Study protocol for a multicenter randomised controlled trial on the (cost)effectiveness of biopsy combined with same-session MR-guided LITT versus biopsy alone in patients with primary irresectable glioblastoma (EMITT trial).

BACKGROUND: Glioblastoma (GBM) is the most common primary, malignant brain tumour with a 5-year survival of 5%. If possible, a glioblastoma is resected and further treated with chemoradiation therapy (CRT), but resection is not feasible in about 30% of cases. Current standard of care in these cases is a biopsy followed by CRT. Magnetic resonance (MR) imaging-guided laser interstitial thermal therapy (LITT) has been suggested as a minimally invasive alternative when surgery is not feasible. However, high-quality evidence directly comparing LITT with standard of care is lacking, precluding any conclusions on (cost-)effectiveness. We therefore propose a multicenter randomized controlled study to assess the (cost-)effectiveness of MR-guided LITT as compared to current standard of care (EMITT trial). METHODS AND ANALYSIS: The EMITT trial will be a multicenter pragmatic randomized controlled trial in the Netherlands. Seven Dutch hospitals will participate in this study. In total 238 patients will be randomized with 1:1 allocation to receive either biopsy combined with same-session MR-guided LITT therapy followed by CRT or the current standard of care being biopsy followed by CRT. The primary outcomes will be health-related quality of life (HR-QoL) (non-inferiority) using EORTC QLQ-C30 + BN20 scores at 5 months after randomization and overall survival (superiority). Secondary outcomes comprise cost-effectiveness (healthcare and societal perspective) and HR-QoL of life over an 18-month time horizon, progression free survival, tumour response, disease specific survival, longitudinal effects, effects on adjuvant treatment, ablation percentage and complication rates. DISCUSSION: The EMITT trial will be the first RCT on the effectiveness of LITT in patients with glioblastoma as compared with current standard of care. Together with the Dutch Brain Tumour Patient association, we hypothesize that LITT may improve overall survival without substantially affecting patients' quality of life. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT05318612).

Antithrombotic Therapy for Symptomatic Peripheral Arterial Disease: A Systematic Review and Network Meta-Analysis.

BACKGROUND: High-quality evidence from trials directly comparing single antiplatelet therapies in symptomatic peripheral arterial disease (PAD) to dual antiplatelet therapies or acetylsalicylic acid (ASA) plus low-dose rivaroxaban is lacking. Therefore, we conducted a network meta-analysis on the effectiveness of all antithrombotic regimens studied in PAD. METHODS: A systematic search was conducted to identify randomized controlled trials. The primary endpoints were major adverse cardiovascular events (MACE) and major bleedings. Secondary endpoints were major adverse limb events (MALE) and acute limb ischaemia (ALI). For each outcome, a frequentist network meta-analysis was used to compare relative risks (RRs) between medication and ASA. ASA was the universal comparator since a majority of studies used ASA as in the reference group. RESULTS: Twenty-four randomized controlled trials were identified including 48,759 patients. With regard to reducing MACE, clopidogrel [RR 0.78, 95% confidence interval (CI) 0.66-0.93], ticagrelor (RR 0.79, 95% CI 0.65-0.97), ASA plus ticagrelor (RR 0.79, 95% CI 0.64-0.97), and ASA plus low-dose rivaroxaban (RR 0.84, 95% CI 0.76-0.93) were more effective than ASA, and equally effective to one another. As compared to ASA, major bleedings occurred more frequently with vitamin K antagonists, rivaroxaban, ASA plus vitamin K antagonists, and ASA plus low-dose rivaroxaban. All regimens were similar to ASA concerning MALE, while ASA plus low-dose rivaroxaban was more effective in preventing ALI (RR 0.67, 95% CI 0.55-0.80). Subgroup analysis in patients undergoing peripheral revascularization revealed that ≥ 3 months after intervention, evidence of benefit regarding clopidogrel, ticagrelor, and ASA plus ticagrelor was lacking, while ASA plus low-dose rivaroxaban was more effective in preventing MACE (RR 0.87, 95% CI 0.78-0.97) and MALE (RR 0.89, 95% CI 0.81-0.97) compared to ASA. ASA plus clopidogrel was not superior to ASA in preventing MACE ≥ 3 months after revascularization. Evidence regarding antithrombotic treatment strategies within 3 months after a peripheral intervention was lacking. CONCLUSION: Clopidogrel, ticagrelor, ASA plus ticagrelor, and ASA plus low-dose rivaroxaban are superior to ASA monotherapy and equally effective to one another in preventing MACE in PAD. Of these four therapies, only ASA plus low-dose rivaroxaban provides a higher risk of major bleedings. More than 3 months after peripheral vascular intervention, ASA plus low-dose rivaroxaban is superior in preventing MACE and MALE compared to ASA but again at the cost of a higher risk of bleeding, while other treatment regimens show non-superiority. Based on the current evidence, clopidogrel may be considered the antithrombotic therapy of choice for most PAD patients, while in patients who underwent a peripheral vascular intervention, ASA plus low-dose rivaroxaban could be considered for the long-term (> 3 months) prevention of MACE and MALE.

