Resultados de investigación

The tryptophan-kynurenine pathway is linked to inflammation. We hypothesize that metabolites implicated in this pathway may be associated with the risk of heart failure (HF) or atrial fibrillation (AF) in a population at high risk of cardiovascular disease. We aimed to prospectively analyze the associations of kynurenine-related metabolites with the risk of HF and AF and to analyze a potential effect modification by the randomized interventions of the PREDIMED (Prevención con Dieta Mediterránea) trial with Mediterranean diet (MedDiet). Two case-control studies nested within the PREDIMED trial were designed. We selected 324 incident HF cases and 502 incident AF cases individually matched with ≤3 controls. Conditional logistic regression models were fitted. Interactions with the intervention were tested for each of the baseline plasma metabolites measured by LC-tandem MS. Higher baseline kynurenine:tryptophan ratio (OR for 1 SD: 1.20; 95% CI: 1.01, 1.43) and higher levels of kynurenic acid (OR: 1.19; 95% CI: 1.01, 1.40) were associated with HF. Quinolinic acid was associated with AF (OR: 1.15; 95% CI: 1.01, 1.32) and HF (OR: 1.25; 95% CI: 1.04, 1.49). The MedDiet intervention modified the positive associations of kynurenine (Pinteraction = 0.006), kynurenic acid (Pinteraction = 0.008), and quinolinic acid (Pinteraction = 0.033) with HF and the association between kynurenic acid and AF (Pinteraction = 0.02). We found that tryptophan-kynurenine pathway metabolites were prospectively associated with higher HF risk and to a lesser extent with AF risk. Moreover, an effect modification by MedDiet was observed for the association between plasma baseline kynurenine-related metabolites and the risk of HF, showing that the positive association of increased levels of these metabolites and HF was restricted to the control group., Sí

Background: Consumption of a Mediterranean diet, adequate levels of physical activity, and energy-restricted lifestyle interventions have been individually associated with improvements in HDL functions. Evidence of intensive interventions with calorie restriction and physical activity is, however, scarce. Objectives: To determine whether an intensive lifestyle intervention with an energy-restricted Mediterranean diet plus physical activity enhanced HDL function compared to a non-hypocaloric Mediterranean eating pattern without physical activity. Methods: In 391 older adults with metabolic syndrome (mean age, 65 years; mean BMI, 33.3 kg/m2) from 1 of the Prevención con Dieta Mediterránea-Plus trial centers, we evaluated the impact of a 6-month intervention with an energy-restricted Mediterranean diet plus physical activity (intensive lifestyle; n = 190) relative to a nonrestrictive Mediterranean diet without physical activity (control; n = 201) on a set of HDL functional traits. These included cholesterol efflux capacity, HDL oxidative/inflammatory index, HDL oxidation, and levels of complement component 3, serum amyloid A, sphingosine-1-phosphate, triglycerides, and apolipoproteins A-I, A-IV, C-III, and E in apoB-depleted plasma. Results: The intensive-lifestyle intervention participants displayed greater 6-month weight reductions (-3.83 kg; 95% CI: -4.57 to -3.09 kg) but no changes in HDL cholesterol compared with control-diet participants. Regarding HDL functional traits, the intensive lifestyle decreased triglyceride levels (-0.15 mg/g protein; 95% CI: -0.29 to -0.014 mg/g protein) and apoC-III (-0.11 mg/g protein; 95% CI: -0.18 to -0.026 mg/g protein) compared to the control diet, with weight loss being the essential mediator (proportions of mediation were 77.4% and 72.1% for triglycerides and apoC-III levels in HDL, respectively). Conclusions: In older adults with metabolic syndrome, an energy-restricted Mediterranean diet plus physical activity improved the HDL triglyceride metabolism compared with a nonrestrictive Mediterranean diet without physical activity. This trial is registered at isrctn.com as ISRCTN89898870., This work was supported by the Instituto de Salud Carlos III (grant numbers: CB06/03/0028, CD17/00122, IFI16/00012, PI15/00047, PI18/00020, and P19/00017), Fundació La Marató de TV3 (grant number: 201512.31), Agència de Gestió d’Ajuts Universitaris i de Recerca (grant number: 2017 BP 00021, 2017 SGR 222, SLT002/16/00088), and the European Regional Development Fund., Sí

