A prospective, comprehensive registry that integrates the molecular analysis of pediatric and adolescent melanocytic lesions.

BACKGROUND: Childhood melanocytic tumors represent a diagnostic and therapeutic challenge, and additional research is needed to better define the natural history of these tumors. METHODS: The authors developed a comprehensive, prospective registry called Molecular Analysis of Childhood Melanocytic Tumors for children and adolescents with an atypical Spitz tumor/Spitz melanoma (AST/SM), conventional or adult-type melanoma (CM), melanoma arising in a giant congenital nevus (MCM), or atypical melanocytic proliferation of other types (OT) to better define the clinical behavior of these lesions by incorporating an integrated clinicopathologic and molecular analysis using centralized pathology review and various platforms, including fluorescence in situ hybridization; array comparative genomic hybridization; and whole genome, exome, and capture targeted panels. RESULTS: From May 2016 to November 2019, 70 children were enrolled with a median age at diagnosis of 9.1 years. Thirty-seven had AST/SM, 17 had CM, 4 had MCM, and 12 had OT. Patients with AST/SM were younger (median age, 7 years), and their tumor most commonly arose in the extremities and trunk. The most common gene rearrangements included MAP3K8 and ALK. None of the 33 patients who underwent a TERT promoter mutation analysis had a mutation, and all patients were alive. Among the CM patients, the median age was 13 years; 11 had a BRAFV600E mutation, and 7 had a TERT promoter mutation. Three patients died of their disease. All 4 patients with MCM harbored an NRASQ61 mutation and died of their disease. The OT group was heterogenous, and all patients survived. CONCLUSIONS: The incorporation of an integrated clinicopathologic and genomic analysis identifies distinct subgroups of pediatric melanocytic lesions that have different clinical behaviors. The integration of this combined diagnostic modality can help to individualize diagnoses and treatments for these patients.

The role of chest computed tomography (CT) as a surveillance tool in children with high-risk neuroblastoma.

BACKGROUND: Standardization of imaging obtained in children with neuroblastoma is not well established. This study examines chest CT in pediatric patients with high-risk neuroblastoma. PROCEDURE: Medical records and imaging from 88 patients with high-risk neuroblastoma, diagnosed at St. Jude Children's Research Hospital between January, 2002 and December, 2009, were reviewed. Surveillance imaging was conducted through 2013. Ten patients with thoracic disease at diagnosis were excluded. Event free survival (EFS) and overall survival (OS) were estimated. Size specific dose estimates for CT scans of the chest, abdomen, and pelvis were used to estimate absolute organ doses to 23 organs. Organ dosimetry was used to calculate cohort effective dose. RESULTS: The 5 year OS and EFS were 51.9% ± 6.5% and 42.6% ± 6.5%, respectively. Forty-six (58.9%) patients progressed/recurred and 41 (52.6%) died of disease. Eleven patients (14%) developed thoracic disease progression/recurrence identified by chest CT (1 paraspinal mass, 1 pulmonary nodules, and 9 nodal). MIBG (metaiodobenzylguanidine) scans identified thoracic disease in six patients. Five of the 11 had normal chest MIBG scans; three were symptomatic and two were asymptomatic with normal chest MIBG scans but avid bone disease. The estimated radiation dose savings from surveillance without CT chest imaging was 42%, 34% when accounting for modern CT acquisition (2011-2013). CONCLUSIONS: Neuroblastoma progression/recurrence in the chest is rare and often presents with symptoms or is identified using standard non-CT imaging modalities. For patients with non-thoracic high-risk neuroblastoma at diagnosis, omission of surveillance chest CT imaging can save 35-42% of the radiation burden without compromising disease detection.

Survival of pediatric patients after relapsed osteosarcoma: the St. Jude Children's Research Hospital experience.

BACKGROUND: Chemotherapy has improved the outcome of patients with newly diagnosed osteosarcoma, but its role in relapsed disease is unclear. METHODS: We reviewed the records of all patients who were treated for relapsed high-grade osteosarcoma at our institution between 1970 and 2004. Postrelapse event-free survival (PREFS) and postrelapse survival (PRS) were estimated, and outcome comparisons were made using an exact log-rank test. RESULTS: The 10-year PREFS and PRS of the 110 patients were 11.8% ± 3.5% and 17.0% ± 4.3%, respectively. Metastasis at initial diagnosis (14%), and relapse in lung only (75%) were not significantly associated with PREFS or PRS. Time from initial diagnosis to first relapse (RL1) ≥18 months (43%), surgery at RL1 (76%), and ability to achieve second complete remission (CR2, 56%) were favorably associated with PREFS and PRS (P ≤ 0.0002). In patients without CR2, chemotherapy at RL1 was favorably associated with PREFS (P = 0.01) but not with PRS. In patients with lung relapse only, unilateral relapse and number of nodules ( ≤ 3) were associated with better PREFS and PRS (P ≤ 0.0005); no patients with bilateral relapse survived 10 years. The median PREFS after treatment with cisplatin, doxorubicin, methotrexate, and ifosfamide was 3.5 months (95% confidence interval, 2.1-5.2), and the median PRS was 8.2 months (95% confidence interval, 5.2-15.1). CONCLUSIONS: Late relapse, surgical resection, and unilateral involvement (in lung relapse only) favorably impact outcome after relapse. Surgery is essential for survival; chemotherapy may slow disease progression in patients without CR2. These data are useful for designing clinical trials that evaluate novel agents.

