BACKGROUND: Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity. The phase 3 ULTIMATE I and II studies showed significant improvements in annualized relapse rate, total number of gadolinium-enhancing (Gd+) T1 lesions, and total number of new or enlarging T2 at Week 96, as well as improvement in the proportion of participants with no evidence of disease activity (NEDA) from Weeks 24-96 with ublituximab vs. teriflunomide. METHODS: In ULTIMATE I (NCT03277261; www.clinicaltrials.gov) (N = 549) and II (NCT03277248; www.clinicaltrials.gov) (N = 545), participants with relapsing multiple sclerosis received ublituximab 450 mg intravenous infusion every 24 weeks (following Day 1 infusion of 150 mg and Day 15 infusion of 450 mg) or teriflunomide 14 mg oral once daily for 96 weeks. Pooled post hoc analyses evaluated NEDA by treatment epoch and participant subtype: age ( ≤ 38 or >38 years), early or later disease (<3 or ≥3 years following diagnosis), treatment history (treatment naïve or previously treated), 0 or ≥1 Gd+ T1 lesions at baseline, and Expanded Disability Status Scale score ≤ 3.5 or >3.5 at baseline. NEDA was defined as no confirmed relapses, no Gd+ T1 lesions, no new or enlarging T2 lesions, and no disability progression confirmed for ≥12 weeks. RESULTS: NEDA rates in the ublituximab vs. teriflunomide cohorts by treatment epoch were: Weeks 0-96, 44.6% vs. 12.4% (3.6 × improvement); Weeks 24-96 (re-baselined), 82.1% vs. 22.5% (3.6 × improvement); and Weeks 48-96 (re-baselined), 88.2% vs. 30.4% (2.9 × improvement) (all p < 0.0001). The primary driver of disease activity in ublituximab-treated participants was new or enlarging T2 lesions during Weeks 0-24. 41.8% of ublituximab-treated participants who had evidence of disease activity in the first year (Weeks 0-48) experienced NEDA in the second year of treatment (Weeks 48-96) compared with 17.3% of teriflunomide-treated participants. At Weeks 24-96 (re-baselined), rates of NEDA were significantly higher with ublituximab than teriflunomide in all participant subtypes (all p < 0.0001). CONCLUSIONS: ULTIMATE I and II pooled post hoc analyses demonstrated a consistent NEDA benefit among ublituximab-treated participants across treatment epochs and key participant subpopulations.
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: This study aimed to evaluate the safety and performance of PowerPICC catheters in a real-world setting. DESIGN: Prospective, observational, multicentre study. SETTING: Nine European countries, involving 14 centres. PARTICIPANTS: General patient population. INTERVENTION: PowerPICC catheter inserted by the clinician as standard of care with routinely collected outcomes followed through device removal or 180 days postinsertion. PRIMARY AND SECONDARY OUTCOMES MEASURES: Safety and performance outcomes were assessed for PowerPICC, PowerPICC SOLO 2 and PowerGroshong PICC. The primary safety endpoint was the incidence of symptomatic venous thrombosis (VT), and secondary safety endpoints included phlebitis, extravasation, vessel laceration, vessel perforation local infection, accidental dislodgment and catheter-related bloodstream infection (CRBSI). The primary performance endpoint was the percentage of patients whose PowerPICC device remained in place through the completion of therapy. The secondary performance endpoints included catheter patency, placement success in a single attempt and usability. RESULTS: The enrolled patients (N=451) received either PowerPICC, PowerPICC SOLO 2 or PowerGroshong PICC catheters. Across all devices, 1.6% of patients developed symptomatic VT, and CRBSI occurred in 1.6% of patients. There were no cases of phlebitis or extravasation and only three cases of vein laceration or vein perforation. The catheters showed high success rates in completing therapy (81.8%), maintaining patency (93.9%) and achieving successful placement in a single attempt (90.4%). Clinicians overwhelmingly agreed that both the guidewire and stylet (93.3% and 94.4%, respectively) were easy or very easy to use. CONCLUSIONS: This study demonstrates the safety and performance of PowerPICC catheters across diverse settings and patient cohorts in real-world hospital settings across Europe. The findings indicate that these catheters are safe and can be effectively used in the general patient setting and when inserted by a variety of clinicians. The low incidence of complications and high success rates further support the clinical utility of these catheters. TRIAL REGISTRATION NUMBER: NCT04263649.
