Pharmacokinetic and safety profiles of repeated-dose prophylactic micafungin in children and adolescents undergoing hematopoietic stem cell transplantation.

Micafungin is a potent echinocandin antifungal that can be used for both prophylaxis and treatment of Candida infections. This open-label study assessed the pharmacokinetics and safety profile of prophylactic micafungin in children and adolescents (aged 4 mo to 16 y) undergoing hematopoietic stem cell transplantation. Patients received once-daily doses of either 1 or 1.5 mg/kg micafungin, based on their body weight, for 10 to 14 days. In total, 40 patients received micafungin. Area under the plasma micafungin concentration-time curve was highest in patients aged 6 to 11 years in the 1.5 mg/kg treatment group. Peak plasma micafungin concentration displayed no age-related differences, but was higher in the 1.5 mg/kg versus the 1 mg/kg group. Clearance at steady state by weight and volume of distribution by weight were considerably higher in patients aged 4 months to 5 years. Results from this study show that age and body weight affect micafungin pharmacokinetics in pediatric patients undergoing hematopoietic stem cell transplantation.

"Ghosts in my body": Seizure-like presentation of hypocalcemic tetany secondary to hypomagnesemia in a patient receiving cetuximab therapy for metastatic medulloblastoma.

Cetuximab, a monoclonal antibody specific for epidermal growth factor receptor, is increasingly used off-label and in early-phase trials for pediatric malignancies. Here, we report a patient with metastatic medulloblastoma receiving therapy with cyclophosphamide, vinblastine, and cetuximab. During evaluation for possible seizures, he was noted to be severely hypocalcemic, hypokalemic, and hypomagnesemic, a consequence of the blockade of renal epidermal growth factor receptor expression. His symptoms rapidly abated with intravenous electrolyte repletion. This case highlights the clinical heterogeneity of tetany and the importance of careful laboratory screening for known adverse effects of chemotherapy, particularly when newer biological agents are used off-study in combination chemotherapeutic regimens.

Undifferentiated sarcoma of the liver: a single institution experience using a uniform treatment approach.

Undifferentiated (embryonal) sarcoma of the liver is a rare malignant tumor, most commonly seen in children aged 6 to 10 years. Previously believed to carry a poor prognosis, more recent reports indicate that treatment regimens combining surgical resection and adjuvant chemotherapy can yield long-term, disease-free survival. In this study, we review 5 pediatric patients with undifferentiated sarcoma of the liver treated with a uniform approach of resection followed by adjuvant chemotherapy and radiation when indicated. All 5 patients are disease free in their first remission at a median of 53 months.

Local control of metastatic sites with radiation therapy in metastatic Ewing sarcoma and rhabdomyosarcoma.

Approximately 20% of children with Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS) present with metastatic disease at initial diagnosis. Overall, the outcome is poor, with an event-free survival of < 20%. Local control at metastatic sites has not been previously reported. We reviewed control of metastatic sites in children with EWS and RMS that received curative intent radiation therapy to each metastatic site. In 13 children, at a median follow-up of 18 months, a single local failure was seen. Toxicity was minimal. Our data suggest that radiation therapy is effective and tolerable in children with metastatic EWS and RMS.

Metastatic alveolar rhabdomyosarcoma in multiple endocrine neoplasia type 2A.

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, accounts for 3% of childhood malignancies. Multiple Endocrine Neoplasia (MEN) type 2A is an autosomal dominant syndrome associated with near universal development of medullary thyroid carcinoma. We describe a previously unreported association of MEN-2A with metastatic alveolar RMS and review the literature on associated hereditary cancer predisposition syndromes and current therapeutic options. The high penetrance of malignancy in patients with MEN warrants a heightened suspicion for the development of nonendocrine malignancies. The diagnosis of RMS should prompt consideration of screening for familial genetic syndromes in certain patients.

Vincristine induced peripheral neuropathy potentiated by voriconazole in a patient with previously undiagnosed CMT1X.

Peripheral neuropathy is a well-known side effect of vincristine, a micro-tubule inhibitor commonly used to treat malignancies. Severe neurologic adverse events can occur in patients with Charcot-Marie-Tooth disease (CMT) treated with vincristine. Voriconazole is an antifungal agent used increasingly in children with malignancy. Because of its metabolism by hepatic p450 enzymes, voriconazole may inhibit the clearance of many medications, including vincristine. We report a case of vincristine related neuropathy that was exacerbated by voriconazole in a patient with previously undiagnosed, X-linked CMT.

Vascular compromise as a cause of sudden death in a pediatric patient with widely metastatic testicular germ cell tumor.

