Citations

Key Points Significant improvement in outcome is a reality for newly diagnosed AL amyloidosis in the past decade. Six-month mortality among transplant ineligible patients has declined since 2005.

Abstract Purpose: Little is known about the role of the immune system in the earliest stages of breast carcinogenesis. We studied quantitative differences in immune cell types between breast tissues from normal donors and those from women with benign breast disease (BBD). Experimental Design: A breast tissue matched case–control study was created from donors to the Susan G. Komen for the Cure Tissue Bank (KTB) and from women diagnosed with BBD at Mayo Clinic (Rochester, MN) who either subsequently developed cancer (BBD cases) or remained cancer-free (BBD controls). Serial tissue sections underwent immunostaining and digital quantification of cell number per mm2 for CD4+ T cells, CD8+ T cells, CD20+ B cells, and CD68+ macrophages and quantification of positive pixel measure for CD11c (dendritic cells). Results: In 94 age-matched triplets, BBD lobules showed greater densities of CD8+ T cells, CD11c+ dendritic cells, CD20+ B cells, and CD68+ macrophages compared with KTB normals. Relative to BBD controls, BBD cases had lower CD20+ cell density (P = 0.04). Nearly 42% of BBD cases had no CD20+ B cells in evaluated lobules compared with 28% of BBD controls (P = 0.02). The absence of CD20+ cells versus the presence in all lobules showed an adjusted OR of 5.7 (95% confidence interval, 1.4–23.1) for subsequent breast cancer risk. Conclusions: Elevated infiltration of both innate and adaptive immune effectors in BBD tissues suggests an immunogenic microenvironment. The reduced B-cell infiltration in women with later breast cancer suggests a role for B cells in preventing disease progression and as a possible biomarker for breast cancer risk. Clin Cancer Res; 23(14); 3945–52. ©2017 AACR.

AbstractBackgroundKleefstra Syndrome (KS) (MIM# 610253) is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase‐1 (EHMT1, GLP). EHMT1 (MIM# 607001) encodes a histone methyltransferase that heterodimerizes with EHMT2 (also known as G9a, MIM# 604599), which together are responsible for mono‐ and dimethylation of H3 lysine 9 (H3K9me1 and ‐me2), resulting in transcriptional repression of target genes.MethodsThis report describes an 18‐year‐old woman with intellectual disability, severely limited speech, hypotonia, microcephaly, and facial dysmorphisms, who was found to have a novel de novo single‐base frameshift deletion in EHMT1.ResultsFunctional studies using patient fibroblasts showed decreased H3K9me2 compared to wild‐type control cells, thus providing a rapid confirmatory test that complements molecular studies.ConclusionWhole exome sequencing revealed a novel frameshift deletion in EHMT1 after a lengthy diagnostic odyssey in this patient. Functional testing using this patient's fibroblasts provides proof‐of‐concept for the analysis of variants of uncertain significance that are predicted to impact EHMT1 enzymatic activity.

Objectives: Investigations of pediatric critical illness typically focus on inpatient cohorts drawn from wide referral areas and diverse healthcare systems. Cohorts amenable to investigating the full spectrum of critical illness as it develops within a community have yet to be studied in the United States. Our objective was to provide the first epidemiologic report of the incidence and presentation of pediatric critical illness within a U.S. population-based birth cohort. Design: Retrospective cohort study. Setting: A geographically defined community (Olmsted, MN) with medical record linkage across all health systems. All ICU services are provided within a single children’s hospital. Patients: A birth cohort of children (n =9,441) born 2003–2007 in Olmsted County, MN. Measurements and Main Results: During the study period, there were a total of 15,277 ICU admissions to Mayo Clinic Children’s Hospital. A total of 577 birth cohort children accounted for 824 of these admissions during the 61,770 person-years of follow-up accumulated. Incidence of first-time ICU admission was 9.3 admits per 1,000 person-years. Admission rates were highest in the first year of life and then declined steadily. Respiratory problems were among the most common reasons for admission at any age and diagnoses reflect changes in health risk factors as children grow and develop over time. After 1 year old, a majority of children admitted have preexisting chronic comorbidities and/or prior ICU stays. In-hospital mortality occurred exclusively in children admitted prior to 5 days of age (n = 4). Seven children died after hospital discharge. Conclusions: This is the first report characterizing critical illness within a population-based birth cohort of U.S. children. The results demonstrate the changing incidence, presentation, and healthcare requirements associated with critical illness across the developmental spectrum as a population of children ages.