Keratin-Positive Giant Cell Tumor of Bone and Soft Tissue With HMGA2::NCOR2 Fusion in Children Under 10 With Response to Imatinib Therapy: A Case Series.

HMGA2::NCOR2 keratin-positive giant cell tumors in children with response to imatinib in an infant.

The RAG1 Ubiquitin Ligase Domain Stimulates Recombination of TCRß and TCRα Genes and Influences Development of αß T Cell Lineages.

RAG1/RAG2 (RAG) endonuclease-mediated assembly of diverse lymphocyte Ag receptor genes by V(D)J recombination is critical for the development and immune function of T and B cells. The RAG1 protein contains a ubiquitin ligase domain that stabilizes RAG1 and stimulates RAG endonuclease activity in vitro. We report in this study that mice with a mutation that inactivates the Rag1 ubiquitin ligase in vitro exhibit decreased rearrangements and altered repertoires of TCRß and TCRα genes in thymocytes and impaired thymocyte developmental transitions that require the assembly and selection of functional TCRß and/or TCRα genes. These Rag1 mutant mice present diminished positive selection and superantigen-mediated negative selection of conventional αß T cells, decreased genesis of invariant NK T lineage αß T cells, and mature CD4+ αß T cells with elevated autoimmune potential. Our findings reveal that the Rag1 ubiquitin ligase domain functions in vivo to stimulate TCRß and TCRα gene recombination and influence differentiation of αß T lineage cells, thereby establishing replete diversity of αß TCRs and populations of αß T cells while restraining generation of potentially autoreactive conventional αß T cells.

NTRK Fusions Identified in Pediatric Tumors: The Frequency, Fusion Partners, and Clinical Outcome.

PURPOSE: Neurotrophic tyrosine receptor kinase (NTRK) fusions have been described as oncogenic drivers in a variety of tumors. However, little is known about the overall frequency of NTRK fusion in unselected pediatric tumors. Here, we assessed the frequency, fusion partners, and clinical course in pediatric patients with NTRK fusion-positive tumors. PATIENTS AND METHODS: We studied 1,347 consecutive pediatric tumors from 1,217 patients who underwent tumor genomic profiling using custom-designed DNA and RNA next-generation sequencing panels. NTRK fusions identified were orthogonally confirmed. RESULTS AND DISCUSSION: NTRK fusions were identified in 29 tumors from 27 patients with a positive yield of 2.22% for all patients and 3.08% for solid tumors. Although NTRK2 fusions were found exclusively in CNS tumors and NTRK1 fusions were highly enriched in papillary thyroid carcinomas, NTRK3 fusions were identified in all tumor categories. The most canonical fusion was ETV6-NTRK3 observed in 10 patients with diverse types of tumors. Several novel NTRK fusions were observed in rare tumor types, including KCTD16-NTRK1 in ganglioglioma and IRF2BP2-NTRK3 in papillary thyroid carcinomas. The detection of an NTRK fusion confirmed the morphologic diagnosis including five cases where the final tumor diagnosis was largely based on the discovery of an NTRK fusion. In one patient, the diagnosis was changed because of the identification of an ETV6-NTRK3 fusion. One patient with infantile fibrosarcoma was treated with larotrectinib and achieved complete pathologic remission. CONCLUSION: NTRK fusions are more frequently seen in pediatric tumors than in adult tumors and involve a broader panel of fusion partners and a wider range of tumors than previously recognized. These results highlight the importance of screening for NTRK fusions as part of the tumor genomic profiling for patients with pediatric cancer.

Management of Congenital Heart Disease Associated with Ellis-van Creveld Short-rib Thoracic Dysplasia.

OBJECTIVE: To evaluate clinical outcome of patients with Ellis-van Creveld syndrome (EVC) in whom congenital heart disease (CHD) repair was delayed intentionally to reduce the risk of postoperative respiratory morbidity and mortality. STUDY DESIGN: This retrospective review of 51 EVC c.1886+5G>T homozygotes born between 2005 and 2014 focused on 18 subjects who underwent surgery for CHD, subdivided into early (mean, 1.3 months) vs delayed (mean, 50.1 months) repair. RESULTS: Growth trajectories differed between control subjects and patients with EVC, and CHD was associated with slower weight gain. Relative to controls, infants with EVC had a 40%-75% higher respiratory rates (independent of CHD) accompanied by signs of compensated respiratory acidosis. Blood gases and respiratory rates approached normal values by age 4 years. Hemodynamically significant CHD was present in 23 children, 18 (78%) of whom underwent surgical repair. Surgery was performed at 1.3 ± 1.3 months for children born between 2005 and 2009 (n = 9) and 50.1 ± 40.2 months (P = .009) for children born between 2010 and 2014 (n = 9). The latter had shorter postoperative mechanical ventilation (1.1 ± 2.4 days vs 49.6 ± 57.1 days; P = .075), shorter intensive care duration of stay (16 ± 24 days vs 48.6 ± 44.2 days; P = .155), and no postoperative tracheostomies (vs 60%; P = .028) or deaths (vs 44%; P = .082). CONCLUSION: Among children with EVC and possibly other short-rib thoracic dysplasias, delayed surgical repair of CHD reduces postoperative morbidity and improves survival. Respiratory rate serves as a simple indicator for optimal timing of surgical repair.