Oral etoposide as a single agent in childhood and young adult cancer in England: Still a poorly evaluated palliative treatment

From Wiley via Jisc Publications RouterHistory: received 2020-10-27, rev-recd 2021-06-04, accepted 2021-06-16, pub-electronic 2021-07-06Article version: VoRPublication status: PublishedAbstract: Background: Oral etoposide is commonly used in palliative treatment of childhood and young adult cancer without robust evidence. We describe a national, unselected cohort of young people in England treated with oral etoposide using routinely collected, population‐level data. Methods: Patients aged under 25 years at cancer diagnosis (1995–2017) with a treatment record of single‐agent oral etoposide in the Systemic AntiCancer Dataset (SACT, 2012–2018) were identified, linked to national cancer registry data using NHS number and followed to 5 January 2019. Overall survival (OS) was estimated for all tumours combined and by tumour group. A Cox model was applied accounting for age, sex, tumour type, prior and subsequent chemotherapy. Results: Total 115 patients were identified during the study period. Mean age was 11.8 years at cancer diagnosis and 15.5 years at treatment with oral etoposide. Median OS was 5.5 months from the start of etoposide; 13 patients survived beyond 2 years. Survival was shortest in patients with osteosarcoma (median survival 3.6 months) and longest in CNS embryonal tumours (15.5 months). Across the cohort, a median of one cycle (range one to nine) of etoposide was delivered. OS correlated significantly with tumour type and prior chemotherapy, but not with other variables. Conclusions: This report is the largest series to date of oral etoposide use in childhood and young adult cancer. Most patients treated in this real world setting died quickly. Despite decades of use, there are still no robust data demonstrating a clear benefit of oral etoposide for survival

Antigen presenting ILC3 regulate T cell-dependent IgA responses to colonic mucosal-associated bacteria

Intestinal immune homeostasis is dependent upon tightly regulated and dynamic host interactions with the commensal microbiota. Immunoglobulin A (IgA) produced by mucosal B cells dictates the composition of commensal bacteria residing within the intestine. While emerging evidence suggests the majority of IgA is produced innately and may be polyreactive, mucosal-dwelling species can also elicit IgA via T cell-dependent mechanisms. However, the mechanisms that modulate the magnitude and quality of T cell-dependent IgA responses remain incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3) regulate steady state interactions between T follicular helper cells (TfH) and B cells to limit mucosal IgA responses. ILC3 used conserved migratory cues to establish residence within the interfollicular regions of the intestinal draining lymph nodes, where they act to limit TfH responses and B cell class switching through antigen presentation. The absence of ILC3-intrinsic antigen presentation resulted in increased and selective IgA coating of bacteria residing within the colonic mucosa. Together these findings implicate lymph node resident, antigen-presenting ILC3 as a critical regulatory checkpoint in the generation of T cell-dependent colonic IgA and suggest ILC3 act to maintain tissue homeostasis and mutualism with the mucosal-dwelling commensal microbiota

Microbiota supplementation with Bifidobacterium and Lactobacillus modifies the preterm infant gut microbiota and metabolome: An observational study

Supplementation with members of the early-life microbiota as “probiotics” is increasingly used in attempts to beneficially manipulate the preterm infant gut microbiota. We performed a large observational longitudinal study comprising two preterm groups: 101 infants orally supplemented with Bifidobacterium and Lactobacillus (Bif/Lacto) and 133 infants non-supplemented (control) matched by age, sex, and delivery method. 16S rRNA gene profiling on fecal samples (n = 592) showed a predominance of Bifidobacterium and a lower abundance of pathobionts in the Bif/Lacto group. Metabolomic analysis showed higher fecal acetate and lactate and a lower fecal pH in the Bif/Lacto group compared to the control group. Fecal acetate positively correlated with relative abundance of Bifidobacterium, consistent with the ability of the supplemented Bifidobacterium strain to metabolize human milk oligosaccharides into acetate. This study demonstrates that microbiota supplementation is associated with a Bifidobacterium-dominated preterm microbiota and gastrointestinal environment more closely resembling that of full-term infants

Extending metrological traceability in qNMR beyond the first dimension

After decades as a niche analytical technique, quantitative NMR (qNMR) has recently gained mainstream sttention largely due to its implementation as a primary ratio measurement method with SI traceability to determine the amount of substance. This method enables rapid and inexpensive value assignment for high-purity, organic small-molecule materials. However, the method is inconsistently applied, particularly in the analysis of high order reference materials; therefore a more comprehensive evaluation of its uncertainties is required for use in certification. Industries such as the pharmaceutical and nutraeuticals are increasingly seeking alternative methods for the measurement of large, structurally complex molecules that are unsuited to standard ID proton qNMR due to spectral overlap. Increased resolution can be achieved through employment of spectral editing and multi-dimensional experiments, such as heteronuclear single coherence spectroscopy (HSQC). However, the inherent direct proportionality of proton content and signal intensity of [sup]1H qNMR is lost through signal attenuation due to various chemical phenomena. Despite this complication, these 2D approaches can be calibrated and optimized for quantification of select analyte species within complex matrices and chemical mixtures. The additional biases seen, such as those arising as a result of imperfect pulses, variations of J-coupling constants and inadequate relaxation delays can be in many cases compensated for. Although such calibration approaches can never be as accurate as [sup]1H qNMR, they provide significant advantages over competing analytical approaches as it is a primary ratio method and therefore does not require a reference material/standard for the analyte. In order to provide value assignments with the highest degree of measurement science, the total uncertainty of the measurement method must be evaluated in a manner, which is both comprehensive and metrologically sound. Presented are well documented approaches to validating [sup]1H qNMR methods and understanding and quantifying biases and uncertainties seen in 2D HSQC qNMR