Faculty Bibliography

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.

Background/UNASSIGNED:Plexiform neurofibromas (PN) in neurofibromatosis 1 (NF1) can cause substantial morbidities. Clinical trials targeting PN have recently described decreases in PN volumes. However, no previous study has assessed the association between changes in PN volumes and PN related morbidities. Our objective was to assess if increasing PN volume in NF1 is associated with increasing PN related morbidity. Methods/UNASSIGNED:Retrospective review of patients enrolled on the NCI NF1 Natural History study with ≥ 7 years of data available. Morbidities including pain, motor dysfunction, vision loss and PN related surgery, were assessed at time of baseline PN MRI with volumetric analysis and time of MRI with maximum PN volume. Results/UNASSIGNED:Forty-one patients (median age at baseline 8 years) with 57 PN were included. At baseline, 40 PN had at least one PN associated morbidity. During the observation period, 27 PN required increasing pain medication, and these PN grew faster per year (median difference 8.3%, 95% CI 2.4, 13.8%) than those PN which did not. PN resulting in motor impairment at baseline (n=11) had larger volumes compared to those that did not (median difference 461 mL, 95% CI 66.9, 820). Conclusions/UNASSIGNED:Many NF1 PN were associated with clinically significant morbidity at baseline, highlighting the need for longitudinal morbidity evaluations starting at an early age to capture changes in PN associated morbidities. Prospective evaluation of standardized patient reported and functional outcomes in clinical trials are ongoing and may allow further characterization of the association of PN volume increase or decrease and clinical changes.

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 nine patients. Best response was partial response (PR) in ten, stable disease (SD) in six, and progressive disease (PD) 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% 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. 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.

Background: Multiple Endocrine Neoplasia (MEN) 2B is a rare hereditary disorder characterized by medullary thyroid cancer (MTC) in early childhood, pheochromocytoma, and mucosal neuromas. Patients with advanced MTC are treated with rearranged during transfection (RET) targeting tyrosine kinase inhibitors (TKIs) such as vandetanib. Despite initial responses, many patients progress on TKI therapy and mechanisms of resistance are yet to be elucidated. We analyzed tumor samples from seven children with MEN2B and MTC enrolled in a natural history study (NCT01660984). Methods: DNA samples from tumor and adjacent normal tissue from paraffin embedded blocks or unstained slides were analyzed by a custom capture next-generation sequencing panel. Bioinformatics analyses identified point mutations, insertions, deletions and copy number variations. Results: Seven patients (median age at study enrollment 14 years, range 11-17 years) with the RET p.Met918Thr germline mutation were included in analysis. Tumor samples were available for three patients pre-TKI (four samples), two patients at progression on TKI (three samples), and two patients both, pre-TKI and at progression (five samples). Pre-TKI samples exhibited few tumor specific mutations or copy number variations and 4/5 patients had loss of chromosome 1p. Progression for one patient was associated with acquisition of a previously unidentified p.Leu790Phe mutation within the kinase domain of the RET gene. Loss of heterozygosity and increase in copy number variations were noted in 4/5 samples at tumor progression. Two patients had copy number loss of chromosome 14 and three had copy number gain of chromosome 1q. Recurrent, somatic, non-synonymous mutations were not identified in the sample set. Conclusion: In children with MEN2B and MTC, we identified increase in copy number variations and a somatic mutation within the RET gene as potential mechanisms of drug resistance. Our data imply that a common genetic mechanism for progression on TKI may not exist within this small sample set and highlight the need for serial collection of tumor tissue. Further, whole genome aneuploidy may provide rationale for the evaluation of cytotoxic chemotherapy in patients who experience progressive disease on TKI therapy. Analysis of additional samples and whole exome DNA and RNA sequencing are ongoing

OBJECTIVE:Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%-50% of individuals with neurofibromatosis type 1 (NF1). PNs that cause airway compromise or pulmonary dysfunction are uncommon but clinically important. Because improvement in sleep quality or airway function represents direct clinical benefit, measures of sleep and pulmonary function may be more meaningful than tumor size as endpoints in therapeutic clinical trials targeting airway PN. METHODS:The Response Evaluation in Neurofibromatosis and Schwannomatosis functional outcomes group reviewed currently available endpoints for sleep and pulmonary outcomes and developed consensus recommendations for response evaluation in NF clinical trials. RESULTS:For patients with airway PNs, polysomnography, impulse oscillometry, and spirometry should be performed to identify abnormal function that will be targeted by the agent under clinical investigation. The functional group endorsed the use of the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R10) or forced expiratory volume in 1 or 0.75 seconds (FEV1 or FEV0.75) as primary pulmonary endpoints. The group defined minimum changes in AHI, R10, and FEV1 or FEV0.75 for response criteria. Secondary sleep outcomes include desaturation and hypercapnia during sleep and arousal index. Secondary pulmonary outcomes include pulmonary resistance and reactance measurements at 5, 10, and 20 Hz; forced vital capacity; peak expiratory flow; and forced expiratory flows. CONCLUSIONS:These recommended sleep and pulmonary evaluations are intended to provide researchers with a standardized set of clinically meaningful endpoints for response evaluation in trials of NF1-related airway PNs.

Arterial ischemic strokes (AIS) localized solely to the midbrain are extremely uncommon in the pediatric population. Elevated lipoprotein (a), which promotes atherosclerosis and a prothrombotic state, has been associated with increased risk of AIS in children and adults. Here we describe a 17-year-old boy and a 15-year-old girl who presented with internuclear ophthalmoplegia secondary to an isolated midbrain AIS. Evaluation for risk factors for AIS in these otherwise healthy adolescents identified hyperlipoproteinemia (a) in combination with other potential prothrombotic conditions suggesting that hypercoagulable states such as hyperlipoproteinemia (a) may have contributed to development of small-vessel arteriopathy and localized AIS.

