Impact of prior systemic therapy on lymphocytic infiltration in surgically resected breast cancer brain metastases.

PURPOSE: Tumor-infiltrating lymphocytes (TILs) have been positively correlated with response to systemic therapy for triple-negative and HER2 + subtypes and improved clinical outcomes in early breast cancer (BC). Less is known about TILs in metastatic sites, particularly brain metastases (BM), where unique immune regulation governs stromal composition. Reactive glial cells actively participate in cytokine-mediated T cell stimulation. The impact of prior medical therapy (chemotherapy, endocrine, and HER2-targeted therapy) on the presence of TILs and gliosis in human breast cancer brain metastases (BCBM) has not been previously reported. METHODS: We examined prior treatment data for 133 patients who underwent craniotomy for resection of BMs from the electronic medical record. The primary endpoint was overall survival (OS) from the time of BM diagnosis. We examined the relationship between prior systemic therapy exposure and the histologic features of gliosis, necrosis, hemorrhage, and lymphocyte infiltration (LI) in BCBMs resected at subsequent craniotomy in univariate analyses. RESULTS: Complete treatment data were available for 123 patients. BCBM LI was identified in 35 of 116 (30%) patients who had received prior systemic treatment versus 5 of 7 (71.4%) who had not {significant by Fisher's exact test p = 0.045}. There were no statistically significant relationships between prior systemic therapy and the three other histologic variables examined. CONCLUSIONS: This observation suggests that systemic therapy may interfere with the immune response to BCBMs and cause exhaustion of anti-tumor immunity. This motivates clinical investigation of strategies to enhance LI for therapeutic benefit to improve outcomes for patients with BCBMs.

Differential outcome subgroups in children with autism spectrum disorder attending early intervention.

BACKGROUND: The finding of positive outcomes at the group level for children with autism spectrum disorder (ASD) who complete comprehensive early intervention programmes often masks considerable individual variability. We therefore aimed to identify subgroups of children based on their response to intervention and to compare outcome variables between groups at two points in time. METHOD: We used model-based cluster analysis to explore response to intervention using a longitudinal design for 210 children with ASD who had completed an early intervention programme. Children were assessed on entry at time 1 and again at time 2, which was after 12 months or when they exited the programme (whichever came first) using measures of ASD symptoms (Social Communication Questionnaire), cognition (Mullen Scales of Early Learning) and adaptive behaviour (Vineland Adaptive Behaviour Scales-II). RESULTS: A two-cluster solution was identified, including a high change group who improved consistently more than the low change group across measures, and showed significantly fewer autism symptoms, higher non-verbal and verbal cognition and adaptive behaviour composite scores at time 1. CONCLUSIONS: The findings indicated that children's response to early intervention is not uniform but instead included subgroups characterised by patterns of high and low change. Further research is needed to identify clinically relevant mediators of differential response group membership.

The Emergent Literacy Skills of Preschool Children with Autism Spectrum Disorder.

A high percentage of school-age students with autism spectrum disorder (ASD) have reading comprehension difficulties leading to academic disadvantage. These difficulties may be related to differences in children's emergent literacy development in the preschool years. In this study, we examined the relationship between emergent literacy skills, broader cognitive and language ability, autism severity, and home literacy environment factors in 57 preschoolers with ASD. The children showed strengths in code-related emergent literacy skills such as alphabet knowledge, but significant difficulties with meaning-related emergent literacy skills. There was a significant relationship between meaning-related skills, autism severity, general oral language skills, and nonverbal cognition. Identification of these meaning-related precursors will guide the targets for early intervention to help ensure reading success for students with ASD.

The proportion of minimally verbal children with autism spectrum disorder in a community-based early intervention programme.

