Plasma concentration guided dosing of drugs used for the treatment of childhood leukaemias: protocol for a systematic review

IntroductionChildhood leukaemia is the most common type of cancer in children and represents among 25% of the diagnoses in children <15 years old. Childhood survival rates have significantly improved within the last 40 years due to a rapid advancement in therapeutic interventions. However, in high-risk groups, survival rates remain poor. Pharmacokinetic (PK) data of cancer medications in children are limited and thus current dosing regimens are based on studies with small sample sizes. In adults, large variability in PK is observed and dose individualisation (plasma concentration guided dosing) has been associated with improved clinical outcomes; whether this is true for children is still unknown. This provides an opportunity to explore this strategy in children to potentially reduce toxicities and ensure optimal dosing. This paper will provide a protocol to systematically review studies that have used dose individualisation of drugs used in the treatment of childhood leukaemias.Methods and analysisSystematic review methodology will be applied to identify, select and extract data from published plasma guided dosing studies conducted in a paediatric leukaemia cohort. Databases (eg, Ovid Embase, Ovid MEDLINE, Ovid Cochrane) and clinical trial registries (CENTRAL, ClinicalTrials.gov and ISRCTN) will be used to perform the systematic literature search (up until February 2021). Only full empirical studies will be included, with primary clinical outcomes (progression-free survival, toxicities, minimal residual disease status, complete cytogenetic response, partial cytogenetic response and major molecular response) being used to decide whether the study will be included. The quality of included studies will be undertaken, with a subgroup analysis where appropriate.Ethics and disseminationThis systematic review will not require ethics approval as there will not be collection of primary data. Findings of this review will be made available through publications in peer-reviewed journals and conference presentations. Gaps will be identified in current literature to inform future-related research.PROSPERO registration numberCRD42021225045.

Weighted pseudo-values for partly unobserved group membership in paediatric stem cell transplantation studies

Generalised pseudo-values have been suggested to evaluate the impact of allogeneic stem cell transplantation on childhood leukaemia. The approach compares long-term survival of two cohorts defined by the availability or non-availability of suitable donors for stem cell transplantation. A patient's cohort membership becomes known only after completed donor search with or without an identified donor. If a patient suffers an event during donor search, stem cell transplantation will no longer be indicated. In such a case, donor search will be ceased and cohort membership will remain unknown. The generalised pseudo-values approach considers donor identification as binary time-dependent covariate and uses inverse-probability-of-censoring weighting to adjust for non-identified donors. The approach leads to time-consuming computations due to multiple redefinitions of the risk set for pseudo-value calculation and an explicit adjustment for waiting-time bias. Here, the problem is looked at from a different angle. By considering the probability that a donor would have been identified after ceasing of donor search, weights for common pseudo-values are defined. This leads to a faster alternative approach as only a single risk set is necessary. Extensive computer simulations show that both, the generalised and the new weighted pseudo-values approach, provide approximately unbiased estimates. Confidence interval coverage is satisfactory for typical clinical scenarios. In situations, where donor identification takes considerably longer than usual, the weighted pseudo-values approach is preferable. Both approaches complement each other as they have different potential in addressing further aspects of the underlying medical question.

Sustained viral remission with directly acting antivirals in the treatment of chronic hepatitis C among adolescent (12-17 years) survivors of childhood leukemia

Studies from India highlight the high prevalence of hepatitis C (6-25%) infection in survivors of childhood cancers. Recently Directly acting antivirals (DAA) have been approved for treatment of Chronic hepatitis C (CHC) in children >12 years of age. Even though there are reports of efficacy and safety of DAAs in the treatment of CHC in hematologic disorders like thalassemia, there is minimal data on the efficacy of DAA in the management of chronic hepatitis C among adolescent survivors of childhood leukaemia. We performed this retrospective analysis to study Sustained viral remission (SVR) with DAA in the treatment of CHC among adolescent (12-17 years) survivors of childhood leukemia. This study also aimed to analyze the genotypic profile of hepatitis C virus and adverse effects of the DAA in this group of adolescents (12-17 years). 5 adolescents (12-17 years) who were diagnosed with CHC during August 2017 to May 2020 were enrolled in this observational study. All belonged to genotype 1; received DAA regimen comprising of sofosbuvir 400 mg and ledipasvir 90 mg for 12 weeks with good drug compliance and no major adverse effects. All of them attained SVR at 12 weeks after completing treatment. This study among adolescent survivors of childhood leukaemia with chronic hepatitis C genotype 1, augments data regarding efficacy of a 12 weeks DAA regimen comprising of sofosbuvir 400 mg and ledipasvir 90 mg in the attainment of SVR at 12 weeks after completing treatment.

