Pharmacokinetic Variability of Mycophenolic Acid in Pediatric and Adult Patients with Hematopoietic Stem Cell Transplantation

The aim of this study was to evaluate the pharmacokinetic variations of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), in both pediatric and adult patients following hematopoietic stem cell transplantation (HSCT). Twenty pediatric patients with a median age of 3 years (range 0.2-12 years) and 13 adult patients with a median age of 54 years (range 18-63 years) were enrolled. Blood samples were collected on days 0, 7, 14, 21, and 30 after allogeneic HSCT. Total and free (unbound) MPA as well as MPA 7-O-glucuronide (MPAG) were quantified using a validated LC-MS/MS assay. The plasma protein binding of MPA and MPAG did not change significantly in pediatric patients over the 1-month sampling period post-HSCT. However, it increased in adult patients from day 7 to day 30 post-HSCT, from 97.3 ± 0.8% to 98.3 ± 0.6% for MPA (P < .05), and 74.6 ± 9.4% to 82.9 ± 8.1% for MPAG (P < .05). The plasma protein binding of MPA was significantly higher in males compared to females in both pediatric (98.3 ± 1.1% vs 97.4 ± 1.1%) and adult (98.1 ± 0.7% vs 97.4 ± 1.2%) patients (P < .05). The MPAG/MPA ratios on a milligram-per-kilogram dose basis in adult patients were significantly higher than those in pediatric patients (4.3 ± 3.4 vs 2.4 ± 2.6; P < .05). Time-dependent plasma protein binding and age-related differences in MPA metabolism at least in part impact the reported large intra- and interindividual variability in MPA pharmacokinetics. These patient and pharmacologic factors, if incorporated into MMF regimen design and modification, may contribute to the rational dose selection of MMF in HSCT patients

The Immune System in Cancer Pathogenesis: Potential Therapeutic Approaches

Interplay among immune activation and cancer pathogenesis provides the framework for a novel subspecialty known as immunooncology. In the rapidly evolving field of immunooncology, understanding the tumor-specific immune response enhances understanding of cancer resistance. This review highlights the fundamentals of incorporating precision medicine to discover new immune biomarkers and predictive signatures. Using a personalized approach may have a significant, positive impact on the use of oncolytics to better guide safer and more effective therapies

Low serum albumin levels prior to pediatric allogeneic HCT are associated with increased need for critical care interventions and increased 6-month mortality

Poor nutritional status in HCT patients is a negative prognostic factor. There are no pediatric studies evaluating albumin levels prior to HCT and need for critical care interventions. We hypothesized that pediatric patients with low albumin levels, routinely measured 30 days (±10 days) prior to allogeneic HCT, have a higher risk of critical care interventions in the post-transplant period. We performed a 5-year retrospective study of pediatric patients who underwent allogeneic HCT for any indication. Patients were categorized based on albumin level. Hypoalbuminemia was defined as <3.1 g/dL. A total of 73 patients were included, with a median age of 7.4 years (IQR 3.3, 13.2). Patients with hypoalbuminemia had higher needs for critical care interventions including non-invasive ventilation (44% vs 8%, P=.01), mechanical ventilation (67% vs 17%, P<.01), and vasoactive therapy (56% vs 16%, P=.01). Patients with hypoalbuminemia also had a higher 6-month mortality (56% vs 17%, P=.02). Our data demonstrate that children undergoing allogeneic HCT with hypoalbuminemia in the pretransplant period are more likely to require critical care interventions and have higher 6-month mortality. These findings identify an at-risk population in which nutritional improvements may be instituted prior to HCT in hopes of improving outcomes

Collection of human genomic DNA from neonates: a comparison between umbilical cord blood and buccal swabs

OBJECTIVE: To compare DNA yield from neonatal umbilical cord blood and buccal swab specimens. STUDY DESIGN: Umbilical cord blood was obtained at birth in a cohort of women enrolled in a preterm labor study. If cord blood was not obtained, neonatal buccal samples were obtained using the Oragene saliva kits. DNA was extracted from all samples using the QIAamp extraction kits. DNA concentration and yield were compared between umbilical cord blood and buccal swabs. RESULTS: DNA concentrations from umbilical cord blood (n = 35) was greater than that obtained from buccal swabs (n = 20) (total sample: 209.0 ± 110.7 ng/μL vs 6.9 ± 6.7 ng/μL respectively, P < .001; partial sample: n = 30 cord blood vs n = 11 buccal, 70.0 ± 51.4 ng/μL vs 11.3 ± 6.7 ng/μL, respectively, P < .001) and produced more total DNA (total sample: 116.5 ± 70.8 μg vs 4.2 ± 4.0 μg, P < .001; partial:14.0 ± 10.3 μg vs 1.1 ± 0.7 μg, respectively, P < .001). CONCLUSION: Buccal swabs yield less neonatal DNA than umbilical cord blood specimens

Differential effects of hydrocortisone, prednisone, and dexamethasone on hormonal and pharmacokinetic profiles: a pilot study in children with congenital adrenal hyperplasia

