Amplification of the locus encoding the oncogenic transcription factor MYCN is a defining feature of high-risk neuroblastoma. Here we present the first dynamic chromatin and transcriptional landscape of MYCN perturbation in neuroblastoma. At oncogenic levels, MYCN associates with E-box binding motifs in an affinity-dependent manner, binding to strong canonical E-boxes at promoters and invading abundant weaker non-canonical E-boxes clustered at enhancers. Loss of MYCN leads to a global reduction in transcription, which is most pronounced at MYCN target genes with the greatest enhancer occupancy. These highly occupied MYCN target genes show tissue-specific expression and are linked to poor patient survival. The activity of genes with MYCN-occupied enhancers is dependent on the tissue-specific transcription factor TWIST1, which co-occupies enhancers with MYCN and is required for MYCN-dependent proliferation. These data implicate tissue-specific enhancers in defining often highly tumor-specific 'MYC target gene signatures' and identify disruption of the MYCN enhancer regulatory axis as a promising therapeutic strategy in neuroblastoma.

No abstract

Chilaiditi syndrome is a rare condition occurring in 0.025% to 0.28% of the population. In these patients, the colon is displaced and caught between the liver and the right hemidiaphragm. Patients' symptoms can range from asymptomatic to acute intermittent bowel obstruction. Diagnosis is best achieved with CT imaging. Identification of Chilaiditi syndrome is clinically significant as it can lead to many significant complications such as volvulus, perforation, and bowel obstruction. If the patient is symptomatic, treatment is usually conservative. Surgery is rarely indicated with indications including ischemia and failure of resolution with conservative management.

A role for antigen-driven stimulation has been proposed in the pathogenesis of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) based largely on the binding properties of monoclonal Ig. However, insights into antigen binding to clonal B cell receptors and in vivo responsiveness of the malignant clone to antigen-mediated stimulation are needed to understand the role of antigenic stimulation in tumor growth. Lysolipid-reactive clonal Ig were detected in Gaucher disease (GD) and some sporadic gammopathies. Here, we show that recombinant Ig (rIg) cloned from sort-purified single tumor cells from lipid-reactive sporadic and GD-associated gammopathy specifically bound lysolipids. Liposome sedimentation and binding assays confirmed specific interaction of lipid-reactive monoclonal Ig with lysolipids. The clonal nature of lysolipid-binding Ig was validated by protein sequencing. Gene expression profiling and cytogenetic analyses from 2 patient cohorts showed enrichment of nonhyperdiploid tumors in lipid-reactive patients. In vivo antigen-mediated stimulation led to an increase in clonal Ig and plasma cells (PCs) in GD gammopathy and also reactivated previously suppressed antigenically related nonclonal PCs. These data support a model wherein antigenic stimulation mediates an initial polyclonal phase, followed by evolution of monoclonal tumors enriched in nonhyperdiploid genomes, responsive to underlying antigen. Targeting underlying antigens may therefore prevent clinical MM.

ObjectivesThe robotic retroauricular approach and transoral endoscopic thyroidectomy vestibular approach (TOETVA) have been employed to avoid anterior neck scarring in thyroidectomy with good success. However, outcomes have yet to be compared between techniques. We compare our initial clinical experience with these approaches for thyroid lobectomy at our institution.MethodsA review of initial consecutive patients who underwent robotic facelift thyroidectomy (RFT) (August 2011–August 2016) at our institution was conducted. This was compared with the same number of initial consecutive patients who underwent TOETVA (September 2016–September 2017) at our institution. Demographics, operative time, pathology, complications, and learning curve were compared between cohorts. Learning curve was defined based on the slope of linear regression models of operative time versus case number.ResultsThere were 20 patients in each cohort. There was no statistically significant difference in demographic data between cohorts. One hundred percent of RFT cases versus 95% TOETVA cases (P = .999) were completed without conversion to standard open technique with median operative times of 201 (124–293) minutes versus 188 (89–343) minutes with RFT and TOETVA, respectively (P = .36). There was no incidence of permanent recurrent laryngeal nerve injury in either cohort. The slopes of the regression models were 0.29 versus −8.32 (P = .005) for RFT and TOETVA, respectively.ConclusionRFT and TOETVA are safe and feasible options for patients motivated to avoid an anterior neck scar. However, the quicker learning curve without the need for a costly robotic system may make TOETVA the preferred technique for institutions wishing to perform anterior cervical incision‐sparing thyroidectomy.Level of Evidence4