Carol S. Bruggers

Phase II Study of Carboplatin in Children With Progressive Low-Grade Gliomas

PURPOSE To assess the rate of tumor response and activity of carboplatin in stabilizing the growth of progressive low-grade gliomas. PATIENTS AND METHODS Eligible patients received carboplatin 560 mg/m(2) intravenously every 4 weeks for 1 year after maximum tumor response or until disease progression or unacceptable toxicity. RESULTS Between October 1993 and October 2000, 81 children (median age, 79 months; range, 6 to 204) were enrolled onto this study. Patients received a median of 11 cycles of carboplatin (range, one to 29). Median follow-up from the time of enrollment was 55 months (range, 10 to 93). The overall objective response (complete response [CR] + partial response [PR] + minor response [MR]) and disease stabilization (CR + PR + stable disease + MR) rates to carboplatin treatment were 28% (95% confidence interval [CI], 18% to 38%) and 85% (95% CI, 74% to 93%), respectively. Eleven and 14 patients suffered progressive disease on study and after stopping therapy, respectively. Toxicity was predominantly myelosuppression and included grade 3/4 neutropenia in 56 patients and grade 3/4 thrombocytopenia in 40 patients. The 3-year failure-free survival (FFS) and overall survival (OS) for all patients were 64% (95% CI, 54% to 76%) and 84% (95% CI, 76% to 93%), respectively. Patients with diencephalic tumors had inferior FFS and OS compared with those with tumor at other sites (38% v 74% for FFS, P =.011; 54% v 91% for OS, P =.004). Neurofibromatosis type 1 patients with progressive low-grade glioma had a significantly better OS (95% v 80%; P =.052). CONCLUSION Carboplatin, in the schedule used in this study, produced disease stabilization or improvement in a majority of children with progressive low-grade glioma, with manageable toxicity. Improved treatment strategies are particularly required for patients with diencephalic tumors.

Preradiation Chemotherapy in Primary High-Risk Brainstem Tumors: Phase II Study CCG-9941 of the Children’s Cancer Group

PURPOSE This Childrens Cancer Group group-wide phase II trial evaluated the efficacy and toxicity of two chemotherapy arms administered before hyperfractionated external-beam radiotherapy (HFEBRT). PATIENTS AND METHODS Thirty-two patients with newly diagnosed brainstem gliomas were randomly assigned to regimen A and 31 to regimen B. Regimen A comprised three courses of carboplatin, etoposide, and vincristine; regimen B comprised cisplatin, etoposide, cyclophosphamide, and vincristine. Both arms included granulocyte colony-stimulating factor. Patients were evaluated by magnetic resonance imaging after induction chemotherapy and HFEBRT at a dose of 72 Gy. RESULTS Ten percent +/- 5% of regimen A patients objectively responded to chemotherapy. For combined induction and radiotherapy, 27% +/- 9% of patients improved. The neuroradiographic response rate for regimen B was 19% +/- 8% for chemotherapy and 23% +/- 9% after HFEBRT. Response rates were not statistically significant between regimens after induction or chemotherapy/HFEBRT. Event-free survival was 17% +/- 5% (estimate +/- SE) at 1 year and 6% +/- 3% at 2 years. Survival was significantly longer among patients who responded to chemotherapy (P <.05). Among patients who received regimen A induction, grades 3 and 4 leukopenia were observed in 50% to 65%, with one toxicity-related death. For regimen B, severe leukopenia occurred in 86% to 100%, with febrile neutropenia in 48% to 60% per course. CONCLUSION Neither chemotherapy regimen meaningfully improved response rate, event-free survival, or overall survival relative to previous series of patients with brainstem gliomas who received radiotherapy with or without chemotherapy.

Acquired von Willebrand disease in twins with autoimmune hypothyroidism: Response to desmopressin and L-thyroxine therapy

Because of menorrhagia, a 13-year-old girl was found to have type I von Willebrand disease and then chronic autoimmune thyroiditis with hypothyroidism. All clinical and laboratory evidence of von Willebrand disease resolved transiently after infusion of desmopressin, and permanently with L-thyroxine therapy. We recommend investigation for hypothyroidism in patients with newly diagnosed acquired von Willebrand disease.

