A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for human immunodeficiency virus-associated tuberculous meningitis: the LASER-TBM trial

Background: Drug regimens that include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in tuberculous meningitis (TBM). Safety data on their use in combination and in the context of human immunodeficiency virus (HIV) are needed to inform clinical trial design. Methods: We conducted a phase 2, open-label, parallel-design, randomized, controlled trial to assess the safety of high-dose rifampicin, linezolid, and high-dose aspirin in HIV-associated TBM. Participants were randomized (1.4:1:1) to 3 treatment arms (1, standard of care [SOC]; 2, SOC + additional rifampicin [up to 35 mg/kg/d] + linezolid 1200 mg/d reducing after 28 days to 600 mg/d; 3, as per arm 2 + aspirin 1000 mg/d) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. Results: A total of 52 participants with HIV-associated TBM were randomized; 59% had mild disease (British Medical Research Council (MRC) grade 1) vs 39% (grade 2) vs 2% (grade 3). AESI or death occurred in 10 of 16 (63%; arm 3) vs 4 of 14 (29%; arm 2) vs 6 of 20 (30%; arm 1; P = .083). The cumulative proportion of AESI or death (Kaplan–Meier) demonstrated worse outcomes in arm 3 vs arm 1 (P = .04); however, only 1 event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (modified Rankin scale) between arms. Conclusions: High-dose rifampicin and adjunctive linezolid can safely be added to the standard of care in HIV-associated TBM. Larger studies are required to determine whether potential toxicity associated with these interventions, particularly high-dose aspirin, is outweighed by mortality or morbidity benefit. Clinical Trials Registration: NCT03927313

Whole-Body MRI in Pediatric Oncology

Whole-body imaging plays a crucial role in the diagnosis and follow-up of pediatric malignancies, as tumor spread may involve different anatomical regions. Until recently, ultrasonography (US) and computed tomography (CT) have been the imaging technique of choice in children with cancer, but nowadays there is an increasing interest in the use of functional imaging techniques like single-photon emission computed tomography (SPECT) and positron emission tomography (PET). By combining these latter techniques with CT, it becomes possible to simultaneously acquire imaging data on the biological behavior of tumor as well as the anatomical localization and extent of tumor spread. Because of the small but not negligible risk of radiation-induced secondary cancers and the significantly improved overall survival rates of children with cancer, there is an increasing interest in the use of radiation-free imaging techniques such as magnetic resonance imaging (MRI). MRI allows for acquiring images with a high spatial resolution and excellent soft tissue contrast throughout the body. Moreover, recent technological advances have resulted in fast diagnostic sequences for whole-body MR imaging, including functional techniques such as diffusion-weighted imaging (DWI). In this chapter, the current status of the technique, major clinical applications, and future perspectives of whole-body MRI in children with cancer will be discussed