeSH
• koronární bypass * metody   MeSH
• lidé MeSH
• nemoci koronárních tepen * chirurgie   komplikace   terapie   MeSH
• prospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transkatetrální implantace aortální chlopně * metody   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• hodnocení ekvivalence MeSH
• multicentrická studie MeSH
• srovnávací studie MeSH

BACKGROUND: Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS. METHODS: In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661; substudy active and recruiting). FINDINGS: Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0-23·4) in the imetelstat group and 17·5 months (12·1-22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9-49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1-26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3-4 treatment-emergent adverse events. The most common treatment-emergent grade 3-4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia (73 [62%] vs five [8%]). No treatment-related deaths were reported. INTERPRETATION: Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs. FUNDING: Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.

• MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• erytropoéza MeSH
• lidé MeSH
• mladiství MeSH
• myelodysplastické syndromy * farmakoterapie   MeSH
• oligonukleotidy * MeSH
• protokoly antitumorózní kombinované chemoterapie MeSH
• trombocytopenie * farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolongs radiographic progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer previously treated with androgen receptor pathway inhibitor (ARPI) and taxane therapy. We aimed to investigate the efficacy of 177Lu-PSMA-617 in patients with taxane-naive metastatic castration-resistant prostate cancer. METHODS: In this phase 3, randomised, controlled trial conducted at 74 sites across Europe and North America, taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer who had progressed once on a previous ARPI were randomly allocated (1:1) to open-label, intravenous 177Lu-PSMA-617 at a dosage of 7·4 GBq (200 mCi) ± 10% once every 6 weeks for six cycles, or a change of ARPI (to abiraterone or enzalutamide, administered orally on a continuous basis per product labelling). Crossover from ARPI change to 177Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. The primary endpoint was radiographic progression-free survival, defined as the time from randomisation until radiographic progression or death, assessed in the intention-to-treat population. Safety was a secondary endpoint. This study is registered with ClinicalTrials.gov (NCT04689828) and is ongoing. In this primary report of the study, we present primary (first data cutoff) and updated (third data cutoff) analyses of radiographic progression-free survival; all other data are based on the third data cutoff. FINDINGS: Overall, of the 585 patients screened, 468 met all eligibility criteria and were randomly allocated between June 15, 2021 and Oct 7, 2022 to receive 177Lu-PSMA-617 (234 [50%] patients) or ARPI change (234 [50%]). Baseline characteristics were mostly similar between groups; median number of 177Lu-PSMA-617 cycles was 6·0 (IQR 4·0-6·0). Of patients assigned to ARPI change, 134 (57%) crossed over to receive 177Lu-PSMA-617. In the primary analysis (median time from randomisation to first data cutoff 7·26 months [IQR 3·38-10·55]), the median radiographic progression-free survival was 9·30 months (95% CI 6·77-not estimable) in the 177Lu-PSMA-617 group versus 5·55 months (4·04-5·95) in the ARPI change group (hazard ratio [HR] 0·41 [95% CI 0·29-0·56]; p<0·0001). In the updated analysis at time of the third data cutoff (median time from randomisation to third data cutoff 24·11 months [IQR 20·24-27·40]), median radiographic progression-free survival was 11·60 months (95% CI 9·30-14·19) in the 177Lu-PSMA-617 group versus 5·59 months (4·21-5·95) in the ARPI change group (HR 0·49 [95% CI 0·39-0·61]). The incidence of grade 3-5 adverse events was lower in the 177Lu-PSMA-617 group (at least one event in 81 [36%] of 227 patients; four [2%] grade 5 [none treatment related]) than the ARPI change group (112 [48%] of 232; five [2%] grade 5 [one treatment related]). INTERPRETATION: 177Lu-PSMA-617 prolonged radiographic progression-free survival relative to ARPI change, with a favourable safety profile. For patients with PSMA-positive metastatic castration-resistant prostate cancer who are being considered for a change of ARPI after progression on a previous ARPI, 177Lu-PSMA-617 may be an effective treatment alternative. FUNDING: Novartis.

