A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma.

BACKGROUND: To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG). METHODS: Everolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. RESULTS: Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression. CONCLUSION: Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.

Fundamental to achieving fast separations with high efficiency: A review of chromatography with superficially porous particles.

Types of particles have been fundamental to LC separation technology for many years. Originally, LC columns were packed with large-diameter (>100 µm) calcium carbonate, silica gel, or alumina particles that prohibited fast mobile-phase speeds because of the slow diffusion of sample molecules inside deep pores. During the birth of HPLC in the 1960s, superficially porous particles (SPP, ≥30 µm) were developed as the first high-speed stationary-phase support structures commercialized, which permitted faster mobile-phase flowrates due to the fast movement of sample molecules in/out of the thin shells. These initial SPPs were displaced by smaller totally porous particles (TPP) in the mid-1970s. But SPP history repeated when UHPLC emerged in the 2000s. Stationary-phase support structures made from sub-3-µm SPPs were introduced to chromatographers in 2006. The initial purpose of this modern SPP was to enable chromatographers to achieve fast separations with high efficiency using conventional HPLCs. Later, the introduction of sub-2-µm SPPs with UHPLC instruments pushed the separation speed and efficiency to a very fast zone. This review aims at providing readers a comprehensive and up-to-date view on the advantages of SPP materials over TPPs historically and theoretically from the material science angle.

Persistent gut microbiota immaturity in malnourished Bangladeshi children.

Therapeutic food interventions have reduced mortality in children with severe acute malnutrition (SAM), but incomplete restoration of healthy growth remains a major problem. The relationships between the type of nutritional intervention, the gut microbiota, and therapeutic responses are unclear. In the current study, bacterial species whose proportional representation define a healthy gut microbiota as it assembles during the first two postnatal years were identified by applying a machine-learning-based approach to 16S ribosomal RNA data sets generated from monthly faecal samples obtained from birth onwards in a cohort of children living in an urban slum of Dhaka, Bangladesh, who exhibited consistently healthy growth. These age-discriminatory bacterial species were incorporated into a model that computes a 'relative microbiota maturity index' and 'microbiota-for-age Z-score' that compare postnatal assembly (defined here as maturation) of a child's faecal microbiota relative to healthy children of similar chronologic age. The model was applied to twins and triplets (to test for associations of these indices with genetic and environmental factors, including diarrhoea), children with SAM enrolled in a randomized trial of two food interventions, and children with moderate acute malnutrition. Our results indicate that SAM is associated with significant relative microbiota immaturity that is only partially ameliorated following two widely used nutritional interventions. Immaturity is also evident in less severe forms of malnutrition and correlates with anthropometric measurements. Microbiota maturity indices provide a microbial measure of human postnatal development, a way of classifying malnourished states, and a parameter for judging therapeutic efficacy. More prolonged interventions with existing or new therapeutic foods and/or addition of gut microbes may be needed to achieve enduring repair of gut microbiota immaturity in childhood malnutrition and improve clinical outcomes.

Anthropology of microbes.

We describe the need to further integrate the fields of human microbial ecology and anthropology and outline some of the potential goals and benefits of this collaborative work.

Importance of Particle Pore Size in Determining Retention and Selectivity in Reversed Phase Liquid Chromatography.

Column selection often centers on the identification of a stationary phase that increases resolution for a certain class of compounds. While gains in resolution are most affected by selectivity of the stationary phase or modifications of the mobile phase, enhancements can still be made with an intentional selection of the packing material's microstructure. Unrestricted mass transfer into the particle's porous structure minimizes band broadening associated with hindered access to stationary phase. Increased efficiency, especially when operating above the optimal flow rates, can be gained if the pore size is significantly larger than the solvated analyte. Less studied are the effects of reduced access to pores due to physical hindrance and its impact on retention. This article explores the relationship between pore size and reversed phase retention, and specifically looks at a series of particle architectures with reversed phase and size exclusion modes to study retention associated with access to stationary phase surface area.

Are sub-2 µm particles best for separating small molecules? An alternative.

Superficially porous particles (SPP) in the 2.5-2.7 µm range provide almost the same efficiency and resolution of sub-2 µm totally porous particles (TPP), but at one-half to one-third of the operating pressure. The advantage of SPP has led to the introduction of sub-2 µm SPP as a natural extension of this technology. While short columns of both SPP and TPP sub-2 µm particles allow very fast separations, the efficiency advantages of these very small particles often are not realized nor sufficient to overcome some of the practical limitations and disadvantages of such small particles. Advantages and disadvantages of columns packed with sub-2 µm particles are described for comparison with the characteristics of larger particles. The authors conclude that while sub-2 µm particles have utility in research studies, columns of larger particles are often better suited for most applications. A suggested 2.0 µm superficially porous particle diameter retains many of the advantages of sub-2 µm particles, but minimizes some of the disadvantages. The characteristics of these new 2.0 µm SPP are described in studies comparing some present sub-2 µm SPP commercial columns for efficiency, column bed homogeneity and stability.

Performance characteristics of new superficially porous particles.

Superficially porous particles (also called Fused-Core, core shell or porous shell particles) show distinct advantages over comparable totally porous particles for separating small molecules. Columns of Fused-Core particles exhibit very high efficiency because of superior eddy dispersion properties (smaller van Deemter A term). The efficiency for columns of 2.7 µm Fused-Core particles actually rivals that for sub-2 µm totally porous particles with only about one-half the back pressure. These Fused-Core particles show special advantages with larger molecules for fast separations at high mobile phase velocities because of superior mass transfer (kinetic) properties (smaller van Deemter C term). This report describes the effect of different particle size and porous shell thicknesses on chromatographic performance for Fused-Core particles. Particle characteristics can significantly affect factors of separation importance. For example, the reduced plate height of packed columns is affected by particle diameter. Interestingly, larger Fused-Core particles show smaller reduced plate heights than smaller Fused-Core particles. Also, porous shell thickness has a strong effect on solute retention as well as separation efficiency, and particle surface area has a direct influence on sample loading characteristics. Fused-Core particles with a wide range of physical characteristics have been developed that allows the preparation of stable, efficient packed columns.