Leptomeningeal Dissemination of Optic Pathway Gliomas in Three Children

We treated three children with optic pathway gliomas who had progressive disease associated with metastatic spread to the leptomeninges. One patient had radiographic resolution of leptomeningeal disease after treatment with intravenous carmustine and oral mercaptopurine but died of progressive pulmonary fibrosis. The second patient was treated with intravenous thiotepa, and the leptomeningeal disease remained stable. The third patient was treated with intravenous vincristine sulfate, cyclophosphamide, cisplatin, and etoposide and had a significant size reduction of the leptomeningeal lesion. Although leptomeningeal dissemination is a seemingly rare event, it is important that all children with optic pathway gliomas be considered for this possibility, particularly after the onset of new, atypical neurologic symptoms.

Spindle cell sarcoma of the kidney with ganglionic elements (malignant ectomesenchymoma) associated with chromosomal abnormalities and a review of the literature.

PURPOSE Malignant ectomesenchymomas are tumors that exhibit both mesenchymal and neuroectodermal elements (1). We report a case thought to represent a malignant ectomesenchymoma arising in the kidney with cytogenetic abnormalities that may provide insight into the biologic basis for this unusual tumor. METHODS We discuss the clinical features, histopathologic findings, cytogenetics, treatment, and outcome of a child with a malignant ectomesenchymoma arising in the kidney. RESULTS An asymptomatic 16-month-old boy had a large abdominal mass. The resected tumor contained sheets of spindled cells that expressed mesenchymal markers and cartilaginous differentiation, interspersed with clusters of ganglion cells that expressed neural markers. No blastemal or epithelial elements were demonstrated. Cytogenetic analysis of the tumor revealed a hyperdiploid count with multiple numerical and structural abnormalities, including a translocation between chromosomes 12 and 15. In addition to the surgical resection, the patient was successfully treated with adjuvant chemotherapy and local radiation therapy. CONCLUSION This is the first report of which we are aware of an ectomesenchymoma arising within the kidney. A subset of malignant ectomesenchymomas may be related to the Ewings family of tumors (EFTs) (2), but this case did not exhibit cytogenetic features consistent with EFT. Thus, the malignant ectomesenchymoma phenotype probably represents a heterogeneous group of tumors with different genotypes and origins. Cytogenetic analysis may be instrumental in determining the appropriate therapeutic approach when faced with such a neoplasm. The outcomes of 12 other children with ectomesenchymoma are reviewed.

Lymphoblastic lymphoma and excessive toxicity from chemotherapy: an unusual presentation for Fanconi anemia.

A 30-month-old boy presented with fever, lymphadenopathy, hepatosplenomegaly, leukocytosis and thrombocytopenia. A lymph node biopsy revealed the diagnosis of T-cell lymphoblastic lymphoma. The boy exhibited an extreme sensitivity to cytotoxic chemotherapy, which led to the diagnosis of Fanconi anemia (FA). A chromosomal fragility test showed excessive breakage and radial forms consistent with the diagnosis of FA. Refractory disease exhibiting an unusual translocation, t(11;14)(p1 3;q32), developed in the patient. Despite therapeutic interventions, the boy died of rapidly progressive disease. Lymphoid malignancies are very uncommon in patients with FA, but as this case demonstrates, they can be the first manifestation of this disorder. Patients with a hematologic malignancy who also manifest physical abnormalities associated with FA should be evaluated for FA before the initiation of chemotherapy. This case further shows the value in looking for underlying chromosome fragility syndromes in normal-appearing children who experience excessive toxicity when treated with standard chemotherapy.

Extracranial relapse of an anaplastic oligodendroglioma in an adolescent: case report and review of the literature.