- MeSH
- centrální žilní katétry škodlivé účinky MeSH
- dospělí MeSH
- flebitida etiologie epidemiologie MeSH
- katetrizace centrálních vén škodlivé účinky přístrojové vybavení metody MeSH
- katétrové infekce * epidemiologie prevence a kontrola MeSH
- lidé středního věku MeSH
- lidé MeSH
- periferní katetrizace škodlivé účinky přístrojové vybavení MeSH
- prospektivní studie MeSH
- senioři MeSH
- zaváděcí katétry škodlivé účinky MeSH
- žilní trombóza epidemiologie etiologie prevence a kontrola MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH
- Geografické názvy
- Evropa MeSH
Patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) for whom autologous hematopoietic cell transplantation (auto-HCT) had failed experienced frequent and durable responses to nivolumab in the phase 2 CheckMate 205 trial. We present updated results (median follow-up, ∼5 years). Patients with R/R cHL who were brentuximab vedotin (BV)-naive (cohort A), received BV after auto-HCT (cohort B), or received BV before and/or after auto-HCT (cohort C) were administered with nivolumab 3 mg/kg IV every 2 weeks until progression or unacceptable toxicity. Patients in cohort C with complete remission (CR) for 1 year could discontinue nivolumab and resume upon relapse. Among 243 patients (cohort A, n = 63; B, n = 80; and C, n = 100), the objective response rate (ORR) was 71.2% (95% confidence interval [CI], 65.1-76.8); the CR rate was 21.4% (95% CI, 16.4-27.1). Median duration of response, CR, and partial remission were 18.2 (95% CI, 14.7-26.1), 30.3, and 13.5 months, respectively. Median progression-free survival was 15.1 months (95% CI, 11.3-18.5). Median overall survival (OS) was not reached; OS at 5 years was 71.4% (95% CI, 64.8-77.1). In cohort C, all 3 patients who discontinued in CR and were subsequently re-treated achieved objective response. No new or unexpected safety signals were identified. This 5-year follow-up of CheckMate 205 demonstrated favorable OS and confirmed efficacy and safety of nivolumab in R/R cHL after auto-HCT failure. Results suggest patients may discontinue treatment after persistent CR and reinitiate upon progression. This trial was registered at www.clinicaltrials.gov as #NCT02181713.
- MeSH
- brentuximab vedotin MeSH
- chronická nemoc MeSH
- Hodgkinova nemoc * patologie MeSH
- imunokonjugáty * MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- nivolumab terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- práce podpořená grantem MeSH
In lung transplantation, antibody-mediated rejection (AMR) diagnosed using the International Society for Heart and Lung Transplantation criteria is uncommon compared with other organs, and previous studies failed to find molecular AMR (ABMR) in lung biopsies. However, understanding of ABMR has changed with the recognition that ABMR in kidney transplants is often donor-specific antibody (DSA)-negative and associated with natural killer (NK) cell transcripts. We therefore searched for a similar molecular ABMR-like state in transbronchial biopsies using gene expression microarray results from the INTERLUNG study (#NCT02812290). After optimizing rejection-selective transcript sets in a training set (N = 488), the resulting algorithms separated an NK cell-enriched molecular rejection-like state (NKRL) from T cell-mediated rejection (TCMR)/Mixed in a test set (N = 488). Applying this approach to all 896 transbronchial biopsies distinguished 3 groups: no rejection, TCMR/Mixed, and NKRL. Like TCMR/Mixed, NKRL had increased expression of all-rejection transcripts, but NKRL had increased expression of NK cell transcripts, whereas TCMR/Mixed had increased effector T cell and activated macrophage transcripts. NKRL was usually DSA-negative and not recognized as AMR clinically. TCMR/Mixed was associated with chronic lung allograft dysfunction, reduced one-second forced expiratory volume at the time of biopsy, and short-term graft failure, but NKRL was not. Thus, some lung transplants manifest a molecular state similar to DSA-negative ABMR in kidney and heart transplants, but its clinical significance must be established.
