Resultados de investigación

Standard treatment for glioblastoma is radiation with concomitant and adjuvant temozolomide for 6 cycles, although the optimal number of cycles of adjuvant temozolomide has long been a subject of debate. We performed a phase II randomized trial investigating whether extending adjuvant temozolomide for more than 6 cycles improved outcome. Glioblastoma patients treated at 20 Spanish hospitals who had not progressed after 6 cycles of adjuvant temozolomide were centrally randomized to stop (control arm) or continue (experimental arm) temozolomide up to a total of 12 cycles at the same doses they were receiving in cycle 6. Patients were stratified by MGMT methylation and measurable disease. The primary endpoint was differences in 6-month progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS), and safety (Clinicaltrials.gov NCT02209948). From August 2014 to November 2018, 166 patients were screened, 7 of whom were ineligible. Seventy-nine patients were included in the stop arm and 80 in the experimental arm. All patients were included in the analyses of outcomes and of safety. There were no differences in 6-month PFS (control 55.7%; experimental 61.3%), PFS, or OS between arms. MGMT methylation and absence of measurable disease were independent factors of better outcome. Patients in the experimental arm had more lymphopenia (P  Continuing temozolomide after 6 adjuvant cycles is associated with greater toxicity but confers no additional benefit in 6-month PFS. 1. Extending adjuvant temozolomide to 12 cycles did not improve 6-month PFS.2. Extending adjuvant temozolomide did not improve PFS or OS in any patient subset.3. Extending adjuvant temozolomide was linked to increased toxicities., Si

Several studies have evaluated the effect of intragastric injection of botulinum toxin A to treat obesity, achieving mixed results. Our objective is to determine the effect of intragastric botulinum toxin A on weight loss, satiety, biomarkers, and quality of life of obese patients prior bariatric surgery. Methods: Design: single-centre, randomised, double-blind, placebo-controlled clinical trial in 52 obese patients on bariatric surgery waiting lists. Two-arm parallel: the treatment group was administered intragastric botulinum toxin A by endoscopy, whereas the control group was administered physiological saline solution. Weight loss was evaluated at weeks 2, 4, 8, 16, and 24, as well as changes in body composition, satiety (Visual analogue scale (VAS) and GCSI questionnaire), quality of life (GIQLI questionnaire), and biomarkers of satiety and appetite. Results: Weight loss at weeks 2, 4, 8, 16, and 24 after the endoscopy, with respect to the basal visit, was 0.6 ± 2 kg, 0.4 ± 2.7 kg, 0.4 ± 3.1 kg, 0.2 ± 4.5 kg, and 0.6 ± 4.3 kg for the control group vs 1.9 ± 2.1 kg, 2 ± 2.6 kg, 2.8 ± 4.1 kg, 3.5 ± 5.3 kg, and 4.5 ± 7 kg for the treatment group, respectively, being differences between groups significant at all times (p = 0.016, 0.031, 0.014, 0.021, and 0.023, respectively). Treatment group patients obtained a significantly higher score for GIQLI questionnaire compared with baseline (104.4 ± 13.9 points vs 97.7 ± 15.6 points; p = 0.024), showing a significant improvement in the section of subjective physical capacity. No significant differences were found regarding perception of satiety, or biomarkers of satiety and appetite. Conclusions: Intragastric injection of botulinum toxin A is an effective and safe procedure to achieve a moderate weight loss and improve quality of life., Yes

