Holly J. Meany

Utility of PET scans to predict disease relapse in pediatric patients with Hodgkin lymphoma

Positron emission tomography (PET) differentiates normal from abnormal cells based on metabolic activity. Numerous studies report that PET scan offers increased sensitivity, specificity and predictive values as compared to computed tomography (CT) in adult lymphoma patients.

18-fluorodeoxyglucose-positron emission tomography (FDG-PET) evaluation of nodular lesions in patients with neurofibromatosis type 1 and plexiform neurofibromas (PN) or malignant peripheral nerve sheath tumors (MPNST)

Individuals with Neurofibromatosis type 1 (NF1) are at risk for developing malignant peripheral nerve sheath tumors (MPNST), which frequently arise in preexisting plexiform neurofibromas (PN). Magnetic resonance imaging (MRI) with volumetric analysis and 18‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET) were utilized to monitor symptomatic nodular lesions.

Clinical Outcome in Children with Recurrent Neuroblastoma Treated with ABT-751 and Effect of ABT-751 on Proliferation of Neuroblastoma Cell Lines and on Tubulin Polymerization In Vitro

ABT‐751, an orally bioavailable sulfonamide, binds β‐tubulin to inhibit microtubule polymerization. We described response and event‐free survival (EFS) in children with neuroblastoma and other solid tumors receiving ABT‐751, assessed in vitro cytotoxicity of ABT‐751 and evaluated the effect of ABT‐751 on tubulin polymerization in peripheral blood mononuclear cells (PBMC) and pediatric tumor cell lines.

Phase 2 Trial of Recombinant Tumor Necrosis Factor-α in Combination With Dactinomycin in Children With Recurrent Wilms Tumor

Tumor necrosis factor (TNF), a peptide produced by macrophages with cytostatic and cytolytic effects, demonstrated single agent antitumor activity and synergistic effect when administered with dactinomycin in in vitro tumor cell lines, in vivo xenograft models, and adult and pediatric phase 1 clinical trials. This phase 2 pediatric trial evaluated the efficacy and further defined the toxicity profile of recombinant TNF (rTNF) and dactinomycin in patients with recurrent or refractory Wilms tumor. On this 2 stage Childrens Cancer Group trial, dactinomycin (15 μg/kg/d, IV) immediately followed by rTNF (200 μg/m2/d, IV), once daily for 5 consecutive days, was administered to patients with recurrent or refractory Wilms tumor. Cycles repeated every 21 days to a maximum of 12 courses. Nineteen of 21 consecutive patients, ranging 0.9 to 16.5 years of age at the time of initial diagnosis, were evaluable for response and toxicity. Three patients (15.8%) had a complete response, 5 (26.3%) had stable disease, and 11 (57.9%) had progressive disease. Following 59 patient treatment cycles, the most commonly observed grade 3/4 toxicities were thrombocytopenia (40.7%), elevated liver transaminases (23.7%), neutropenia (20.3%), leucopenia (13.6%), anemia (11.9%), and myalgias (10.2%). Before completion of stage 2, the study closed due to unavailability of rTNF. The documented complete responses and disease stabilization suggest antitumor activity of rTNF with dactinomycin in patients with recurrent Wilms tumor. The combination was well tolerated. Although grade 3/4 adverse events were reported, dose adjustments were not required. Toxicities resolved without significant interventions.

Significance of clinical and biologic features in Stage 3 neuroblastoma: A report from the International Neuroblastoma Risk Group project

International Neuroblastoma Staging System (INSS) Stage 3 neuroblastoma is a heterogeneous disease. Data from the International Neuroblastoma Risk Group (INRG) database were analyzed to define patient and tumor characteristics predictive of outcome.

Pediatric Phase I Trial Design Using Maximum Target Inhibition as the Primary Endpoint

The extent to which a drug inhibits a target responsible for a therapeutic effect is a more rational primary endpoint for dose-finding studies of more selective anticancer drugs than the conventional endpoint of dose-limiting toxicity (DLT) used for cytotoxic agents. An adaptive phase I trial design incorporating maximum target inhibition as the primary endpoint was developed to define the optimal dose of talabostat, a dipeptidyl peptidase (DPP) inhibitor, in children with relapsed or refractory solid tumors. The relationship between dose and effect (percent inhibition of serum DPP-4) was assessed using a maximum effect model. Maximum target inhibition was defined as greater than 90% DPP-4 inhibition in five or more of six patients 24 hours post-dose. If DLT was to occur, the trial would adapt to a traditional phase I design with a more conservative dose escalation. At the 600 microg/m(2) dose level, serum DPP-4 inhibition at 24 hours was 85%. No talabostat-related DLT occurred. The maximum effect model predicted that 1200 microg/m(2) of talabostat would maximally inhibit DPP-4. This adaptive trial design appears to be feasible, safe, and efficient and warrants further evaluation for development of molecularly targeted agents.

Malignant Peripheral Nerve Sheath Tumors: Prognostic and Diagnostic Markers and Therapeutic Targets

Malignant peripheral nerve sheath tumors (MPNSTs) are the most common malignancy associated with NF1. At present, complete surgical removal is the only successful treatment for MPNST, and the outcome for unresectable, recurrent, or metastatic MPNST remains poor. Because 50 % of MPNSTs arise in individuals with NF1, and because the prognosis of NF1-associated MPNST appears to be worse than that of sporadic tumors, many studies of MPNST have used NF1 models and comparisons between sporadic and NF1 MPNST. Currently, molecular analyses and preclinical testing are beginning to aid in the identification of promising therapies to target these neoplasms. Knowledge of the epidemiology, clinical presentation, diagnosis, and prognostic factors for MPNST is anticipated to allow for earlier detection of, and more successful treatment for, MPNST.

Platinum plus bortezomib for the treatment of pediatric renal medullary carcinoma: Two cases.

Renal medullary carcinoma (RMC) was first described over two decades ago as the seventh sickle nephropathy. Survival after diagnosis with metastatic disease still rarely extends beyond 1 year, with recent reports of median overall survival in patients treated with platinum therapy being just 10 months. We describe our experience using platinum‐based chemotherapy plus the proteasome inhibitor bortezomib to treat metastatic RMC in two pediatric patients who had complete responses. One patient passed away 7 years after diagnosis, while another remains disease free nearly 2 years from diagnosis.

Significance of clinical and biologic features in Stage 3 neuroblastoma

International Neuroblastoma Staging System (INSS) Stage 3 neuroblastoma is a heterogeneous disease. Data from the International Neuroblastoma Risk Group (INRG) database were analyzed to define patient and tumor characteristics predictive of outcome.

Significance of clinical and biologic features in Stage 3 neuroblastoma: A report from the International Neuroblastoma Risk Group project: Features Stage 3 Neuroblastoma

International Neuroblastoma Staging System (INSS) Stage 3 neuroblastoma is a heterogeneous disease. Data from the International Neuroblastoma Risk Group (INRG) database were analyzed to define patient and tumor characteristics predictive of outcome.