Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification (HO) for which there is presently no definitive treatment. Research studies have identified multiple potential targets for therapy in FOP, and novel drug candidates are being developed for testing in clinical trials. A complementary approach seeks to identify approved drugs that could be re-purposed for off-label use against defined targets in FOP. One such drug is imatinib mesylate, a tyrosine kinase inhibitor originally developed for use in patients with chronic myeloid leukemia (CML). Imatinib has the desirable effect of attacking multiple targets involved in the early hypoxic and inflammatory stages of FOP flare-ups, including HIF1-α, PDGFRα, c-KIT, and multiple MAP kinases. RESULTS: Based on compelling biologic rationale, strong preclinical data, and a favorable safety profile, imatinib has been prescribed on an off-label basis in a non-trial setting in seven children with continuous FOP flare-ups, predominantly in the axial regions, and which were not responsive to standard-of-care regimens. Anecdotal reports in these seven isolated cases document that the medication was well-tolerated with a ubiquitous reported decrease in the intensity of flare-ups in the six children who took the medication. CONCLUSIONS: These early clinical observations support the implementation of clinical trials in children with uncontrolled FOP flare-ups to determine if imatinib may ameliorate symptoms or alter the natural history of this debilitating and life-threatening disease.

Laparoscopic removal of extraosseous Ewing's sarcoma of the kidney in a pediatric patient.

In the pediatric population, to the best of our knowledge, only 2 cases of renal extraosseous Ewing's sarcoma/primitive neuroectodermal tumor (EES/PNET) have been published. We report the initial case of renal EES/PNET occurring in a 10-year-old girl treated by a laparoscopic radical nephrectomy. The regimen used is the first documented use of neoadjuvant chemotherapy prior to laparoscopic radical nephrectomy for PNET. This approach obviated the need for a large incision and a prolonged postsurgical recovery. The minimally invasive nature of the laparoscopic procedure allowed for a rapid convalescence and resumption of her chemotherapy regimen within 14 days of the surgery.

Effect of duration of treatment on treatment outcome for patients with clear-cell sarcoma of the kidney: a report from the National Wilms' Tumor Study Group.

PURPOSE: To evaluate the effect of conventional and standard (ST) versus pulse-intensive (PI) chemotherapy and short-duration versus long-duration chemotherapy on relapse-free survival (RFS) and overall survival rates of patients with clear-cell sarcoma of the kidney (CCSK) entered onto the National Wilms' Tumor Study (NWTS)-4. PATIENTS AND METHODS: The 5-year and 8-year RFS rates were determined for patients with CCSK treated on the NWTS-4. After August 6, 1986, 40 previously untreated children younger than 16 years with CCSK were randomly assigned, after the completion of 6 months of chemotherapy, to discontinue (short) or continue 9 additional months (long) of treatment with chemotherapy regimens that included vincristine and either divided-dose (ST) courses (5 days) or single-dose (PI) treatment with dactinomycin and divided-dose (ST) courses (3 days) or single-dose (PI) treatment with doxorubicin. RESULTS: For patients with CCSK, the 5- and 8-year RFS rates were 65.2% and 60.6%, respectively, for patients randomly assigned to the short chemotherapy and 87.8% (both 5- and 8-year RFS) for patients randomly assigned to the long chemotherapy (P =.08). The overall survival rates for patients at 5 and 8 years were 95.5% and 85.9%, respectively, for the short chemotherapy and 87.5% (both 5- and 8-year overall survival) for the long chemotherapy (P =.99). In NWTS-4, the overall survival rates for patients with CCSK improved from NWTS-3 (83% v 66.9% at 8 years, respectively; P <.01). CONCLUSION: CCSK patients exhibit an improved RFS from a longer course of therapy when using vincristine, doxorubicin, and dactinomycin, but their long-term survival is unchanged compared with patients receiving 6 months of therapy. The overall survival rates for patients with CCSK have improved from NWTS-3.

Long-Term, Disease-Free Survival of a Patient With a Primitive Neuroectodermal/Ewing Sarcoma in the Mobile Spine With Extracompartmental Extension.

STUDY DESIGN: Case report. INTRODUCTION: Long-term survival of a patient with a Ewing sarcoma family of tumors/primitive neuroectodermal tumors of the central spine with pathologic fracture and extradural extension is presented. Literature-based evidence for a survival benefit with modern neoadjuvant chemotherapy and en bloc resection with and without radiotherapy is reviewed. CASE REPORT: More than 10-year clinical and radiographic follow-up is given for a 14-cm-diameter tumor originating from the L4 body with pathologic fracture, unilateral pedicle involvement, and extradural canal extension. Neoadjuvant chemotherapy led to 90% tumor regression and the authors' subsequent en bloc resection attempt. The postoperative chemotherapy was resumed early and postoperative radiotherapy was administered owing to positive microscopic margins. The patient is alive more than 10 years after completing treatment and is without evidence of recurrent disease or secondary malignancy. Late effects of chemotherapy are limited to mild cardiomyopathy controlled with medication. CONCLUSIONS: The Ewing sarcoma family of tumors of the spinal column accounts for approximately 2% of Ewing sarcoma lesions of the skeletal system; local and systemic relapses are higher than for the extremity sites. Survival is enhanced by en bloc surgical resection in cases where clear margins are obtained, but the prognosis of patients with central (spine and pelvis) sites is typically poor. This case adds to the literature with documentation of high quality of life with long-term, disease-free survival after modern chemotherapy surgical intervention and combined radiotherapy, a finding suggested in recent large Surveillance, Epidemiology, and End Results database studies and smaller case series of this uncommon, high-grade spinal tumor. Neoadjuvant chemotherapy with attempted en bloc resection, and postoperative radiotherapy to the resected tumor bed if there are microscopic positive margins, can still lead to long-term, disease-free survival.

Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.

CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.371Y>H altered Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome.

Phase 2 trial of recombinant tumor necrosis factor-alpha 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 Children's Cancer Group trial, dactinomycin (15 microg/kg/d, IV) immediately followed by rTNF (200 microg/m/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.