Background
Eosinophilic esophagitis (EoE) is a clinicopathologic entity of increasing worldwide prevalence. IL-5 is essential for eosinophil trafficking and anti-IL-5 therapy decreases esophageal eosinophilia. EoE is associated with a prominent mast cell infiltration.
Objective
We investigated whether anti-IL-5 (mepolizumab) treatment reduced esophageal mast cell accumulation in pediatric EoE biopsy specimens from a previous randomized anti-IL-5 trial.
Methods
A sub-analysis was completed for children treated with 0.55, 2.5, or 10mg/kg of mepolizumab monthly for 12 weeks followed by no treatment until week 24. Quantitative immunochemistry was used to assess eosinophils, tryptase-positive mast cells, IL-9+ cells, and mast cell-eosinophil couplets prior to and following treatment.
Results
43 patient biopsies had adequate tissue for paired analysis. 40% of subjects responded to anti-IL-5 (defined as <15 eosinophils per hpf following mepolizumab therapy) and 77% of all subjects had decreased numbers of mast cells following anti-IL-5. In responders, epithelial mast cells decreased from 62 to 19 per hpf (p<0.001), were significantly lower than in non-responders following therapy (p<0.05), and correlated with eosinophil numbers (r=0.75, p<0.0001). Mast cells and eosinophils were found in couplets prior to therapy and these were significantly decreased only in responders following anti-IL-5 (p<0.001). Esophageal eosinophils comprised the majority of cells that made the mast cell growth factor IL-9. IL-9+ cells decreased from 102 to 71 per hpf (p<0.001) following anti-IL-5.
Conclusions
Pediatric EoE patients had significantly fewer mast cells, IL-9+ cells, and mast cell-eosinophil couplets in the esophageal epithelium following anti-IL-5 therapy. Since eosinophils were one source of IL-9, they may support esophageal mastocytosis.
, and Iris Schrijver, MD 22 Purpose: The aim of the study was to determine the actual GJB2 and GJB6 mutation frequencies in North America after several years of generalized testing for autosomal recessive nonsyndromic sensorineural hearing loss to help guide diagnostic testing algorithms, especially in light of molecular diagnostic follow-up to universal newborn hearing screening. Methods:Mutation types, frequencies, ethnic distributions, and genotype-phenotype correlations for GJB2 and GJB6 were assessed in a very large North American cohort. Results: GJB2 variants were identified in 1796 (24.3%) of the 7401 individuals examined, with 399 (5.4%) homozygous and 429 (5.8%) compound heterozygous. GJB6 deletion testing was performed in 12.0% (888/7401) of all cases. The Ͼ300-kb deletion was identified in only nine individuals (1.0%), all of whom were compound heterozygous for mutations in GJB2 and GJB6. Among a total of 139 GJB2 variants identified, 53 (38.1%) were previously unreported, presumably representing novel pathogenic or benign variants. Conclusions: The frequency and distribution of sequence changes in GJB2 and GJB6 in North America differ from those previously reported, suggesting a considerable role for loci other than GJB2 and GJB6 in the etiology of autosomal recessive nonsyndromic sensorineural hearing loss, with minimal prevalence of the GJB6 deletion. Genet Med 2007:9(7):413-426.
Hypersensitivity reactions (HSRs) to chemotherapy agents can present a serious challenge to treating patients with preferred or first-line therapies. Allergic reactions through an immunologic mechanism have been established for platinum and taxane agents, which are used to treat a wide variety of cancers including gynecologic cancers. Platin HSRs typically occur after multiple cycles of chemotherapy, reflecting the development of drug IgE sensitization, while taxane HSRs often occur on first or second exposure. Despite observed differences between platin and taxane HSRs, drug desensitization has been an effective method to reintroduce both chemotherapeutic agents safely. Skin testing is the primary diagnostic tool used to risk-stratify patients after initial HSRs, with more widespread use for platinum agents than taxanes. Different practices exist around the use of skin testing, drug challenge, and choice of desensitization protocol. Here, we review the epidemiology, mechanism, and clinical presentation of HSRs to platinum and taxane agents, as well as key controversies in their evaluation and management.
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