Is routine pelvic surveillance imaging necessary in patients with Wilms tumor?

BACKGROUND: It is unclear whether routine pelvic imaging is needed in patients with Wilms tumor. Thus, the primary objective of the current study was to examine the role of routine pelvic computed tomography (CT) in a cohort of pediatric patients with Wilms tumor. METHODS: With institutional review board approval, the authors retrospectively identified 110 patients who had Wilms tumor diagnosed between January 1999 and December 2009 with surveillance imaging that continued through March 2011. The authors estimated overall survival (OS), event-free survival (EFS), and dosimetry from dose length product (DLP) conversion to the effective dose (ED) for every CT in a subgroup of 80 patients who had CT studies obtained using contemporary scanners (2002-2011). Metal-oxide-semiconductor field-effect transistor (MOSFET) dosimeters were placed within organs of anthropomorphic phantoms to directly calculate the truncal ED. ED(DLP) was correlated with ED(MOSFET) to calculate potential pelvic dose savings. RESULTS: Eighty patients underwent 605 CT examinations that contained DLP information, including 352 CT scans of the chest, abdomen, and pelvis; 123 CT scans of the chest and abdomen; 102 CT scans of the chest only; 18 CT scans of the abdomen and pelvis; 9 CT scans of the abdomen only; and 1 CT that was limited to the pelvis. The respective 5-year OS and EFS estimates were 92.8% ± 3% and 2.6% ± 4.3%. Sixteen of 110 patients (15%) developed a relapse a median of 11.3 months (range, 5.0 months to 7.3 years) after diagnosis, and 4 patients died of disease recurrence. Three patients developed pelvic relapses, all 3 of which were symptomatic. The estimated ED savings from sex-neutral CT surveillance performed at a 120-kilovolt peak without pelvic imaging was calculated as 30.5% for the average patient aged 1 year, 30.4% for the average patient aged 5 years, 39.4% for the average patient aged 10 years, and 44.9% for the average patient aged 15 years. CONCLUSIONS: Omitting pelvic CT from the routine, off-therapy follow-up of patients with Wilms tumor saved an average 30% to 45% of the ED without compromising disease detection.

Pulmonary function after whole lung irradiation in pediatric patients with solid malignancies.

BACKGROUND: Although whole lung irradiation is used to treat pulmonary metastases of pediatric solid malignancies, few studies have addressed its long-term pulmonary consequences. METHODS: The authors conducted a retrospective study of longitudinal changes in 171 pulmonary function tests (PFTs) and their relation with clinical features in 48 survivors of pediatric malignant solid tumors treated with whole lung irradiation. RESULTS: Although active respiratory symptoms were seen in only 9 patients (18.8%), abnormalities in forced vital capacity (FVC; 58.3%), forced expiratory volume in 1 second (FEV(1) ; 64.6%), total lung capacity (TLC; 72.9%), and diffusion capacity of the lung for carbon monoxide corrected for hemoglobin (DLCO(corr) ; 70.8%) were common. At a median follow-up of 9.7 years after whole lung irradiation, FVC, FEV(1) , and TLC significantly declined longitudinally (P = .04, .03, and .02, respectively). Focal pulmonary boost irradiation was significantly associated with abnormal FEV(1) /FVC (P = .03), forced expiratory flow between 25% and 75% forced vital capacity (P = .005), residual volume (RV; P = .005), and RV/TLC (P = .002). Ten patients had baseline PFTs, and FVC, FEV(1) , TLC, and DLCO(corr) worsened immediately after radiation, followed by transient improvement but subsequent decline. Thirteen of 32 (40.6%) patients aged >18 years were smokers. CONCLUSIONS: Pulmonary dysfunction was prevalent after whole lung irradiation and worsened over time, although most patients were asymptomatic. Boost irradiation impaired pulmonary function, and a significant proportion of patients were smokers. Further studies are planned to assess the predictors and clinical consequences of progressive PFT abnormalities and to evaluate educational interventions.

A single-arm pilot phase II study of gefitinib and irinotecan in children with newly diagnosed high-risk neuroblastoma.