Common maternal infections during pregnancy and childhood leukaemia in the offspring: findings from six international birth cohorts

Background Previous epidemiological studies have found positive associations between maternal infections and childhood leukaemia; however, evidence from prospective cohort studies is scarce. We aimed to examine the associations using large-scale prospective data. Methods Data were pooled from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA (recruitment 1950s-2000s). Primary outcomes were any childhood leukaemia and acute lymphoblastic leukaemia (ALL); secondary outcomes were acute myeloid leukaemia (AML) and any childhood cancer. Exposures included maternal self-reported infections [influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections and urinary tract infection (including cystitis)] and infection-associated symptoms (fever and diarrhoea) during pregnancy. Covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multilevel Cox models. Results Among 312 879 children with a median follow-up of 13.6 years, 167 leukaemias, including 129 ALL and 33 AML, were identified. Maternal urinary tract infection was associated with increased risk of any leukaemia [HR (95% CI) 1.68 (1.10–2.58)] and subtypes ALL [1.49 (0.87–2.56)] and AML [2.70 ([0.93–7.86)], but not with any cancer [1.13 (0.85–1.51)]. Respiratory tract infection was associated with increased risk of any leukaemia [1.57 (1.06–2.34)], ALL [1.43 (0.94–2.19)], AML [2.37 (1.10–5.12)] and any cancer [1.33 (1.09–1.63)]; influenza-like illness showed a similar pattern but with less precise estimates. There was no evidence of a link between other infections and any outcomes. Conclusions Urinary tract and respiratory tract infections during pregnancy may be associated with childhood leukaemia, but the absolute risk is small given the rarity of the outcome.

Cannabinoid exposure as a major driver of pediatric acute lymphoid Leukaemia rates across the USA: combined geospatial, multiple imputation and causal inference study

Background Acute lymphoid leukaemia (ALL) is the commonest childhood cancer whose incidence is rising in many nations. In the USA, between 1975 and 2016, ALL rates (ALLRs) rose 93.51% from 1.91 to 3.70/100,000 < 20 years. ALL is more common in Caucasian-Americans than amongst minorities. The cause of both the rise and the ethnic differential is unclear, however, prenatal cannabis exposure was previously linked with elevated childhood leukaemia rates. We investigated epidemiologically if cannabis use impacted nationally on ALLRs, its ethnic effects, and if the relationship was causal. Methods State data on overall, and ethnic ALLR from the Surveillance Epidemiology and End Results databank of the Centre for Disease Control (CDC) and National Cancer Institute (NCI) were combined with drug (cigarettes, alcoholism, cannabis, analgesics, cocaine) use data from the National Survey of Drug Use and Health; 74.1% response rate. Income and ethnicity data was from the US Census bureau. Cannabinoid concentration was from the Drug Enforcement Agency Data. Data was analyzed in R by robust and spatiotemporal regression. Results In bivariate analyses a dose-response relationship was demonstrated between ALLR and Alcohol Use Disorder (AUD), cocaine and cannabis exposure, with the effect of cannabis being strongest (β-estimate = 3.33(95%C.I. 1.97, 4.68), P = 1.92 × 10− 6). A strong effect of cannabis use quintile on ALLR was noted (Chi.Sq. = 613.79, P = 3.04 × 10− 70). In inverse probability weighted robust regression adjusted for other substances, income and ethnicity, cannabis was independently significant (β-estimate = 4.75(0.48, 9.02), P = 0.0389). In a spatiotemporal model adjusted for all drugs, income, and ethnicity, cannabigerol exposure was significant (β-estimate = 0.26(0.01, 0.52), P = 0.0444), an effect increased by spatial lagging (THC: β-estimate = 0.47(0.12, 0.82), P = 0.0083). After missing data imputation ethnic cannabis exposure was significant (β-estimate = 0.64(0.55, 0.72), P = 3.1 × 10− 40). 33/35 minimum e-Values ranged from 1.25 to 3.94 × 1036 indicative of a causal relationship. Relaxation of cannabis legal paradigms had higher ALLR (Chi.Squ.Trend = 775.12, P = 2.14 × 10− 112). Cannabis legal states had higher ALLR (2.395 ± 0.039 v. 2.127 ± 0.008 / 100,000, P = 5.05 × 10− 10). Conclusions Data show that ALLR is associated with cannabis consumption across space-time, is associated with the cannabinoids, THC, cannabigerol, cannabinol, cannabichromene, and cannabidiol, contributes to ethnic differentials, demonstrates prominent quintile effects, satisfies criteria for causality and is exacerbated by cannabis legalization.