• MeSH
• androsteny * terapeutické užití   MeSH
• antagonisté androgenních receptorů terapeutické užití   MeSH
• benzamidy terapeutické užití   MeSH
• dipeptidy * terapeutické užití   MeSH
• doba přežití bez progrese choroby MeSH
• fenylthiohydantoin * terapeutické užití   MeSH
• heterocyklické sloučeniny monocyklické * terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lutecium * terapeutické užití   MeSH
• nádory prostaty rezistentní na kastraci * farmakoterapie   patologie   MeSH
• nitrily * terapeutické užití   MeSH
• prostatický specifický antigen krev   MeSH
• radionuklidy terapeutické užití   MeSH
• senioři MeSH
• taxoidy terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: At the first interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, the addition of pembrolizumab to chemoradiotherapy provided a statistically significant and clinically meaningful improvement in progression-free survival in patients with locally advanced cervical cancer. We report the overall survival results from the second interim analysis of this study. METHODS: Eligible patients with newly diagnosed, high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of nodal status), locally advanced, histologically confirmed, squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer were randomly assigned 1:1 to receive five cycles of pembrolizumab (200 mg) or placebo every 3 weeks with concurrent chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Pembrolizumab or placebo and cisplatin were administered intravenously. Patients were stratified at randomisation by planned external beam radiotherapy type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cervical cancer stage at screening (FIGO 2014 stage IB2-IIB node positive vs III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy [equivalent dose of 2 Gy]). Primary endpoints were progression-free survival per RECIST 1.1 by investigator or by histopathological confirmation of suspected disease progression and overall survival defined as the time from randomisation to death due to any cause. Safety was a secondary endpoint. FINDINGS: Between June 9, 2020, and Dec 15, 2022, 1060 patients at 176 sites in 30 countries across Asia, Australia, Europe, North America, and South America were randomly assigned to treatment, with 529 patients in the pembrolizumab-chemoradiotherapy group and 531 patients in the placebo-chemoradiotherapy group. At the protocol-specified second interim analysis (data cutoff Jan 8, 2024), median follow-up was 29·9 months (IQR 23·3-34·3). Median overall survival was not reached in either group; 36-month overall survival was 82·6% (95% CI 78·4-86·1) in the pembrolizumab-chemoradiotherapy group and 74·8% (70·1-78·8) in the placebo-chemoradiotherapy group. The hazard ratio for death was 0·67 (95% CI 0·50-0·90; p=0·0040), meeting the protocol-specified primary objective. 413 (78%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 371 (70%) of 530 in the placebo-chemoradiotherapy group had a grade 3 or higher adverse event, with anaemia, white blood cell count decreased, and neutrophil count decreased being the most common adverse events. Potentially immune-mediated adverse events occurred in 206 (39%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 90 (17%) of 530 patients in the placebo-chemoradiotherapy group. This study is registered with ClinicalTrials.gov, NCT04221945. INTERPRETATION: Pembrolizumab plus chemoradiotherapy significantly improved overall survival in patients with locally advanced cervical cancer These data, together with results from the first interim analysis, support this immuno-chemoradiotherapy strategy as a new standard of care for this population. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

• MeSH
• adenokarcinom farmakoterapie   mortalita   radioterapie   MeSH
• adenoskvamózní karcinom farmakoterapie   mortalita   radioterapie   MeSH
• chemoradioterapie * metody   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• humanizované monoklonální protilátky * škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory děložního čípku * farmakoterapie   mortalita   radioterapie   MeSH
• protinádorové látky imunologicky aktivní terapeutické užití   škodlivé účinky   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• senioři MeSH
• spinocelulární karcinom farmakoterapie   mortalita   radioterapie   MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: Percutaneous active mechanical circulatory support (MCS) devices are being increasingly used in the treatment of acute myocardial infarction-related cardiogenic shock (AMICS) despite conflicting evidence regarding their effect on mortality. We aimed to ascertain the effect of early routine active percutaneous MCS versus control treatment on 6-month all-cause mortality in patients with AMICS. METHODS: In this individual patient data meta-analysis, randomised controlled trials of potential interest were identified, without language restriction, by querying the electronic databases MEDLINE via PubMed, Cochrane Central Register of Controlled Trials, and Embase, as well as ClinicalTrials.gov, up to Jan 26, 2024. All randomised trials with 6-month mortality data comparing early routine active MCS (directly in the catheterisation laboratory after randomisation) versus control in patients with AMICS were included. The primary outcome was 6-month all-cause mortality in patients with AMICS treated with early routine active percutaneous MCS versus control, with a focus on device type (loading, such as venoarterial extracorporeal membrane oxygenation [VA-ECMO] vs unloading) and patient selection. Hazard ratios (HRs) of the primary outcome measure were calculated using Cox regression models. This study is registered with PROSPERO, CRD42024504295. FINDINGS: Nine reports of randomised controlled trials (n=1114 patients) were evaluated in detail. Overall, four randomised controlled trials (n=611 patients) compared VA-ECMO with a control treatment and five randomised controlled trials (n=503 patients) compared left ventricular unloading devices with a control treatment. Two randomised controlled trials also included patients who did not have AMICS, who were excluded (55 patients [44 who were treated with VA-ECMO and 11 who were treated with a left ventricular unloading device]). The median patient age was 65 years (IQR 57-73); 845 (79·9%) of 1058 patients with data were male and 213 (20·1%) were female. No significant benefit of early unselected MCS use on 6-month mortality was noted (HR 0·87 [95% CI 0·74-1·03]; p=0·10). No significant differences were observed for left ventricular unloading devices versus control (0·80 [0·62-1·02]; p=0·075), and loading devices also had no effect on mortality (0·93 [0·75-1·17]; p=0·55). Patients with ST-elevation cardiogenic shock without risk of hypoxic brain injury had a reduction in mortality with MCS use (0·77 [0·61-0·97]; p=0·024). Major bleeding (odds ratio 2·64 [95% CI 1·91-3·65]) and vascular complications (4·43 [2·37-8·26]) were more frequent with MCS use than with control. INTERPRETATION: The use of active MCS devices in patients with AMICS did not reduce 6-month mortality (regardless of the device used) and increased major bleeding and vascular complications. However, patients with ST-elevation cardiogenic shock without risk of hypoxic brain injury had a reduction in mortality after MCS use. Therefore, the use of MCS should be restricted to certain patients only. FUNDING: The Heart Center Leipzig at Leipzig University and the Foundation Institut für Herzinfarktforschung.