Seeking consent rapidly in acute stroke trials is crucial as interventions are time sensitive. We explored the association between consent pathways and time to enrollment in the TICH-2 (Tranexamic Acid in Intracerebral Haemorrhage-2) randomized controlled trial. Consent was provided by patients or by a relative or an independent doctor in incapacitated patients, using a 1-stage (full written consent) or 2-stage (initial brief consent followed by full written consent post-randomization) approach. The computed tomography-to-randomization time according to consent pathways was compared using the Kruskal-Wallis test. Multivariable logistic regression was performed to identify variables associated with onset-to-randomization time of ≤3 hours. Of 2325 patients, 817 (35%) gave self-consent using 1-stage (557; 68%) or 2-stage consent (260; 32%). For 1507 (65%), consent was provided by a relative (1 stage, 996 [66%]; 2 stage, 323 [21%]) or a doctor (all 2-stage, 188 [12%]). One patient did not record prerandomization consent, with written consent obtained subsequently. The median (interquartile range) computed tomography-to-randomization time was 55 (38-93) minutes for doctor consent, 55 (37-95) minutes for 2-stage patient, 69 (43-110) minutes for 2-stage relative, 75 (48-124) minutes for 1-stage patient, and 90 (56-155) minutes for 1-stage relative consents (P The use of initial brief consent was associated with shorter times to enrollment, while maintaining good participant retention. Seeking written consent from relatives was associated with significant delays. URL: https://www.isrctn.com; Unique identifier: ISRCTN93732214., Si

While osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) with sensitising EGFR and acquired T790M mutations, progression inevitably occurs. The angiogenic pathway is implicated in EGFR TKI resistance. BOOSTER is an open-label randomised phase II trial investigating the efficacy and safety of combined osimertinib 80 mg daily and bevacizumab 15 mg/kg every 3 weeks, versus osimertinib alone, in patients with EGFR-mutant advanced NSCLC and acquired T790M mutations after failure on previous EGFR TKI therapy. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR) and adverse events (AEs). Between May 2017 and February 2019, 155 patients were randomised (combination: 78; osimertinib: 77). At data cut-off of 22 February 2021, median follow-up was 33.8 months [interquartile range (IQR): 26.5-37.6 months] and 129 (83.2%) PFS events were reported in the intention-to-treat population. There was no difference in median PFS between the combination [15.4 months; 95% confidence interval (CI) 9.2-18.0 months] and osimertinib arm (12.3 months; 95% CI 6.2-17.2 months; stratified log-rank P = 0.83), [hazard ratio (HR) = 0.96; 95% CI 0.68-1.37]. Median OS was 24.0 months (95% CI 17.8-32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm (stratified log-rank P = 0.91), (HR = 1.03; 95% CI 0.67-1.56). Exploratory analysis revealed a significant interaction of smoking history with treatment for PFS (adjusted P = 0.0052) with a HR of 0.52 (95% CI 0.30-0.90) for smokers, and 1.47 (95% CI 0.92-2.33) for never smokers. ORR was 55% in both arms and the median time to treatment failure was significantly shorter in the combination than in the osimertinib arm, 8.2 months versus 10.8 months, respectively (P = 0.0074). Safety of osimertinib and bevacizumab was consistent with previous reports with grade ≥3 treatment-related AEs (TRAEs) reported in 47% and 18% of patients on combination and osimertinib alone, respectively. No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone. Grade ≥3 TRAEs were more common in patients on combination., Si

Aripiprazole and risperidone are 2 of the most used second-generation antipsychotics (SGAs) worldwide. Previous evidence shows a similar effect of these SGAs on weight and metabolic changes in the short term. However, a longer period is necessary for a better assessment of the SGA´s metabolic profile. We aimed to compare the long-term (1-year) metabolic profile of these 2 antipsychotics on a sample of drug-naïve first episode-psychosis (FEP) patients. A total 188 drug-naïve patients, suffering from a first episode of non-affective psychosis (FEP), were randomly assigned to treatment with either aripiprazole or risperidone. Weight and glycemic/lipid parameters were recorded at baseline and after 1-year follow-up. We observed significant weight increments in both groups (9.2 kg for aripiprazole and 10.5 kg for risperidone) after 1 year of treatment. Despite this, weight and body mass index changes did not significantly differ between treatment groups (P > .05). Similarly, both treatment groups presented similar metabolic clinical impact with a comparable increase in the proportion of participants meeting criteria for metabolic disorders such as obesity or hypercholesterolemia, but not for metabolic syndrome (Δ9.2% vs Δ4.3%) or hypertriglyceridemia (Δ21.9% vs Δ8.0%), where aripiprazole showed worse outcomes than risperidone. This study shows that aripiprazole and risperidone share a similar long-term metabolic profile. After 1 year of antipsychotic treatment, drug-naïve FEP patients in both treatment groups presented a significant increase in weight and metabolic changes, leading to a greater prevalence of metabolic disorders., Si