- MeSH
- lidé MeSH
- podpůrné srdeční systémy * MeSH
- srdce MeSH
- srdeční selhání * chirurgie MeSH
- transplantace plic * MeSH
- transplantace srdce * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- směrnice pro lékařskou praxi MeSH
BACKGROUND: Obesity is an important health problem in cardiac surgery and among patients requiring postcardiotomy venoarterial extracorporeal membrane oxygenation (V-A ECMO). Still, whether these patients are at risk for unfavorable outcomes after postcardiotomy V-A ECMO remains unclear. The current study evaluated the association between body mass index (BMI) and in-hospital outcomes in this setting. METHODS: The Post-cardiotomy Extracorporeal Life Support (PELS-1) study is an international, multicenter study. Patients requiring postcardiotomy V-A ECMO in 36 centers from 16 countries between 2000 and 2020 were included. Patients were divided in 6 BMI categories (underweight, normal weight, overweight, class I, class II, and class III obesity) according to international recommendations. Primary outcome was in-hospital mortality, and secondary outcomes included major adverse events. Mixed logistic regression models were applied to evaluate associations between BMI and mortality. RESULTS: The study cohort included 2046 patients (median age, 65 years; 838 women [41.0%]). In-hospital mortality was 60.3%, without statistically significant differences among BMI classes for in-hospital mortality (P = .225) or major adverse events (P = .126). The crude association between BMI and in-hospital mortality was not statistically significant after adjustment for comorbidities and intraoperative variables (class I: odds ratio [OR], 1.21; 95% CI, 0.88-1.65; class II: OR, 1.45; 95% CI, 0.86-2.45; class III: OR, 1.43; 95% CI, 0.62-3.33), which was confirmed in multiple sensitivity analyses. CONCLUSIONS: BMI is not associated to in-hospital outcomes after adjustment for confounders in patients undergoing postcardiotomy V-A ECMO. Therefore, BMI itself should not be incorporated in the risk stratification for postcardiotomy V-A ECMO.
- MeSH
- kardiochirurgické výkony * škodlivé účinky MeSH
- kardiogenní šok etiologie MeSH
- lidé MeSH
- mimotělní membránová oxygenace * škodlivé účinky MeSH
- mortalita v nemocnicích MeSH
- obezita komplikace MeSH
- retrospektivní studie MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
IMPORTANCE: Left ventricular assist devices (LVADs) enhance quality and duration of life in advanced heart failure. The burden of nonsurgical bleeding events is a leading morbidity. Aspirin as an antiplatelet agent is mandated along with vitamin K antagonists (VKAs) with continuous-flow LVADs without conclusive evidence of efficacy and safety. OBJECTIVE: To determine whether excluding aspirin as part of the antithrombotic regimen with a fully magnetically levitated LVAD is safe and decreases bleeding. DESIGN, SETTING, AND PARTICIPANTS: This international, randomized, double-blind, placebo-controlled study of aspirin (100 mg/d) vs placebo with VKA therapy in patients with advanced heart failure with an LVAD was conducted across 51 centers with expertise in treating patients with advanced heart failure across 9 countries. The randomized population included 628 patients with advanced heart failure implanted with a fully magnetically levitated LVAD (314 in the placebo group and 314 in the aspirin group), of whom 296 patients in the placebo group and 293 in the aspirin group were in the primary analysis population, which informed the primary end point analysis. The study enrolled patients from July 2020 to September 2022; median follow-up was 14 months. INTERVENTION: Patients were randomized in a 1:1 ratio to receive aspirin (100 mg/d) or placebo in addition to an antithrombotic regimen. MAIN OUTCOMES AND MEASURES: The composite primary end point, assessed for noninferiority (-10% margin) of placebo, was survival free of a major nonsurgical (>14 days after implant) hemocompatibility-related adverse events (including stroke, pump thrombosis, major bleeding, or arterial peripheral thromboembolism) at 12 months. The principal secondary end point was nonsurgical bleeding events. RESULTS: Of the 589 analyzed patients, 77% were men; one-third were Black and 61% were White. More patients were alive and free of hemocompatibility events at 12 months in the placebo group (74%) vs those taking aspirin (68%). Noninferiority of placebo was demonstrated (absolute between-group difference, 6.0% improvement in event-free survival with placebo [lower 1-sided 97.5% CI, -1.6%]; P < .001). Aspirin avoidance was associated with reduced nonsurgical bleeding events (relative risk, 0.66 [95% confidence limit, 0.51-0.85]; P = .002) with no increase in stroke or other thromboembolic events, a finding consistent among diverse subgroups of patient characteristics. CONCLUSIONS AND RELEVANCE: In patients with advanced heart failure treated with a fully magnetically levitated LVAD, avoidance of aspirin as part of an antithrombotic regimen, which includes VKA, is not inferior to a regimen containing aspirin, does not increase thromboembolism risk, and is associated with a reduction in bleeding events. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04069156.