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. DLBCL is an aggressive disease that can be cured with upfront standard chemoimmunotherapy schedules. However, in approximately 35-40% of the patients DLBCL relapses, and therefore, especially in this setting, the search for new prognostic and predictive biomarkers is an urgent need. Natural killer (NK) are effector cells characterized by playing an important role in antitumor immunity due to their cytotoxic capacity and a subset of circulating NK that express CD8 have a higher cytotoxic function. In this substudy of the R2-GDP-GOTEL trial, we have evaluated blood CD8+ NK cells as a predictor of treatment response and survival in relapsed/refractory (R/R) DLBCL patients. 78 patients received the R2-GDP schedule in the phase II trial. Blood samples were analyzed by flow cytometry. Statistical analyses were carried out in order to identify the prognostic potential of CD8+ NKs at baseline in R/R DLBCL patients. Our results showed that the number of circulating CD8+ NKs in R/R DLBCL patients were lower than in healthy donors, and it did not change during and after treatment. Nevertheless, the level of blood CD8+ NKs at baseline was associated with complete responses in patients with R/R DLBCL. In addition, we also demonstrated that CD8+ NKs levels have potential prognostic value in terms of overall survival in R/R DLBCL patients. CD8+ NKs represent a new biomarker with prediction and prognosis potential to be considered in the clinical management of patients with R/R DLBCL. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001620-29 EudraCT, ID:2014-001620-29., Si

Recent years have seen great advances in the use of clinical ultrasound imaging in both hospital emergency departments and out-of-hospital settings. However, all new techniques require up-to-date definitions of competencies relevant to the clinical realities of different specialties and the geographic settings in which specialists work. To that end, a group of experts in clinical ultrasound reviewed the evidence available in the literature and strictly applied the Delphi method to define the competencies relevant to emergency physicians. The group worked with the starting premise that clinical ultrasound imaging should be a common competency across the specialty., En los últimos años se han producido grandes avances en el uso de la ecografía clínica tanto en los servicios de urgencias hospitalarios como en el ámbito extrahospitalario. Sin embargo, toda nueva técnica requiere de definiciones actualizadas de competencias relevantes para las realidades clínicas de las diferentes especialidades y los entornos geográficos en los que trabajan los especialistas. Para ello, un grupo de expertos en ecografía clínica revisó la evidencia disponible en la literatura y aplicó estrictamente el método Delphi para definir las competencias relevantes para los médicos de urgencias. El grupo trabajó con la premisa de partida de que la ecografía clínica debería ser una competencia común para toda la especialidad., Yes

Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't;Comment in: Hemophilia Therapy--Navigating Speed Bumps on the Innovation Highway. [N Engl J Med. 2016], The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.)., Si, 2016-11-26

Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M and has demonstrated efficacy in non-small cell lung cancer (NSCLC) central nervous system metastases. In this phase I study, we assessed the effects of normal renal function (NRF) and severe renal impairment (SRI) on the pharmacokinetics (PK) of osimertinib in patients with solid tumors. Part A: patients with NRF (creatinine clearance [CrCL] ≥90 mL/min), and SRI, (CrCL <30 mL/min), received a single 80-mg oral dose of osimertinib and standard PK measures were assessed. Part B: patients with SRI were treated for 3 months to obtain safety data, if deemed clinically appropriate. The geometric mean osimertinib plasma concentrations were higher in patients with SRI (n = 7) vs NRF (n = 8) and were highly variable. Osimertinib exposure based on Cmax and area under the plasma concentration-time curve, was 1.19-fold (90% CI: 0.6, 2.0) and 1.85-fold (90% CI: 0.9, 3.6), respectively, higher for patients with SRI vs patients with NRF, with no clear correlation between CrCL and exposure. No new safety signals were identified after 12 weeks of osimertinib 80 mg continuous dosing. PK parameters pooled across this study and other phase I, II, and III osimertinib clinical studies (exploratory population PK analysis), showed minimal correlation between CrCL and total clearance. In conclusion, no dose adjustment is required for osimertinib for patients with SRI., Si

To compare the efficacy and safety of chondroitin sulfate plus glucosamine hydrochloride (CS+GH) versus celecoxib in patients with knee osteoarthritis and severe pain. Double-blind Multicentre Osteoarthritis interVEntion trial with SYSADOA (MOVES) conducted in France, Germany, Poland and Spain evaluating treatment with CS+GH versus celecoxib in 606 patients with Kellgren and Lawrence grades 2-3 knee osteoarthritis and moderate-to-severe pain (Western Ontario and McMaster osteoarthritis index (WOMAC) score ≥301; 0-500 scale). Patients were randomised to receive 400 mg CS plus 500 mg GH three times a day or 200 mg celecoxib every day for 6 months. The primary outcome was the mean decrease in WOMAC pain from baseline to 6 months. Secondary outcomes included WOMAC function and stiffness, visual analogue scale for pain, presence of joint swelling/effusion, rescue medication consumption, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria and EuroQoL-5D. The adjusted mean change (95% CI) in WOMAC pain was -185.7 (-200.3 to -171.1) (50.1% decrease) with CS+GH and -186.8 (-201.7 to -171.9) (50.2% decrease) with celecoxib, meeting the non-inferiority margin of -40: -1.11 (-22.0 to 19.8; p=0.92). All sensitivity analyses were consistent with that result. At 6 months, 79.7% of patients in the combination group and 79.2% in the celecoxib group fulfilled OMERACT-OARSI criteria. Both groups elicited a reduction >50% in the presence of joint swelling; a similar reduction was seen for effusion. No differences were observed for the other secondary outcomes. Adverse events were low and similarly distributed between groups. CS+GH has comparable efficacy to celecoxib in reducing pain, stiffness, functional limitation and joint swelling/effusion after 6 months in patients with painful knee osteoarthritis, with a good safety profile. NCT01425853., Si