The STARS trial (Stroke Treatment With Acute Reperfusion and Simvastatin) was conducted to demonstrate the efficacy and safety of simvastatin treatment in acute stroke. STARS07 was a multicentre, phase IV, prospective, randomized, double-blind, placebo-controlled trial. Patients with Acute ischemic stroke recruited within 12 hours from symptom onset were randomized to oral simvastatin 40 mg or placebo, once daily for 90 days. Primary outcome was proportion of independent patients (modified Rankin Scale score of ≤2) at 90 days. Safety end points were hemorrhagic transformation, hemorrhagic events, death, infections, and serious adverse events. From April 2009 to March 2014, 104 patients were included. Fifty-five patients received intravenous tissue-type plasminogen activator. No differences were found between treatment arms regarding the primary outcome (adjusted odds ratio, 0.99 [0.35-2.78]; P=0.98). Concerning safety, no significant differences were found in the rate of hemorrhagic transformation of any type, nor symptomatic hemorrhagic transformation. There were no differences in other predefined safety outcomes. In post hoc analyses, for patients receiving tissue-type plasminogen activator, a favorable effect for simvastatin treatment was noted with higher proportion of patients experiencing major neurological recovery (adjusted odds ratio, 4.14 [1.18-14.4]; P=0.02). Simvastatin plus tissue-type plasminogen activator combination seems safe in acute stroke, with low rates of bleeding complications. Because of the low recruitment, the STARS trial was underpowered to detect differences in simvastatin efficacy., Si

Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after ≥125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 versus 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 versus 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (≥40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II., Si

Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't;, The prevalence of and risk factors for central nervous system recurrence in patients with acute promyelocytic leukemia are not well established and remain a controversial matter. Between 1996 and 2005, 739 patients with newly diagnosed acute promyelocytic leukemia enrolled in two consecutive trials (PETHEMA LPA96 and LPA99) received induction therapy with all-trans retinoic acid and idarubicin. Consolidation therapy comprised three courses of anthracycline monochemotherapy (LPA96), with all-trans retinoic acid and reinforced doses of idarubicin in patients with an intermediate or high risk of relapse (LPA99). Central nervous system prophylaxis was not given. Central nervous system relapse was documented in 11 patients. The 5-year cumulative incidence of central nervous system relapse was 1.7% (LPA96 3.2% and LPA99 1.2%; p=0.09). The cumulative incidence was 0%, 0.8%, and 5.5% in low-, intermediate-, and high-risk patients, respectively. Relapse risk score (p=0.0001) and the occurrence of central nervous system hemorrhage during induction (5-year cumulative incidence 18.7%, p=0.006) were independent risk factors for central nervous system relapse. This study shows a low incidence of central nervous system relapse in patients with acute promyelocytic leukemia following therapy with all-trans retinoic acid and anthracycline without specific central nervous system prophylaxis. Central nervous system relapse was significantly associated with high white blood cell counts and prior central nervous system hemorrhage, which emerged as independent prognostic factors., Si