BACKGROUND: Estimates of the proportion of children with autism spectrum disorder (ASD) who are minimally verbal vary from 25%to 35%. However, there is a lack of consensus in defining minimally verbal and few detailed reports of communication outcomes for these children following intervention. The aim of this study was to explore how minimally verbal children have been defined and to document the proportion of minimally verbal children in a group of children with ASD receiving a community based early intervention programme. METHOD: A longitudinal cohort design was used to examine the proportion of children who met criteria for minimally verbal in 246 children with ASD when they entered and exited an early intervention programme. RESULTS: Overall, 26.3% of the children in this study exited the programme using 'fewer than five spontaneous and functional words' and 36.4% exited not using 'two word phrases' as indicated by direct assessment. However, our findings were mixed depending on measures and definitions used, with parent report indicating that as many as 29.4% of children were not 'naming at least three objects' consistently, and 43.3% not using 'phrases with a noun and verb' consistently at exit. More than half of the children who entered the programme with minimal speech exited the programme with a similar language profile. A small percentage of children (1.2%-4.7%) regressed in their language level over time. CONCLUSIONS: Despite advances in early intervention, and access to services at a younger age, around a quarter of individuals with ASD in this study exited early intervention with significant communication needs. Our findings are considered in relation to the literature and clinical implications, and future research directions are discussed.

Pharmacogenetic screening for susceptibility to fetal malformations in women.

OBJECTIVE: To present a review of the literature and research on the pharmacogenetics of congenital defects, with a focus on the need for predictive maternal genotype assays. DATA SOURCE: MEDLINE searches (January 1985-January 1999), past reference reviews, and unpublished research. STUDY SELECTION: Review of relevant human, animal, and basic science studies. DATA EXTRACTION: Data on research on polymorphisms, genotyping, cytochrome P450 enzyme systems, epoxide hydrolase, folate metabolism, metabolism of anticonvulsant medications, molecular genetics of neural tube defects, variations in drug metabolism, and environmental exposures were evaluated. DATA SYNTHESIS: Data synthesis includes not only a review of the literature but suggests ways such data might be used to facilitate the development of maternal genotype assays, with the goal of preventing birth defects. CONCLUSIONS: Individuals vary in how they metabolize drugs and handle toxic environmental exposures. In an ideal pregnancy, there is no or limited exposure to medications and environmental agents. However, in women with chronic medical conditions such as heart disease and seizures, this is often not possible. Unfortunately, no techniques have been available to identify those at risk in this population. Gene polymorphisms for a specific enzyme may result in an absence or reduction in the level of enzyme activity or in no change at all, with little effect on the structure/function of the gene product(s); they are not associated with clinical phenotypes in either the mother or the fetus. Other polymorphisms may be only markers. Thus, developing genotyping assays for women that are predictive of phenotype expression in the fetus is the key to screening for polymorphisms. As more mutations are identified and clinical, pharmacologic, biologic, and pharmacokinetic relationships are established, using these polymorphisms to develop a genotyping assay for women may become a clinical reality, possibly leading to preventive prepregnancy or prenatal treatment that may play an increasingly effective role in maternal care.

Analysis of select folate pathway genes, PAX3, and human T in a Midwestern neural tube defect population.

Neural tube defects (NTDs) are a common birth defect, seen in approximately 1/1,000 births in the United States. NTDs are considered a complex trait where several genes, interacting with environmental factors, create the phenotype. Using a Midwestern NTD population consisting of probands, parents, and siblings from Iowa, Minnesota, and Nebraska, we analyzed a range of candidate genes, including 5,10-methylenetetrahydrofolate reductase (MTHFR), folate receptors-alpha (FOLR1; hereafter abbreviated "FR-alpha") and -beta (FOLR2; hereafter, "FR-beta"), methionine synthase (hereinafter, "MS"), T, the human homolog of the murine Brachyury gene, and the paired-box homeotic gene 3 (PAX3), for association with NTDs. We were unable to demonstrate an association using a previously described Ala-->Val mutation in MTHFR and the majority of our NTD populations. However, we discovered a silent polymorphism in exon 6 of MTHFR which conserved a serine residue and which showed significant association with NTDs in our Iowa population. Analysis of exon 7 of MTHFR then demonstrated an Ala-->Glu mutation which was significantly associated with our Iowa NTD population; however, we could not replicate this result either in a combined Minnesota/ Nebraska or in a California NTD population. Using polymorphic markers for MS, FR-beta, T, and PAX3, we were unable to demonstrate linkage disequilibrium with our NTD populations. A mutation search of FR-alpha revealed one proband with a de novo silent mutation of the stop codon. This work provides a new panel of genetic variants for studies of folate metabolism and supports, in some NTD populations, an association between MTHFR and NTDs.