The Use of Gene Expression Profiling and Biomarkers in Melanoma Diagnosis and Predicting Recurrence: Implications for Surveillance and Treatment.

Cutaneous melanoma is becoming more prevalent in the United States and has the highest mortality among cutaneous malignancies. The majority of melanomas are diagnosed at an early stage and, as such, survival is generally favorable. However, there remains prognostic uncertainty among subsets of early- and intermediate-stage melanoma patients, some of whom go on to develop advanced disease while others remain disease-free. Melanoma gene expression profiling (GEP) has evolved with the notion to help bridge this gap and identify higher- or lower-risk patients to better tailor treatment and surveillance protocols. These tests seek to prognosticate melanomas independently of established AJCC 8 cancer staging and clinicopathologic features (sex, age, primary tumor location, thickness, ulceration, mitotic rate, lymphovascular invasion, microsatellites, and/or SLNB status). While there is a significant opportunity to improve the accuracy of melanoma prognostication and diagnosis, it is equally important to understand the current landscape of molecular profiling for melanoma treatment. Society guidelines currently do not recommend molecular testing outside of clinical trials for melanoma clinical decision making, citing insufficient high-quality evidence guiding indications for the testing and interpretation of results. The goal of this chapter is to review the available literature for GEP testing for melanoma diagnosis and prognostication and understand their place in current treatment paradigms.

A multi-enhancer RET regulatory code is disrupted in Hirschsprung disease.

The major genetic risk factors for Hirschsprung disease (HSCR) are three common polymorphisms within cis-regulatory elements (CREs) of the receptor tyrosine kinase gene RET, which reduce its expression during enteric nervous system (ENS) development. These risk variants attenuate binding of the transcription factors RARB, GATA2, and SOX10 to their cognate CREs, reduce RET gene expression, and dysregulate other ENS and HSCR genes in the RET-EDNRB gene regulatory network (GRN). Here, we use siRNA, ChIP, and CRISPR-Cas9 deletion analyses in the SK-N-SH cell line to ask how many additional HSCR-associated risk variants reside in RET CREs that affect its gene expression. We identify 22 HSCR-associated variants in candidate RET CREs, of which seven have differential allele-specific in vitro enhancer activity, and four of these seven affect RET gene expression; of these, two enhancers are bound by the transcription factor PAX3. We also show that deleting multiple variant-containing enhancers leads to synergistic effects on RET gene expression. These, coupled with our prior results, show that common sequence variants in at least 10 RET enhancers affect HSCR risk, seven with experimental evidence of affecting RET gene expression, extending the known RET-EDNRB GRN to reveal an extensive regulatory code modulating disease risk at a single gene.

The Effect of Energy Devices, Nerve Monitors, and Drains on Thyroidectomy Outcomes: An American College of Surgeons National Surgical Quality Improvement Project Database Analysis.

The effect of energy devices, nerve monitors, and drains on thyroidectomy outcomes has been examined for each tool independently. Current literature supports the routine use of energy devices and nerve monitors and does not support the routine use of drains. The effect of these operative tools is interrelated and should be examined concurrently. The aim of this study was to describe the risk-adjusted effect of each of these tools on thyroidectomy outcomes. A retrospective analysis of 17 985 open thyroidectomy procedures was conducted using the American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) 2016-2018 thyroidectomy targeted procedure database. All open thyroidectomies were included. The risk-adjusted effect of energy devices, nerve monitors, and drains on 30-day outcomes was calculated by multiple logistic regression. Energy devices were associated with a decreased risk of hematoma and decreased extended length of stay without increased risk of hypocalcemia or recurrent laryngeal nerve injury. Nerve monitors were associated with a decreased risk of overall morbidity, decreased recurrent laryngeal nerve injury, and decreased extended length of stay without an increased risk of adverse outcomes. Drains were associated with an increased risk of bleeding, reoperation, and extended length of stay without decreasing hematoma. Our results support the routine use of energy devices and nerve monitors for thyroidectomy and do not support the routine use of drains for thyroidectomy.