Oligodendroglioma is an uncommon childhood tumor and is more chemosensitive than other malignant glial neoplasms. Treatment involves gross total resection, and if anaplastic, radiation and chemotherapy. Distinct genetic alterations are associated with improved prognosis. We report a child with a low-grade oligodendroglioma that recurred as a high-grade oligodendroglioma and ultimately as extraneural systemic relapse. It was initially responsive to temozolomide, cyclophosphamide, etoposide, and carboplatin, perhaps predicted by combined loss of heterozygosity at 1p and 19q. This chemotherapy may be promising in treating malignant oligodendroglioma. However, he succumbed to progressive systemic disease. Positron emission spectroscopy scan was useful in sequentially assessing his disease.

Successful therapy in a child with a congenital peripheral medulloepithelioma and disruption of hindquarter development.

PURPOSE Medulloepithelioma is an embryonal multipotential neuroepithelial tumor with a striking potential for divergent differentiation. It is usually intraocular or intracerebral and associated with a good prognosis only if completely surgically excised. Data regarding therapy in children with incompletely resected tumors are limited. PATIENT AND METHODS A girl was born with a large, peripheral, congenital medulloepithelioma associated with complete absence of the left hindquarter and anus. Plain film, ultrasonography, and magnetic resonance imaging demonstrated complete absence of the left kidney and hemipelvis. A subtotal resection of the mass and reconstruction of the tumor-related anatomical defects were performed. RESULTS Pathologic examination showed neuroglia and pseudostratified neuroectoderm diagnostic of medulloepithelioma. She was treated with multiagent chemotherapy including vincristine, cisplatin, cyclophosphamide, carboplatin, and etoposide. She is now 50 months of age and developing normally without recurrent disease. CONCLUSIONS A child with an incompletely resected congenital peripheral medulloepithelioma who has experienced long-term disease-free survival after treatment with chemotherapy is described. This report supports a role for adjuvant chemotherapy in the treatment of children with peripheral medulloepithelioma.

Successful treatment of acquired factor VIII deficiency in a child using activated factor VII concentrates: case report and review of the literature.

Acquired factor VIII deficiency is a rare life-threatening disorder that should be suspected in individuals without a prior bleeding history who present with mucous membrane, muscle, and/or urinary tract bleeding. The authors describe a 5-year-old girl with epistaxis, intramuscular bleeding, and forearm compartment syndrome requiring emergent fasciotomy. Coagulation studies showed a factor VIII level of less than 1%. The prolonged activated partial thromboplastin time corrected immediately when mixed with normal plasma at a 1:1 ratio but became prolonged again following incubation at 37 degrees C. She was treated successfully with serial administrations of activated factor VII concentrates and immunosuppression with corticosteroids. Activated factor VII concentrates should be considered as an option for patients of all ages with acquired factor VIII deficiency.

A phase 2 feasibility study of sequential, dose intensive chemotherapy to treat progressive low-grade gliomas in children.

Background Low-grade gliomas (LGGs) comprise nearly 35% of pediatric brain tumors and often occur in young children. Many cannot be resected and radiation therapy can be associated with excessive toxicity in children. Centrally located tumors in young children, and those that progress after radiation remain therapeutic challenges. This phase 2 feasibility trial investigated dose intense, sequential chemotherapy in children with LGG. Procedure Ten patients less than 21 years of age with progressive LGGs were enrolled. Courses 1 and 4 consisted of carboplatin and etoposide; courses 2 and 5 consisted of cyclophosphamide and vincristine; courses 3 and 6 consisted of lomustine, procarbazine, and vincristine. Dose adjustments were made to maximize dose intensity but minimize toxicity. Results Fifty-five of 60 planned chemotherapy courses were administered in 10 patients. One patient with stable disease after 3 courses had complete surgical resection. Two patients taking anticonvulsants experienced prolonged myelosuppression, necessitating removal from study after 5 chemotherapy courses. During 5 of 6 chemotherapy courses, more than 80% of the planned chemotherapy dose intensity was delivered. Two patients had complete responses, 2 patients had partial responses, 3 patients had minor responses, and 3 patients had disease stabilization. No children had life threatening infection or hemorrhage. No patient experienced progressive disease during therapy. Conclusions Administration of sequential, dose intense chemotherapy was feasible and clinically tolerated. Concurrent anticonvulsant therapy limited dose intensity in 2 patients. Although efficacy appeared consistent with published larger series, small patient number in this study precludes definitive conclusions.