- MeSH
- Aspirin škodlivé účinky MeSH
- cévní mozková příhoda * etiologie prevence a kontrola farmakoterapie MeSH
- dvojitá slepá metoda MeSH
- fibrinolytika škodlivé účinky MeSH
- inhibitory agregace trombocytů škodlivé účinky MeSH
- krvácení etiologie MeSH
- lidé MeSH
- podpůrné srdeční systémy * škodlivé účinky MeSH
- srdeční selhání * patofyziologie MeSH
- tromboembolie * etiologie prevence a kontrola MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- komentáře MeSH
- práce podpořená grantem MeSH
BACKGROUND: We investigated the clinical outcomes after cardiac valvular surgery procedures concomitant (CCPs) with left ventricular assist device (LVAD) implantation compared to propensity score (PS) matched controls using the European Registry for Patients with Mechanical Circulatory Support (EUROMACS) data. METHODS: Between 2006 and 2018, 2760 continuous-flow LVAD patients were identified. Of these, 533 underwent a CCP during the LVAD implant. RESULTS: Cardiopulmonary bypass time (p < 0.001) and time for implant (p < 0.001) were both significantly longer in the LVAD+CCP group. Hospital mortality was comparable between the two groups from the unmatched population (15.7% vs. 14.1%, p = 0.073). Similarly, short-to-mid-term survival was similar in both groups, with 1-year, 3-year, and 5-year survival rates of 67.9%, 48.2%, and 27.7% versus 66.4%, 46.1%, and 26%, respectively (log-rank, p = 0.25). The results were similar in the PS-matched population. Hospital mortality was comparable between the two groups (18.9% vs. 17.4%, p = 0.074). The short-to-mid-term Kaplan-Meier survival analysis was similar for both groups, with 1-year, 3-year, and 5-year survival rates of 63.4%, 49.2%, and 24.7% versus 66.5%, 46%, and 25.1%, respectively (log-rank, p = 0.81). In the unmatched population, LVAD+CCP patients had longer intensive care unit (ICU) stays (p < 0.0001), longer mechanical ventilation time (p = 0.001), a higher rate of temporary right ventricular assist device (RVAD) support (p = 0.033), and a higher rate of renal replacement therapy (n = 35, 6.6% vs. n = 89, 4.0%, p = 0.014). In the PS-matched population, the LVAD+CCP patients had longer ICU stays (p = 0.019) and longer mechanical ventilation time (p = 0.002). CONCLUSIONS: The effect of additive valvular procedures (CCPs) does not seem to affect short-term survival, significantly, based on our registry data analysis. However, the decision to perform CCPs should be balanced with the projected type of surgery and preoperative characteristics. LVAD+CCP patients remain a delicate population and adverse device-related events should be strictly monitored and managed.
- MeSH
- lidé MeSH
- podpůrné srdeční systémy * škodlivé účinky MeSH
- registrace MeSH
- retrospektivní studie MeSH
- srdeční selhání * epidemiologie chirurgie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Transplanted lungs suffer worse outcomes than other organ transplants with many developing chronic lung allograft dysfunction (CLAD), diagnosed by physiologic changes. Histology of transbronchial biopsies (TBB) yields little insight, and the molecular basis of CLAD is not defined. We hypothesized that gene expression in TBBs would reveal the nature of CLAD and distinguish CLAD from changes due simply to time posttransplant. Whole-genome mRNA profiling was performed with microarrays in 498 prospectively collected TBBs from the INTERLUNG study, 90 diagnosed as CLAD. Time was associated with increased expression of inflammation genes, for example, CD1E and immunoglobulins. After correcting for time, CLAD manifested not as inflammation but as parenchymal response-to-wounding, with increased expression of genes such as HIF1A, SERPINE2, and IGF1 that are increased in many injury and disease states and cancers, associated with development, angiogenesis, and epithelial response-to-wounding in pathway analysis. Fibrillar collagen genes were increased in CLAD, indicating matrix changes, and normal transcripts were decreased-dedifferentiation. Gene-based classifiers predicted CLAD with AUC 0.70 (no time-correction) and 0.87 (time-corrected). CLAD related gene sets and classifiers were strongly prognostic for graft failure and correlated with CLAD stage. Thus, in TBBs, molecular changes indicate that CLAD primarily reflects severe parenchymal injury-induced changes and dedifferentiation.
BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.
- MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- gastrointestinální látky terapeutické užití MeSH
- humanizované monoklonální protilátky terapeutické užití MeSH
- infliximab terapeutické užití MeSH
- injekce subkutánní MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- stupeň závažnosti nemoci MeSH
- ulcerózní kolitida farmakoterapie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