BACKGROUND: Based on pre-clinical and clinical activity in adult refractory tumors, and absence of significant neuro-, nephro-, or oto-toxicity, we conducted a pediatric phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and pharmacokinetics of satraplatin, an oral platinum analogue, in children and young adults with refractory solid tumors. PROCEDURE: Satraplatin was administered orally once daily on days 1-5 of a 28-day cycle at dose level (DL) 1 (60 mg/m(2) /dose), and DL2 (80 mg/m(2) /dose). Toxicities, responses, satraplatin pharmacokinetics, and pharmacogenomic expression of specific DNA repair genes were evaluated. RESULTS: Nine patients received 1-15 cycles (median = 2). The MTD was exceeded at DL2 with delayed prolonged myelosuppression as dose-limiting toxicity (DLT) in 2/4 patients. At DL1, 0/5 patients had DLTs. Common non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No significant neuro-, nephro-, or oto-toxicity was observed. No objective responses were observed but 2 patients experienced prolonged disease stabilization (---6-15 cycles). Satraplatin exposure (day 1 plasma ultrafiltrate area under the curve) was similar at DL1 and DL2. A strong correlation between estimated creatinine clearance and satraplatin pharmacokinetic parameters (clearance, area under the curve, and peak concentration) was observed. CONCLUSIONS: The MTD of oral satraplatin in children with solid tumors was 60 mg/m(2) /dose daily x5 days every 28 days, which is lower than the adult recommended dose of 80-120 mg/m(2) /dose. The toxicity profile was similar to adults and delayed myelosuppression was the DLT. No significant neuro-, nephro- or oto-toxicities were observed.

To characterize spinal abnormalities in patients with neurofibromatosis type 1 (NF1) using magnetic resonance imaging (MRI). NF1 patients with at least one spine MRI were selected from participants prospectively enrolled in the National Cancer Institute NF1 Natural History Study. Data were analyzed retrospectively. Ninety-seven patients (38 females, median age 14.2 years, standard deviation [SD] 7.6) had baseline imaging of the spine, and 26 patients (27 %) had one follow-up spine MRI (follow up time 2.5 years, SD 1.1, range 0.7-4.7). Seventy-eight patients (80 %) had spinal neurofibromas, with rising frequency from 70 % in patients younger than 10 years to 80 % in patients aged 10-18 years to 89 % in individuals older than 18 years of age. At baseline, 33/97 patients (34 %) had MRI changes consistent with spinal cord compression that was most prevalent at the cervical (43 %) and lumbar spine region (40 %). Seven of nine patients with progression of their spinal neurofibromas developed cord compression. Paraspinal plexiform neurofibromas (PNs) were present in 77/97 patients (79 %), of which 68 patients (88 %) had concomitant spinal neurofibromas. Spinal curvature abnormality was present in 50/97 patients (51 %, 20 females, median age 14.6 years, SD 7.6). Patients with paraspinal PNs had six-fold higher odds of developing spinal curvature abnormalities compared to patients without PN (OR = 5.9, 95 % CI 1.81 to 19.44, p = 0.0033). A total of 58/97 patients (60 %, median age 16.1 years, SD 7.8, range 4.8-48.2 years) presented with neurologic abnormalities that progressed in 12/26 patients (46 %). Substantial spinal neurofibroma and paraspinal PN burden was observed in our study population, which represents a selective group of patients with specifically more severe tumor involvement than the general NF1 population. Occurrence and progression of spinal neurofibromas on repeat evaluations highlight the need for longitudinal clinical monitoring in patients with known spinal disease.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have been associated with elevated TSH as a drug class effect. Prior studies of vandetanib in adults with medullary thyroid carcinoma (MTC) described an increase in levothyroxine (LT) requirement. We studied TSH, free T4, and LT dosing in children and adolescents enrolled in the phase I/II trial of vandetanib for medullary thyroid cancer (MTC). METHODS: Data from 13 patients with multiple endocrine neoplasia type 2B (MEN 2B) and MTC were analyzed [6 M, 7 F, median age 13.0 y (9.1-17.3)] Eleven patients (85%) had undergone prior thyroidectomy and all received single-drug therapy with vandetanib for > 6 months. Confirmed compliance with vandetanib (67-150 mg/m(2)/day) and LT was a necessary inclusion criterion. RESULTS: While on vandetanib treatment, all 11 athyerotic patients exhibited significantly increased TSH levels. The baseline TSH level was 4.37 mclU/ml (0.08 - 23.30); in comparison, the first peak TSH concentration on vandetanib was 15.70 mclU/ml (12.50 - 137.00, p = 0.0010). The median time to reach the initial peak of elevated TSH was 1.8 months (0.3 - 9.3). Free T4 levels remained within the normal reference range. An increase from a baseline LT dose of 91 mcg/m(2)/day (+/-24) to 116 mcg/m(2)/day (+/-24) was required in order to resume normative TSH levels (p = 0.00005), equal to an increase of 36.6% (+/-16.56) in the dosage of LT in mcg/day. For the 2 patients with intact thyroid glands, free T4 and TSH remained normal over a combined 6 patient years of follow up. CONCLUSIONS: In our cohort of pediatric MTC patients, athyreotic patients with preexisting hypothyroidism developed increased TSH and reduced free T4 during the first few months of treatment with vandetanib, necessitating an increase in LT dosage. Additional patients with normal thyroid function before treatment and intact glands (n = 2) maintained normal thyroid function tests during treatment. Elevated TSH in athyreotic patients may be due to an indirect effect of vandetanib on the metabolism of thyroid hormone, or to altered TSH sensitivity at the pituitary. Proper recognition and management of abnormal thyroid hormone levels is critical in growing children on TKIs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00514046.