• MeSH
• infarkt myokardu * mortalita   komplikace   MeSH
• kardiogenní šok * terapie   mortalita   etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mimotělní membránová oxygenace * metody   MeSH
• následné studie MeSH
• podpůrné srdeční systémy * MeSH
• randomizované kontrolované studie jako téma MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH

BACKGROUND: Patients with unfavourable subset cancer of unknown primary (CUP) have a poor prognosis when treated with standard platinum-based chemotherapy. Whether first-line treatment guided by comprehensive genomic profiling (CGP) can improve outcomes is unknown. The CUPISCO trial was designed to inform a molecularly guided treatment strategy to improve outcomes over standard platinum-based chemotherapy in patients with newly diagnosed, unfavourable, non-squamous CUP. The aim of the trial was to compare the efficacy and safety of molecularly guided therapy (MGT) versus standard platinum-based chemotherapy in these patients. This was to determine whether the inclusion of CGP in the initial diagnostic work-up leads to improved outcomes over the current standard of care. We herein report the primary analysis. METHODS: CUPISCO was a phase 2, prospective, randomised, open-label, active-controlled, multicentre trial done at 159 sites in 34 countries outside the USA. Patients with central eligibility review-confirmed disease (acceptable histologies included adenocarcinoma and poorly differentiated carcinoma) and an Eastern Cooperative Oncology Group performance status of 0 or 1, evaluated by CGP, who reached disease control after three cycles of standard first-line platinum-based chemotherapy were randomly assigned 3:1 via a block-stratified randomisation procedure to MGT versus chemotherapy continuation for at least three further cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03498521, and follow-up is ongoing. FINDINGS: From July 10, 2018, to Dec 9, 2022, 636 (42%) of 1505 screened patients were enrolled. Median follow-up in the treatment period was 24·1 months (IQR 11·6-35·6). Of 438 patients who reached disease control after induction chemotherapy, 436 were randomly assigned: 326 (75%) to the MGT group and 110 (25%) to the chemotherapy group. Median progression-free survival in the intention-to-treat population was 6·1 months (95% CI 4·7-6·5) in the MGT group versus 4·4 months (4·1-5·6) in the chemotherapy group (hazard ratio 0·72 [95% CI 0·56-0·92]; p=0·0079). Related adverse event rates per 100-patient-years at risk were generally similar or lower with MGT versus chemotherapy. INTERPRETATION: In patients with previously untreated, unfavourable, non-squamous CUP who reached disease control after induction chemotherapy, CGP with subsequent MGTs resulted in longer progression-free survival than standard platinum-based chemotherapy. On the basis of these results, we recommend that CGP is performed at initial diagnosis in patients with unfavourable CUP. FUNDING: F Hoffmann-La Roche.

