Amanda Wheeler

5-Hydroxymethylcytosine signatures in cell-free DNA provide information about tumor types and stages

5-Hydroxymethylcytosine (5hmC) is an important mammalian DNA epigenetic modification that has been linked to gene regulation and cancer pathogenesis. Here we explored the diagnostic potential of 5hmC in circulating cell-free DNA (cfDNA) using a sensitive chemical labeling-based low-input shotgun sequencing approach. We sequenced cell-free 5hmC from 49 patients of seven different cancer types and found distinct features that could be used to predict cancer types and stages with high accuracy. Specifically, we discovered that lung cancer leads to a progressive global loss of 5hmC in cfDNA, whereas hepatocellular carcinoma and pancreatic cancer lead to disease-specific changes in the cell-free hydroxymethylome. Our proof-of-principle results suggest that cell-free 5hmC signatures may potentially be used not only to identify cancer types but also to track tumor stage in some cancers.

Performance and Practice Guideline for the Use of Neoadjuvant Systemic Therapy in the Management of Breast Cancer

PurposeThe American Society of Breast Surgeons (ASBrS) sought to provide an evidence-based guideline on the use of neoadjuvant systemic therapy (NST) in the management of clinical stage II and III invasive breast cancer.MethodsA comprehensive nonsystematic review was performed of selected peer-reviewed literature published since 2000. The Education Committee of the ASBrS convened to develop guideline recommendations.ResultsA performance and practice guideline was prepared to outline the baseline assessment and perioperative management of patients with clinical stage II–III breast cancer under consideration for NST.RecommendationsPreoperative or NST is emerging as an important initial strategy for the management of invasive breast cancer. From the surgeon’s perspective, the primary goal of NST is to increase the resectability of locally advanced breast cancer, increase the feasibility of breast-conserving surgery and sentinel node biopsy, and decrease surgical morbidity. To ensure optimal patient selection and efficient patient care, the guideline recommends: (1) baseline breast and axillary imaging; (2) minimally invasive biopsies of breast and axillary lesions; (3) determination of tumor biomarkers; (4) systemic staging; (5) care coordination, including referrals to medical oncology, radiation oncology, plastic surgery, social work, and genetic counseling, if indicated; (6) initiation of NST; (7) post-NST breast and axillary imaging; and (8) decision for surgery based on extent of disease at presentation, patient choice, clinical response to NST, and genetic testing results, if performed.

The diagnostic value of nipple discharge cytology: Breast imaging complements predictive value of nipple discharge cytology

Papilloma is the most common finding associated with pathologic nipple discharge. In the absence of breast imaging abnormalities, the incidence of occult malignancy is <3%.

A Review of Anatomy, Physiology, and Benign Pathology of the Nipple

The nipple and areola are pigmented areas of modified skin that connect with the underlying gland of the breast via ducts. The fairly common congenital anomalies of the nipple include inversion, clefts, and supernumerary nipples. The anatomy of the nipple areolar complex is discussed as a foundation to review anatomical variants, and the physiologic development of the nipple, including changes in puberty and pregnancy, as well as the basis of normal physiologic discharge, are addressed. Skin conditions affecting the nipple include eczema, which, while similar to eczema occurring elsewhere on the body, poses unique aspects in terms of diagnosis and treatment. This article concludes with discussion on the benign abnormalities that develop within the nipple, including intraductal papilloma and nipple adenoma.

Metastases to the Breast: Alveolar Soft Part Sarcoma in Adolescents

Metastases to the breast comprise 0.5%-2% of breast neoplasms. This is a case report of an 18-year-old woman with an alveolar soft part sarcoma metastatic to the breast.

Abstract P2-01-05: Correlation of percutaneously biopsied axillary lymph nodes marked with black tattoo ink prior to neoadjuvant chemotherapy with sentinel lymph nodes in breast cancer patients

Introduction: Sonographic evaluation of the axilla and percutaneous biopsy of abnormal lymph nodes with fine needle aspiration (FNA) or core needle biopsy (CNB) has become more common practice in patients with newly diagnosed breast cancer prior to neoadjuvant chemotherapy (NAC). Sentinel lymph node (SLN) biopsy is considered the gold standard for axillary staging in clinically node negative breast cancer patients. Currently, there is no clear correlation of sonographically detected abnormal lymph nodes and open surgical assessment. We conducted an exploratory pilot study which marked suspicious axillary lymph nodes with black tattoo ink at the time of percutaneous needle biopsy prior to NAC. Black nodes visualized during axillary surgery were evaluated in comparison to SLNs. Methods: Breast cancer patients with clinical and/or sonographically suspicious axillary lymph nodes prior to NAC were included in the study. Following FNA or CNB biopsy of node, 0.1 to 0.5 ml of a sterile, highly purified, biocompatible fine carbon suspension (Spot™) was injected into the cortex of the lymph node and adjacent soft tissue. A total of 12 patients were injected with black ink prior to NAC. Intraoperative presence of black pigment was assessed and correlation between sentinel and tattooed nodes were evaluated. Results: Nine patients had a positive percutaneous lymph node biopsy prior to NAC. The average number of days that elapsed between injection and to surgery was 130 days. A successful SLN procedure was performed in all patients. A black tattooed node was identified in all patients and correlated to a SLN. 7 patients were down-staged in the axilla and 6 patients did not go onto completion axillary dissection. One patient with a negative SLN had a completion axillary dissection, but no additional positive lymph nodes were found. Four patients with positive SLN had a completion axillary dissection (1 of whom was a false negative percutaneous biopsy). In all four patients, the positive sentinel node contained visible black ink. There was one patient who had an additional positive sentinel node, which was not black. Two axillary dissections contained additional positive nodes. Conclusion: Black ink tattooing with sterile black ink (Spot™), successfully marked suspicious lymph nodes prior to NAC. These correlated to a SLN. In node positive patients with a partial response in the axillary lymph nodes following neoadjuvant chemotherapy, previously marked, black-inked node proved to be the persistent positive node. Tattooing of lymph nodes at the time of percutaneous biopsy may improve the accuracy of surgical axillary staging by aiding in the intra-operative identification of previously biopsied nodes. Citation Format: Nicole Choy, Jafi Lipson, Sunita Pal, Debra Ikeda, Long Trinh, Kimberly Allison, Michael Ozawa, Amanda Wheeler, Irene Wapnir. Correlation of percutaneously biopsied axillary lymph nodes marked with black tattoo ink prior to neoadjuvant chemotherapy with sentinel lymph nodes in breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-01-05.