BACKGROUND: Little is known about the comparative effects of different glucocorticoids on the adrenal and growth hormone (GH) axes in children with congenital adrenal hyperplasia (CAH). We sought to compare the effects of hydrocortisone (HC), prednisone (PDN), and dexamethasone (DEX) in children with classic CAH and to investigate a potential role of pharmacogenetics. METHODS: Subjects were randomly assigned to three sequential 6-week courses of HC, PDN, and DEX, each followed by evaluation of adrenal hormones, IGF-1, GH, and body mass index (BMI). Single nucleotide polymorphism (SNP) analysis of genes in the glucocorticoid pathway was also performed. RESULTS: Nine prepubertal subjects aged 8.1 ± 2.3 years completed the study. Mean ACTH, androstenedione, and 17-hydroxyprogesterone (17-OHP) values were lower following the DEX arm of the study than after subjects received HC (p ≤ 0.016) or PDN (p ≤ 0.002). 17-OHP was also lower after HC than PDN (p < 0.001). There was no difference in IGF-1, GH, or change in BMI. SNP analysis revealed significant associations between hormone concentrations, pharmacokinetic parameters, and variants in several glucocorticoid pathway genes (ABCB1, NR3C1, IP013, GLCCI1). CONCLUSIONS: DEX resulted in marked adrenal suppression suggesting that its potency relative to hydrocortisone and prednisone was underestimated. SNPs conferred significant differences in responses between subjects. Although preliminary, these pilot data suggest that incorporating pharmacogenetics has the potential to eventually lead to targeted therapy in children with CAH

Genetic Variants Associated With Vincristine‐Induced Peripheral Neuropathy in Two Populations of Children With Acute Lymphoblastic Leukemia

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149215/1/cpt1324_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149215/2/cpt1324.pd

Pharmacotherapy and pregnancy: Highlights from the first International Conference for Individualized Pharmacotherapy in Pregnancy

Data are sparse on the effects of medication use during pregnancy. Half of the world's population is women. The majority of women become pregnant, and many of those women take some kind of medication during their pregnancy, even if only for a short time. The majority of drugs have not been rigorously studied in pregnant women to determine the most effective dose with the least potential for adverse effects. Instead, women are given “cookie‐cutter” therapy, using doses extrapolated from nonpregnant women, men, or pregnant animals. This can lead to problems. Instead, individualization of pharmacotherapy in pregnancy promises to take individual women and determine the optimal dose and drug for them to maximize the effect of the drug while attempting to minimize the side effects to them and their unborn babies. Because this field of study is underrepresented, we held a conference to bring together researchers and experts to discuss current knowledge, issues, and challenges surrounding individualized pharmacotherapy in pregnancy. Speakers came from the NIH, the Food and Drug Administration (FDA), and various research centers in the United States and Canada. Below are the summaries of the discussions at the conference. Full notes from the panel discussions are available from the authors on request

Gene Co-Expression Networks Restructured Gene Fusion in Rhabdomyosarcoma Cancers

Rhabdomyosarcoma is subclassified by the presence or absence of a recurrent chromosome translocation that fuses the FOXO1 and PAX3 or PAX7 genes. The fusion protein (FOXO1-PAX3/7) retains both binding domains and becomes a novel and potent transcriptional regulator in rhabdomyosarcoma subtypes. Many studies have characterized and integrated genomic, transcriptomic, and epigenomic differences among rhabdomyosarcoma subtypes that contain the FOXO1-PAX3/7 gene fusion and those that do not; however, few investigations have investigated how gene co-expression networks are altered by FOXO1-PAX3/7. Although transcriptional data offer insight into one level of functional regulation, gene co-expression networks have the potential to identify biological interactions and pathways that underpin oncogenesis and tumorigenicity. Thus, we examined gene co-expression networks for rhabdomyosarcoma that were FOXO1-PAX3 positive, FOXO1-PAX7 positive, or fusion negative. Gene co-expression networks were mined using local maximum Quasi-Clique Merger (lmQCM) and analyzed for co-expression differences among rhabdomyosarcoma subtypes. This analysis observed 41 co-expression modules that were shared between fusion negative and positive samples, of which 17/41 showed significant up- or down-regulation in respect to fusion status. Fusion positive and negative rhabdomyosarcoma showed differing modularity of co-expression networks with fusion negative (n = 109) having significantly more individual modules than fusion positive (n = 53). Subsequent analysis of gene co-expression networks for PAX3 and PAX7 type fusions observed 17/53 were differentially expressed between the two subtypes. Gene list enrichment analysis found that gene ontology terms were poorly matched with biological processes and molecular function for most co-expression modules identified in this study; however, co-expressed modules were frequently localized to cytobands on chromosomes 8 and 11. Overall, we observed substantial restructuring of co-expression networks relative to fusion status and fusion type in rhabdomyosarcoma and identified previously overlooked genes and pathways that may be targeted in this pernicious disease