Cytotoxicity-Related Gene Expression and Chromatin Accessibility Define a Subset of CD4+ T Cells That Mark Progression to Type 1 Diabetes

Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of children at risk associated with progression to islet autoimmunity. We analyzed gene expression with RNA sequencing in CD4⁺ and CD8⁺ T cells, natural killer (NK) cells, and B cells, and chromatin accessibility by assay for transposase-accessible chromatin sequencing (ATAC-seq) in CD4⁺ T cells, in five genetically at risk children with islet autoantibodies who progressed to diabetes over a median of 3 years (“progressors”) compared with five children matched for sex, age, and HLA-DR who had not progressed (“nonprogressors”). In progressors, differentially expressed genes (DEGs) were largely confined to CD4⁺ T cells and enriched for cytotoxicity-related genes/pathways. Several top-ranked DEGs were validated in a semi-independent cohort of 13 progressors and 11 nonprogressors. Flow cytometry confirmed that progression was associated with expansion of CD4⁺ cells with a cytotoxic phenotype. By ATAC-seq, progression was associated with reconfiguration of regulatory chromatin regions in CD4⁺ cells, some linked to differentially expressed cytotoxicity-related genes. Our findings suggest that cytotoxic CD4⁺ T cells play a role in promoting progression to type 1 diabetes.     

Minimal Disease in the Sentinel Lymph Node: How to Best Measure Sentinel Node Micrometastases to Predict Risk of Additional Non-Sentinel Lymph Node Disease

Background  

Volume of disease in the sentinel lymph node (SLN) is a significant predictor of additional nodal metastasis. This study assesses incidence of residual non-SLN disease in a large cohort of women with minimal SLN metastases and compares three methods of SLN micrometastasis volume measurement to determine which best predicts residual disease on completion axillary lymph node dissection (cALND).     

Breast‐Specific Gamma Imaging Influences Surgical Management in Patients with Breast Cancer

Breast‐specific gamma imaging (BSGI) is a physiologic breast imaging modality that provides more sensitive detection of breast lesions than mammography or ultrasound, and appears to have greater specificity than breast MRI. The purpose of this study was to evaluate how often BSGI changed surgical management in patients with breast cancer. Charts were reviewed from 218 consecutive eligible patients who had preoperative evaluation with BSGI or MRI before surgery for breast cancer from January 2008 to May 2010. Patients who were initially considered eligible for breast‐conserving therapy (BCT) were evaluated to determine how many ultimately had mastectomies. Patients who underwent mastectomy because of personal choice or ineligibility for BCT were excluded. Management was changed to mastectomy in 11.9% of those who had BSGI and 28.9% of those who had MRI. Review of pathology demonstrated that all patients who underwent mastectomies were not candidates for breast conservation. 15.4% of patients who underwent BCT based on BSGI findings required a single re‐excision due to positive surgical margins. 14.4% required mastectomy. In the MRI group, 18.8% required a single re‐excision, and 6.3% required mastectomy. Evaluation with BSGI changed management to mastectomy in a substantial proportion of patients believed to be eligible for BCT following standard imaging. BSGI is effective in evaluation of extent of disease in patients with breast cancer, and is comparable to MRI in terms of its influence on surgical management.