• MeSH
• adenokarcinom farmakoterapie   MeSH
• cílená molekulární terapie MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory neznámé primární lokalizace * farmakoterapie   genetika   MeSH
• prospektivní studie MeSH
• protokoly antitumorózní kombinované chemoterapie * terapeutické užití   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

• MeSH
• lidé MeSH
• péče o dítě * MeSH
• populační růst * MeSH
• zařízení denní péče pro děti MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• Geografické názvy
• Japonsko MeSH

BACKGROUND: Nemolizumab, an interleukin (IL)-31 receptor subunit α antagonist, inhibits the IL-31 pathway of itch and skin inflammation in atopic dermatitis. Two international phase 3 studies were done to assess the efficacy and safety of nemolizumab in atopic dermatitis. In this Article we report results for the 16-week initial treatment period of both trials. METHODS: ARCADIA 1 and ARCADIA 2 were identical 48-week randomised, double-blind, placebo-controlled phase 3 trials in adult and adolescent participants (aged ≥12 years) with moderate-to-severe atopic dermatitis, associated pruritus, and inadequate response to topical steroids. Participants were enrolled from 281 clinics, hospitals, and academic centres in 22 countries across both trials, and were randomly assigned (2:1) to receive nemolizumab 30 mg subcutaneously (baseline loading dose 60 mg) or matching placebo once every 4 weeks with background topical corticosteroids (TCS) with or without topical calcineurin inhibitors (TCI; ie, TCS-TCI background treatment). Randomisation was done via interactive response technology and stratified by baseline disease and pruritus severity. Study staff and participants were masked throughout the study, with outcome assessors masked until database lock. Coprimary endpoints at week 16 post-baseline were Investigator's Global Assessment (IGA) success (score of 0 [clear skin] or 1 [almost clear skin] with a ≥2-point improvement from baseline) and at least 75% improvement in Eczema Area and Severity Index score from baseline (EASI-75 response). Outcome rates were compared between groups with the Cochran-Mantel-Haenszel test adjusting for randomisation strata. The key secondary endpoints were the proportion of participants with Peak Pruritus Numerical Rating Scale (PP-NRS) score improvement of at least 4 points at weeks 1, 2, 4, and 16; PP-NRS score below 2 at weeks 4 and 16; Sleep Disturbance Numerical Rating Scale score improvement of at least 4 points at week 16; EASI-75 response plus PP-NRS score improvement of at least 4 points at week 16; and IGA success plus PP-NRS score improvement of at least 4 points at week 16. Efficacy analyses were done on an intention-to-treat basis; safety analyses included all participants who received one dose of nemolizumab or placebo. Both studies are completed (ClinicalTrials.gov: ARCADIA 1, NCT03985943 and ARCADIA 2, NCT03989349). FINDINGS: Between Aug 9, 2019, and Nov 2, 2022, 1728 participants were enrolled across both trials: 1142 were allocated to nemolizumab plus TCS-TCI (620 in ARCADIA 1 and 522 in ARCADIA 2) and 586 to placebo plus TCS-TCI (321 in ARCADIA 1 and 265 in ARCADIA 2). ARCADIA 1 included 500 (53%) male participants and 441 (47%) female participants, and ARCADIA 2 included 381 (48%) male participants and 406 (52%) female participants. Mean age ranged from 33·3 (SD 15·6) years to 35·2 (17·0) years across the treatment groups. Both trials met the coprimary endpoints; at week 16, a greater proportion of participants receiving nemolizumab plus TCS-TCI versus placebo plus TCS-TCI had IGA success (ARCADIA 1: 221 [36%] of 620 vs 79 [25%] of 321, adjusted percentage difference 11·5% [97·5% CI 4·7-18·3], p=0·0003; ARCADIA 2: 197 [38%] of 522 vs 69 [26%] of 265, adjusted difference 12·2% [4·6-19·8], p=0·0006) and an EASI-75 response (ARCADIA 1: 270 [44%] vs 93 [29%], adjusted difference 14·9% [7·8-22·0], p<0·0001; ARCADIA 2: 220 [42%] vs 80 [30%], adjusted difference 12·5% [4·6-20·3], p=0·0006). Significant benefits were observed with nemolizumab for all key secondary endpoints including improvement in itch, as early as week 1, and sleep improvement by week 16. The safety profile was similar between nemolizumab plus TCS-TCI and placebo plus TCS-TCI. In the safety sets, 306 (50%) of 616 participants (ARCADIA 1) and 215 (41%) of 519 participants (ARCADIA 2) who received nemolizumab plus TCS-TCI had at least one treatment-emergent adverse event (serious treatment-emergent adverse events in six [1%] and 13 [3%], respectively); and 146 (45%) of 321 (ARCADIA 1) and 117 (44%) of 263 (ARCADIA 2) who received placebo plus TCS-TCI had at least one treatment-emergent adverse event (serious treatment-emergent adverse events in four [1%] and three [1%], respectively). Ten serious treatment-emergent adverse events possibly related to nemolizumab were reported in five (1%) participants in ARCADIA 2. No deaths occurred. INTERPRETATION: Nemolizumab plus TCS-TCI was efficacious and showed statistically and clinically significant improvements in inflammation and itch in adults and adolescents with moderate-to-severe atopic dermatitis. Nemolizumab might offer a valuable extension of current therapies if approved. FUNDING: Galderma.