Right Breast Mastectomy and Reconstruction with Tissue Expander under Thoracic Paravertebral Blocks in a 12-Week Parturient

Paravertebral blocks are becoming increasingly utilized for breast surgery with studies showing improved postoperative pain control, decreased need for opioids, and less nausea and vomiting. We describe the anesthetic management of an otherwise healthy woman who was 12 weeks pregnant presenting for treatment of her breast cancer. For patients undergoing breast mastectomy and reconstruction with tissue expanders, paravertebral blocks offer an anesthetic alternative when general anesthesia is not desired.

Secondary use of electronic medical records for clinical research: challenges and opportunities

With increasingly ubiquitous electronic medical record (EMR) implementation accelerated by the adoption of the HITECH Act, there is much interest in the secondary use of collected data to improve outcomes and promote personalized medicine. A plethora of research has emerged using EMRs to investigate clinical research questions and assess variations in both treatments and outcomes. However, whether because of genuine complexities of modeling disease physiology or because of practical problems regarding data capture, data accuracy, and data completeness, the state of current EMR research is challenging and gives rise to concerns regarding study accuracy and reproducibility. This work explores challenges in how different experimental design decisions can influence results using a specific example of breast cancer patients undergoing excision and reconstruction surgeries from EMRs in an academic hospital and the Veterans Health Administration (VHA) We discuss emerging strategies that will mitigate these limitations, including data sharing, application of natural language processing, and improved EMR user design.

T cell receptor sequencing of early-stage breast cancer tumors identifies altered clonal structure of the T cell repertoire

Significance The recent advances in cancer immunotherapy motivated us to investigate the clonal structure of the T cell receptor repertoire in breast tumors, normal breast, and blood in the same individuals. We found quantitatively distinct clonal structures in all three tissues, which enabled us to predict whether tissue is normal or tumor solely by comparing the repertoire of the tissue with blood. T cell receptor sequences shared between patients’ tumors are rare and, in general, do not appear to be specific to the cancer. Tumor-infiltrating T cells play an important role in many cancers, and can improve prognosis and yield therapeutic targets. We characterized T cells infiltrating both breast cancer tumors and the surrounding normal breast tissue to identify T cells specific to each, as well as their abundance in peripheral blood. Using immune profiling of the T cell beta-chain repertoire in 16 patients with early-stage breast cancer, we show that the clonal structure of the tumor is significantly different from adjacent breast tissue, with the tumor containing ∼2.5-fold greater density of T cells and higher clonality compared with normal breast. The clonal structure of T cells in blood and normal breast is more similar than between blood and tumor, and could be used to distinguish tumor from normal breast tissue in 14 of 16 patients. Many T cell sequences overlap between tissue and blood from the same patient, including ∼50% of T cells between tumor and normal breast. Both tumor and normal breast contain high-abundance “enriched” sequences that are absent or of low abundance in the other tissue. Many of these T cells are either not detected or detected with very low frequency in the blood, suggesting the existence of separate compartments of T cells in both tumor and normal breast. Enriched T cell sequences are typically unique to each patient, but a subset is shared between many different patients. We show that many of these are commonly generated sequences, and thus unlikely to play an important role in the tumor microenvironment.

The Biology Behind the American College of Surgeons Oncology Group Z0011 Trial

Author Contributions: Drs Choi and Senthil had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Choi, Garberoglio, Senthil. Acquisition, analysis, or interpretation of data: Choi, Blount, Perez, Chavez de Paz, Rodriguez, Surrusco, Lum, Senthil. Drafting of the manuscript: Choi, Chavez de Paz, Rodriguez, Senthil. Critical revision of the manuscript for important intellectual content: Choi, Blount, Perez, Surrusco, Garberoglio, Lum, Senthil. Statistical analysis: Chavez de Paz, Rodriguez, Lum. Administrative, technical, or material support: Choi, Perez, Surrusco, Lum, Senthil. Study supervision: Garberoglio, Lum, Senthil.