Background and aims: Parenteral nutrition (PN) composition could play a role in the management of systemic inflammatory response and intestinal barrier disruption. We aimed to evaluate changes in biomarkers of inflammation, oxidative status and intestinal permeability in patients with type 2 diabetes mellitus (T2DM) who received different PN lipid formulas. Methods: This was a prospective study, including 94 patients with T2DM who received omega (n)-3 polyunsaturated fatty acids (PUFA)-enriched PN, a mixture of medium and long chain triglycerides (MCT/LCT) PN, or an olive oil-based PN. Serum levels of biomarkers of oxidative status, intestinal permeability and inflammation biomarkers were determined at day 1 and day 5 after PN initiation. Registered under ClinicalTrials.gov Identifier no. NCT02706119. Results: At day 5 after the onset of PN, the MCT/LCT group had a significant reduction of 2 proinflammatory cytokines [interleukin (IL)-15, IL-17A], elevation of the anti-inflammatory cytokine IL-13 and increase of zonulin and indoxylsulfate. The olive oil group showed a statistically significant reduction of 5 proinflammatory cytokines [IL-1β, IL-17A, IL-6, cytokine-leukemia inhibitory factor (LIF) and tumor necrosis factor alpha (TNF-α)] and reduced concentrations of the anti-inflammatory cytokine IL-1RA, while the n-3 PUFA-enriched group presented a statistically significant reduction of 8 proinflammatory cytokines (interferon-gamma, IL-1β, IL-15, IL-17A, IL-6, LIF, monocyte chemoattractant protein 1, and TNF-α). In the between-group comparisons, indoxylsulfate significantly increased in the MCT/LCT group compared to the n-3 PUFA-enriched group, while 8-isoprostane and indoxylsulfate significantly increased in the MCT/LCT group compared to the other groups and superoxide dismutase significantly decreased in the MCT/LCT group compared to the other groups. Conclusion: In patients with T2DM, PN lipid composition exerts a profound impact on proinflammatory, prooxidative and intestinal permeability biomarkers., Yes

Comparar los niveles de glucemia e incidencia de hiperglucemia en el postoperatorio de cirugía general usando sueros con diferente concentración de glucosa. Ensayo clínico aleatorizado, abierto, no ciego, en pacientes no diabéticos, que ingresan en Cuidados Intensivos Pediátricos tras cirugía electiva, de 6 meses a 14 años, peso superior a 6 kg, glucemia >60 mg/dl y firma de consentimiento informado, manteniéndose a dieta con sueroterapia de mantenimiento intravenosa mediante suero con glucosa al 3,3 o 5%. Se determinan niveles de glucemia preoperatoria, al ingreso, y a las 8, 24 y 48 h, comparando los valores medios y la incidencia de hiperglucemia (glucemia > 150 mg/dl) en ambos grupos. Un total de 60 pacientes recibieron suero glucosalino 1/3 (51 mEq/l de sodio y 33 g/l de glucosa) y 70 pacientes suero glucosalino 5/0,9% (154 mEq/l de sodio y 50 g/l de glucosa). La glucemia media fue mayor en el grupo al 5%, sin diferencia estadística. No hubo diferencia en la incidencia de hiperglucemia; 8 h: 26% del grupo 3,3% vs. 21,3% del grupo 5% (p = 0,63); 24 h: 20% vs. 22,7% (p = 0,8); 48 h: 19% vs. 23,1% (p = 0,78). En el postoperatorio de cirugía general, el uso de soluciones glucosadas al 3,3% consigue niveles de glucemia similares a los detectados en pacientes que reciben suero con glucosa 5%, con una incidencia de hiperglucemia similar., To compare plasma glucose levels and incidence of hyperglycaemia in the post-operative period after general surgery using fluids with different glucose. A randomised, open-label, non-blind, clinical trial was conducted on patients admitted to Paediatric Intensive Care Unit after elective surgery. The inclusion criteria were from 6 months to 14 years of age, with a weight greater than 6kg, onset glucose level >60mg/dL, and a signed informed consent, with no oral intake and maintenance intravenous fluid therapy using fluids with 3.3% or 5% glucose. Plasma glucose levels were measured before surgery, on admission, and 8, 24, and 48h, with the mean glucose levels and incidence of hyperglycaemia (glucose level >150mg/dL) in both groups being compared. A total of 60 patients received glucose/saline 1/3 (51mEq/L sodium and 33g/L glucose), and 70 glucose/saline 5/0.9% (154mEq/L sodium and 50g/L glucose). Mean glucose levels were higher in the group receiving glucose 5%, with no statistical difference. There was no significant difference in the incidence of hyperglycaemia; 8h: 26% in the 3.3% group vs. 21.3% in the 5% group (P=.63); 24h: 20% vs. 22.7% (P=.8); and 48h: 19% vs. 23.1% (P=.78). The use of fluids with 3.3% glucose in the post-operative period of general surgery maintains mean glucose levels in a similar range to that of patients receiving fluids with 5% glucose, with no difference in the incidence of hyperglycaemia., Si