CheckMate 171 (NCT02409368) is an open-label, multicentre, phase 2 trial of nivolumab in previously treated advanced squamous non-small cell lung cancer (NSCLC), conducted as part of a post-approval commitment to the European Medicines Agency (EMA). We report outcomes from this trial. Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 and disease progression during/after ≥1 systemic treatment (≥1 being platinum-based chemotherapy) for advanced or metastatic disease were treated with nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary end-point was incidence of grade 3-4 treatment-related select adverse events (AEs). Other end-points included overall survival (OS) and safety. Of 811 patients treated, 103 had ECOG PS 2; 278 were aged ≥70 years and 125 were ≥75 years of age. Minimum follow-up was ~18 months. Safety was similar across populations; the most frequent grade 3-4 treatment-related select AEs in all treated patients were diarrhoea (1%), increased alanine aminotransferase (ALT, 1%), pneumonitis (0.7%), colitis (0.6%) and increased aspartate aminotransferase (AST, 0.5%). Median OS was similar in all treated patients and those aged ≥70 and ≥75: 10.0 months, 10.0 months and 11.2 months, respectively. Median OS was 5.2 months in patients with ECOG PS 2. These results suggest that nivolumab is well tolerated and active in patients with advanced, relapsed squamous NSCLC, including the elderly, with OS outcomes consistent with phase 3 data. In patients with ECOG PS 2, nivolumab had similar tolerability, but outcomes were worse, as expected in this difficult-to-treat, poor prognosis population. NCT02409368., Si

Retrospective analysis of a prospective study. The study aimed to evaluate and compare the clinical results of three surgical techniques for the resection of the hypertrophic ligamentum flavum in patients with lumbar stenosis. Lumbar spinal stenosis is a common degenerative condition. Biportal endoscopic surgery is a modern technique that has gained popularity in recent years. Although various techniques have been proposed for resecting the ligament, no studies have identified the most superior method. This retrospective study enrolled patients with severe lumbar canal stenosis who underwent biportal endoscopic "Z" technique decompression between 2021 and 2023. Patients with any clinical or radiological signs of spondylolisthesis were excluded. The resection of the ligamentum flavum was classified into piecemeal resection, one-piece "butterfly" resection, and the novel variant "two-wings" or two-piece resection. Several demographic and clinical statistical variables were collected, with a specific focus on surgical time, postoperative complications, and clinical outcomes. Ninety lumbar decompression surgeries were performed on 70 patients. The patients were divided into the butterfly group (en bloc) with 27 levels, "two-wings" group with 35 levels, and "piecemeal" group with 28 levels. No significant differences in demographics or clinical variables were found among the three groups. However, piecemeal resection was associated with a higher incidence of dural tears and a longer surgical time (p The results revealed that removing the ligamentum flavum en bloc (either in two pieces or one) may reduce the surgical time and incidence of dural tears. Randomized and prospective studies are warranted to establish definitive conclusions., Si

Few options exist for patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. We aimed to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) versus chemotherapy in this patient population. We conducted this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at 217 academic medical centres and community oncology practices mainly in Europe, North America, and the Asia-Pacific region. Patients (aged ≥18 years) with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy were randomly assigned (1:1), via an interactive voice and web response system with a permuted block design (block size of four), to receive atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m2, paclitaxel 175 mg/m2, or 75 mg/m2 docetaxel) intravenously every 3 weeks. Randomisation was stratified by PD-L1 expression (expression on Between Jan 13, 2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11·1 months [95% CI 8·6-15·5; n=116] vs 10·6 months [8·4-12·2; n=118]; stratified hazard ratio [HR] 0·87, 95% CI 0·63-1·21; p=0·41), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15·9 months [95% CI 10·4 to not estimable] vs 8·3 months [5·6-13·2]; HR 0·57, 95% CI 0·26-1·26). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3-4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients). Atezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favourable compared with chemotherapy, Exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting., Si