A SCIENTIFIC EXPLORATION OF SHADGARBHAKAR BHAVA (SIX PROCREATIVE FACTORS) FOR THE CAUSATION OF CHILDHOOD LEUKEMIA IN PURVIEW OF EPIGENETICS: A REVIEW

This is a systematic review article in which classical literature of Ayurveda & contemporary science on subject of Garbhavakranti were explored from the library of my parent institute and other relevant sources were used. The data obtained were critically analyzed and presented. Objectives of this work are to assess lag of Shadgarbhakar Bhava for causation of Childhood Leukemia, determine the embryological aspects of Shadgarbhakar Bhava as per Ayurvedic and Modern perspective of Childhood Leukemia and to suggest a protocol for prevention of said disease. Original Research and published articles available on google scholar Pub-med and Med-scape, Reference Materials, Textbooks, Review Articles are the source of data. Conglomeration of Shadgarbhakar Bhava play vital role in appropriate development of an embryo. Intra-uterine environment can be modified by proper practicing of Satmyaja Bhava, Satvaja Bhava and Rasaja Bhava which produces healthy impact on embryo while Matraja Bhava, Pitraja Bhava and Atmaja Bhava cannot be changed. Lag of Shadgarbhakar Bhava causes diseases in offspring. Childhood leukaemia is one of these, maternal and nutritional factor have major role in this. Occurrence of Childhood Leukemia can be prevented by proper preconception counselling, antenatal care, and good mode of conduct exhibited by mother and father.

Quality of life of transplanted children and their parents: a cross-sectional study

Background Transplantation is a saving therapeutic that has heavy consequences. The quality of life (QoL) of transplanted children and their parents has been little studied and should help physicians better manage these patients. The objectives of the study were to assess: (1) the QoL of transplanted children and parents and compare it with that of children with other chronic conditions associated with long-term consequences, and (2) potential variables modulating the QoL. Methods This cross-sectional study was performed in a multidisciplinary paediatric unit (Timone Hospital, Marseille, France). Children were less than 18 years old; had a liver, kidney or heart transplant; and had a time since transplantation of 1–10 years. Socio-demographics and clinical data were recorded from medical forms. The QoL was assessed using the VSP-A (Vécu et Santé Perçue de l’Adolescent et de l’Enfant) and the WhoQoL self-reported questionnaires. Results Forty-five families were included (response rate: 76%). The transplanted organs were the liver for 20 children, the kidney for 15 children, and the heart for 10 children. The QoL of transplanted children reported by their parents was better than that of children with inborn errors of metabolism and similar to that of childhood leukaemia survivors. The QoL of parents of transplanted children was better than that of parents of children with inborn errors of metabolism and did not differ from French norms. The QoL did not differ according to the nature of the transplanted organ, sex or the main sociodemographic data. The main modulators decreasing QoL were residual treatment level, medications switch and the presence of another regular treatment. Conclusion Transplanted children and their families reported a fairly preserved QoL compared to children with other chronic health conditions. Special attention should be given to QoL modulators related to therapeutic management (medication switches, regular treatments) that might be amenable to improve the QoL. Trial registration Ethics committee of Aix-Marseille University, France (reference number: 2014-08-04-03, 24/4/2015; https://www.univ-amu.fr/fr/public/comite-dethique).