Association between probiotics and enteral nutrition in an experimental acute pancreatitis model in rats.

BACKGROUND/OBJECTIVES: Recently, a randomized controlled trial showed that probiotic prophylaxis was associated with an increased mortality in enterally fed patients with predicted severe pancreatitis. In a rat model for acute pancreatitis, we investigated whether an association between probiotic prophylaxis and enteral nutrition contributed to the higher mortality rate. METHODS: Male Sprague-Dawley rats were allocated to four groups: 1) acute pancreatitis (n = 9), 2) acute pancreatitis and probiotic prophylaxis (n = 10), 3) acute pancreatitis and enteral nutrition (n = 10), and 4) acute pancreatitis, probiotic prophylaxis and enteral nutrition (n = 11). Acute pancreatitis was induced by intraductal glycodeoxycholate and intravenous cerulein infusion. Enteral nutrition, saline, probiotics and placebo were administered through a permanent jejunal feeding. Probiotics or placebo were administered starting 4 days before induction of pancreatitis and enteral nutrition 1 day before start until the end of the experiment, 6 days after induction of pancreatitis. Tissue samples and body fluids were collected for microbiological and histological examination. RESULTS: In all animals, serum amylase was increased six hours after induction of pancreatitis. After fulfilling the experiment, no differences between groups were found in histological severity of pancreatitis, degree of discomfort, weight loss, histological examination of small bowel and bacterial translocation (all p > 0.05). Overall mortality was 10% without differences between groups (p = 0.54). CONCLUSION: No negative association was found between prophylactic probiotics and enteral nutrition in acute pancreatitis. No new clues for a potential mechanism responsible for the higher mortality and bowel ischaemia in the PROPATRIA study were found.

Injectable bone-graft substitutes: current products, their characteristics and indications, and new developments.

More than a decade has passed since the first injectable bone substitutes were introduced for use in orthopaedic trauma, and over recent years the number of commercial products has increased dramatically. Despite the fact that these bone substitutes have been on the market for many years, knowledge amongst potential users on how and when they might be useful is still fairly limited. Most injectable bone substitutes belong to one of two major groups: by far the largest group contains products based on various calcium phosphate (CP) mixtures, whilst the smaller group consists of calcium sulphate (CS) compounds. Following mixing, the CP or CS paste can be injected into--for instance--a fracture space for augmentation as an alternative to bone graft, or around a screw for augmentation if the bone is weak. Within minutes an in situ process makes the substitute hard; the mechanical strength in compression resembles that of cancellous bone, whereas the strength in bending and shear is lower. Over time, CP products undergo remodelling through a cell-mediated process that seems to mimic the normal bone remodelling, whilst CS products are dissolved through a faster process that is not cell-mediated. For CP, a number of clinical studies have shown that it can be useful for augmentation of metaphyseal fractures when a space is present. Randomised studies have verified that CP works especially well in tibial plateau fractures when compared with conventional bone grafting. So far the number of clinical studies on CS products is very low. Development at present seems to be heading towards premixed or directly mixed products as well as new compounds that contain fibres or other components to enhance bending and shear strength. Products that are based on combinations of CP and CS are also being developed to combine the fast-dissolving CS with the stronger and more slowly remodelling CP. Injectable bone substitutes, and especially CS, have also been targeted as potentially good carriers for antibiotics and growth factors.