• MeSH
• aplikace lokální MeSH
• atopická dermatitida * farmakoterapie   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• hormony kůry nadledvin aplikace a dávkování   terapeutické užití   MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   terapeutické užití   MeSH
• inhibitory kalcineurinu aplikace a dávkování   terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• pruritus * farmakoterapie   MeSH
• stupeň závažnosti nemoci 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
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: Anti-inflammatory therapy with long-term colchicine prevented vascular recurrence in coronary disease. Unlike coronary disease, which is typically caused by atherosclerosis, ischaemic stroke is caused by diverse mechanisms including atherosclerosis and small vessel disease or is frequently due to an unknown cause. We aimed to investigate the hypothesis that long-term colchicine would reduce recurrent events after ischaemic stroke. METHODS: We did a randomised, parallel-group, open-label, blinded endpoint assessed trial comparing long-term colchicine (0·5 mg orally per day) plus guideline-based usual care with usual care only. Hospital-based patients with non-severe, non-cardioembolic ischaemic stroke or high-risk transient ischaemic attack were eligible. The primary endpoint was a composite of first fatal or non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation (defined as an admission to an inpatient unit or a visit to an emergency department that resulted in at least a 24 h stay [or a change in calendar date if the hospital admission or discharge times were not available]) for unstable angina. The p value for significance was 0·048 to adjust for two prespecified interim analyses conducted by the data monitoring committee, for which the steering committee and trial investigators remained blinded. The trial was registered at ClinicalTrials.gov (NCT02898610) and is completed. FINDINGS: 3154 patients were randomly assigned between Dec 19, 2016, and Nov 21, 2022, with the last follow-up on Jan 31, 2024. The trial finished before the anticipated number of outcomes was accrued (367 outcomes planned) due to budget constraints attributable to the COVID-19 pandemic. Ten patients withdrew consent for analysis of their data, leaving 3144 patients in the intention-to-treat analysis: 1569 (colchicine and usual care) and 1575 (usual care alone). A primary endpoint occurred in 338 patients, 153 (9·8%) of 1569 patients allocated to colchicine and usual care and 185 (11·7%) of 1575 patients allocated to usual care alone (incidence rates 3·32 vs 3·92 per 100 person-years, hazard ratio 0·84; 95% CI 0·68-1·05, p=0·12). Although no between-group difference in C-reactive protein (CRP) was observed at baseline, patients treated with colchicine had lower CRP at 28 days and at 1, 2, and 3 years (p<0·05 for all timepoints). The rates of serious adverse events were similar in both groups. INTERPRETATION: Although no statistically significant benefit was observed on the primary intention-to-treat analysis, the findings provide new evidence supporting the rationale for anti-inflammatory therapy in further randomised trials. FUNDING: Health Research Board Ireland, Deutsche Forschungsgemeinschaft (German Research Foundation), and Fonds Wetenschappelijk Onderzoek Vlaanderen (Research Foundation Flanders), Belgium.

• MeSH
• cévní mozková příhoda prevence a kontrola   MeSH
• hospitalizace statistika a číselné údaje   MeSH
• infarkt myokardu prevence a kontrola   MeSH
• ischemická cévní mozková příhoda * prevence a kontrola   MeSH
• kolchicin * aplikace a dávkování   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• recidiva MeSH
• sekundární prevence * metody   MeSH
• senioři MeSH
• tranzitorní ischemická ataka prevence a kontrola   farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT. METHODS: The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258. FINDINGS: Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238). INTERPRETATION: Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined. FUNDING: Janssen and Leukemia & Lymphoma Society.

• MeSH
• adenin * analogy a deriváty   aplikace a dávkování   terapeutické užití   MeSH
• autologní transplantace * MeSH
• cyklofosfamid * aplikace a dávkování   terapeutické užití   MeSH
• dexamethason aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• doxorubicin aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfom z plášťových buněk * terapie   farmakoterapie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• piperidiny * aplikace a dávkování   terapeutické užití   MeSH
• prednison aplikace a dávkování   terapeutické užití   MeSH
• protokoly antitumorózní kombinované chemoterapie * terapeutické užití   MeSH
• rituximab * aplikace a dávkování   terapeutické užití   MeSH
• senioři MeSH
• transplantace hematopoetických kmenových buněk metody   MeSH
• vinkristin * aplikace a dávkování   terapeutické užití   MeSH
• výsledek terapie 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
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Geografické názvy
• Evropa MeSH
• Izrael MeSH