BACKGROUND: Gefitinib potently inhibits neuroblastoma proliferation in vitro, and the gefitinib/irinotecan combination shows greater than additive activity against neuroblastoma xenografts. This Phase II pilot study estimated the rate of response to two courses of intravenous irinotecan plus oral gefitinib in children with untreated high-risk neuroblastoma. METHODS: Two courses of irinotecan [15 mg/m(2)/day (daily ×5)×2] were combined with 12 daily doses of gefitinib (112.5 mg/m(2)/day). Response was assessed after 6 weeks. A response rate >55% was sought. RESULTS: Of the 23 children enrolled, 19 were evaluable for response. Median age at diagnosis was 3.1 years (range, 18 days-12.7 years). Most patients were older than 24 months (n = 20; 87%), male (n = 18; 78%), white (n = 16; 70%), had INSS 4 disease (n = 19; 83%), and had adrenal primary tumors (n = 18; 78%); nine patients (39%) had amplified tumor MYCN. The toxicity of gefitinib/irinotecan was mild and reversible (nausea, 5/20; diarrhea, 8/20; vomiting, 7/20). Five patients had partial responses; 9 others had a 23%-60% decrease in primary tumor volume and/or improved MIBG scans or decreased bone or bone marrow tumor burden. Median (range) systemic irinotecan exposure (AUC) was 283 ng/ml*hr (range, 163-890 ng/ml*hr) and 28 ng/ml*hr (3.6-297 ng/ml*hr) for the active metabolite, SN-38. No relation was observed between response and tumor expression of EGFR, MRP2-4, ABCG2, and Pgp. CONCLUSIONS: Although the gefitinib/irinotecan combination was very tolerable and induced responses, it was not sufficiently active to warrant further investigation. Initial investigational studies of this type can preclude the necessity for larger, longer, and costlier trials.

Renal function after ifosfamide, carboplatin and etoposide (ICE) chemotherapy, nephrectomy and radiotherapy in children with Wilms tumour.

We prospectively evaluated tumour response and renal function in 12 newly diagnosed children with high-risk Wilms tumour receiving ifosfamide, carboplatin and etoposide (ICE) chemotherapy. Two cycles of ICE were followed by 5 weeks of vincristine, dactinomycin and doxorubicin (Adriamycin) (VDA), and nephrectomy, radiotherapy, additional VDA, and a third ICE cycle. Carboplatin dosage was based on glomerular filtration rate (GFR) to achieve targeted systemic exposure (6mg/ml min). Mean GFR (measured by technetium 99m-DTPA clearance) declined by 7% after 2 cycles of ICE and by 38% after nephrectomy; the mean carboplatin dose was reduced 32% after nephrectomy. Mean GFR remained stable after the third ICE cycle. Although urinary beta(2)-microglobulin excretion increased during therapy, no patient had clinically significant renal tubular dysfunction at the end of treatment. Treatment with ICE, nephrectomy and radiotherapy significantly reduces GFR, largely as the result of nephrectomy. Adjustment of carboplatin dosage on the basis of GFR and careful monitoring of renal function may alleviate nephrotoxicity.

Phase I clinical trial of oxaliplatin in children and adolescents with refractory solid tumors.

PURPOSE: To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors and to determine whether carbamazepine reduces oxaliplatin-induced neurotoxicity. PATIENTS AND METHODS: Three regimens of oxaliplatin (given intravenously over 2 hours) were tested: regimen A (100 mg/m2, 130 mg/m2, or 160 mg/m2 every 3 weeks to determine the MTD of oxaliplatin); regimen B (to determine whether carbamazepine starting 24 hours before and ending 48 hours after oxaliplatin reduced the dose-limiting neurotoxicity and increased the MTD of regimen A); and regimen C (to evaluate the safety of a fixed dose two-thirds the MTD of regimen A given every 2 weeks [more frequent administration but comparable dose intensity]). RESULTS: Twenty-six patients were enrolled on regimens A (n = 11), B (n = 6), and C (n = 9). The DLT was grade 3 pharyngolaryngeal dysesthesia, sensory neuropathy, and ataxia at 160 mg/m2. The MTD was 130 mg/m2 every 3 weeks. At the MTD, the median clearance rate of ultrafiltrable platinum was 9.7 L/h/m2 (range, 6.5 to 15.5 L/h/m2). Addition of carbamazepine permitted dose escalation to 160 mg/m2 without DLT. DLT was not observed with a fixed dose of 85 mg/m2 given every 2 weeks. On all regimens, hematologic toxicity was mild. No significant nephrotoxicity, ototoxicity, or cumulative neurologic toxicity was observed. CONCLUSION: The DLT, MTD, PK, and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors are similar to those observed in adults. Carbamazepine may reduce the dose-limiting neurotoxicity of oxaliplatin.