Multiple Endocrine Neoplasia Type 2B Presents Early in Childhood but Often Is Undiagnosed for Years.

We describe the presenting symptoms and signs of multiple endocrine neoplasia type 2B in a cohort of children. Improved awareness of the early nonendocrine signs of multiple endocrine neoplasia type 2B could lead to earlier diagnosis before the development of medullary thyroid cancer and possibly its metastasis.

Pheochromocytoma in Children and Adolescents With Multiple Endocrine Neoplasia Type 2B.

Context: Multiple endocrine neoplasia type 2B (MEN2B) is characterized by early-onset medullary thyroid cancer in virtually all cases and a 50% lifetime risk of pheochromocytoma (PHEO) development. The literature on PHEO in patients with MEN2B is limited with most data being reported from adult studies that primarily address MEN2A. Objective: The aim of the current study is to describe PHEO development in a cohort of pediatric patients with MEN2B. Design: Retrospective chart review of patients with MEN2B evaluated at the National Institutes of Health in the period between July 2007 and February 2018. Results: A total of 38 patients were identified (21 males and 17 females). Mean age at MEN2B diagnosis was 10.6 ± 3.9 years. Eight patients (21%) developed PHEO in the course of follow-up to date, all of whom were sporadic cases with the classic M918T RET mutation. PHEO was diagnosed based on biochemical and/or imaging screening studies in five patients, whereas three patients presented with symptoms of excess catecholamines. PHEO was diagnosed at a mean age 15.2 ± 4.6 (range, 10 to 25) years and 4.0 ± 3.3 years after MEN2B diagnosis. Only one patient was diagnosed with PHEO as the initial manifestation of MEN2B after she presented with hypertension and secondary amenorrhea. Conclusion: Undiagnosed PHEO can be associated with substantial morbidity. Current American Thyroid Association guidelines recommend PHEO screening starting at age 11 for the high-/highest risk group. The youngest patient diagnosed with PHEO in our cohort was an asymptomatic 10-year-old, suggesting that PHEO development may begin before the screening-recommended age of 11, though remains clinically undetectable and thus the current screening guidelines seem appropriate.

A Phase II Trial of Vandetanib in Children and Adults with Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor.

PURPOSE: Gastrointestinal stromal tumors (GIST) are resistant to cytotoxic chemotherapy and radiotherapy. Most GIST in children are wild-type for KIT and PDGFRA (WT GIST) and deficient in expression of succinate dehydrogenase (dSDH GIST). We tested the activity of vandetanib, an oral small-molecule inhibitor of VEGFR2, EGFR, and RET, in patients with dSDH GIST. PATIENTS AND METHODS: Phase II study of vandetanib (300 mg orally once daily to patients ≥18 years, and 100 mg/m2/dose to patients < 18 years) on a continuous dosing schedule (1 cycle = 28 days) to assess the clinical activity (partial and complete response rate RECIST v1.1) in patients with dSDH GIST. A Simon optimal two-stage design (target response rate 25%, rule out 5%) was used: If ≥1 of 9 patients in stage 1 responded, enrollment would be expanded to 24 patients, and if ≥3 of 24 responded, vandetanib would be considered active. RESULTS: Nine patients (7 female and 2 male; median age, 24 years; range, 11-52) with metastatic disease were enrolled. Three of the initial 5 adult patients developed treatment-modifying toxicities. After a protocol amendment, two adults received vandetanib at 200 mg/dose with improved tolerability. The two children (<18 years old) enrolled did not experience treatment-modifying toxicities. No partial or complete responses were observed (median number of cycles, 4; range, 2-18). CONCLUSIONS: Vandetanib at a dose of 300 mg daily was not well tolerated by adults with dSDH GIST. Two of 9 patients had prolonged stable disease, but no partial or complete responses were observed, and vandetanib is thus not considered active in dSDH GIST.

Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib.

Purpose: Vandetanib is well-tolerated in patients with advanced medullary thyroid carcinoma (MTC). Long-term outcomes and mechanisms of MTC progression have not been reported previously.Experimental Design: We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression.Results: Seventeen patients [8 male, age 13 (9-17)* years] enrolled; 16 had a RET p.Met918Thr germline mutation. The duration of vandetanib therapy was 6.1 (0.1-9.7+)* years with treatment ongoing in 9 patients. Best response was partial response in 10, stable disease in 6, and progressive disease in one patient. Duration of response was 7.4 (0.6-8.7+)* and 4.9 (0.6-7.8+)* years in patients with PR and SD, respectively. Six patients died 2.0 (0.4-5.7)* years after progression. Median progression-free survival (PFS) was 6.7 years [95% confidence interval (CI): 2.3 years-undefined] and 5-year overall survival (OS) was 88.2% (95% CI: 60.6%-96.9%). Of 16 patients with a RET p.Met918Thr mutation, progression-free survival was 6.7 years (95% CI: 3.1-undefined) and 5-year overall survival was 93.8% (95% CI: 63.2%-99.1%). No patients terminated treatment because of toxicity. DNA sequencing of tissue samples (n = 11) identified an increase in copy number alterations across the genome as a potential mechanism of drug resistance [*median (range)].Conclusions: This study demonstrates that vandetanib is safe and results in sustained responses in children and adolescents with hereditary MTC. Our preliminary molecular data suggest that an increase in copy number abnormalities may be associated with tumor progression in hereditary MTC patients treated with vandetanib. Clin Cancer Res; 24(4); 753-65. ©2017 AACR.