During hospitalization for evaluation of a large testicular tumor with extensive metastatic disease, this 14-year-old boy collapsed while showering and could not be resuscitated. At autopsy, there was no evidence of thromboembolic phenomenon, a known cause of sudden death in metastatic testicular tumors and other large abdominal tumors. However, marked compression of the inferior vena cava by a large pelvicoabdominal tumor mass and findings suggestive of systemic-portal shunting were consistent with the death due to the impaired venous return via the inferior vena cava.

BCL6 expression correlates with monomorphic histology in children with posttransplantation lymphoproliferative disease.

Posttransplantation lymphoproliferative disease (PTLD) is a complication of organ transplantation with high mortality. Predicting response to first-line therapy, reduction of immune suppression, is difficult because of the heterogeneity of lesions and disease behavior. We sought to determine if BCL6 protein expression in PTLD cells is associated with poor outcome. In a cohort of 25 children with PTLD, 9 of the patients' tumor specimens were positive for BCL6 protein expression. Eight of 13 monomorphic lesions were BCL6 positive, compared with 1 of 11 evaluable polymorphic lesions (P=0.01). Only 1 of the patients with BCL6 expression responded to reduced immune suppression (P=0.19). Recipients of heart transplants who developed PTLD had reduced overall survival rates compared with recipients of other organ transplants who developed PTLD (P=0.04).

Renal medullary carcinoma: ultrastructural studies may benefit diagnosis.

Renal medullary carcinoma is a recently described highly aggressive malignancy that in most instances exhibits a constellation of clinical and light microscopic features sufficiently distinctive to enable a quick and confident diagnosis. Presented are three examples where, because of unusual elements in the clinical presentation, electron microscopic examination proved beneficial in establishing the diagnosis.

Resection of neurogenic tumors in children: is thoracoscopy superior to thoracotomy?

BACKGROUND: Minimally invasive resection of solid tumors is controversial because of concerns of inadequate resection and local recurrence. Thoracoscopy has been used in the diagnosis of mediastinal tumors in children, but its role in resection is unproved. The purpose of this study was to compare thoracoscopic and open approaches to the resection of thoracic neurogenic tumors in children. STUDY DESIGN: The tumor registry of a regional children's hospital was queried to identify patients who underwent resection of neurogenic tumors over a 6-year period. Thoracoscopic and open groups were compared for demographic, operative, oncologic, and outcomes characteristics. RESULTS: Seventeen children underwent resection of mediastinal neurogenic tumors (10 thoracoscopic resections, 7 open resections). Mean age was 4.7 years (range 6 months to 12 years). The thoracoscopic and open groups showed no difference in operative time or blood loss. Tumors in the two groups were comparable in size (5.2+/-2.2 cm versus 5.7+/-2.6 cm), histology, surgical margin, and stage. Hospital stay was shorter after thoracoscopic resection (1.9+/-0.7 days versus 4.1+/-2.5 days, p<0.05). There were no regional recurrences. Distant metastases developed in one patient in each group. Eight of 10 children with malignant tumors remain disease-free at an average of 25 months of followup (range 3 to 80 months). CONCLUSIONS: Thoracoscopic resection of neurogenic tumors achieved similar local control and disease-free survival when compared with open resection in this preliminary series. These results were accompanied by a shorter hospital stay. These findings suggest that thoracoscopic resection of neurogenic tumors in children may offer advantages to open resection and should be studied in the context of a large, cooperative trial.

Primary high-grade B-cell lymphoma of the breast with concurrent IGH-BCL2 and MYC-IGL translocations in an adolescent patient.

BCL2 and MYC are oncogenes often deregulated in lymphomas. Concurrent IGH-BCL2 and MYC translocations result in a highly aggressive behavior of these tumors. Both primary breast lymphoma and lymphoma with concurrent BCL2-IGH and MYC translocations are rare and are primarily seen in adult patients. As a result of limited clinician experience and the condition's rarity, it poses a great challenge to pediatric pathologists and oncologists in terms of making an accurate diagnosis and choosing better treatment regimens. In this article, we report a case of an adolescent patient who presented with high-grade breast lymphoma with concurrent BCL2-IGH and MYC-IGL translocations, and we review the clinical, pathological, and genetic features; management strategies; and outcomes associated with this unusual neoplasm.

Thymoma in children: report of 2 cases and review of the literature.

Thymoma is an uncommon and slow-growing neoplasm. It is derived from thymic epithelial cells and comprises about 20% to 30% of mediastinal masses in adults, but only about 1% in pediatric patients. Patients usually present with mass-associated respiratory symptoms, superior vena cava syndrome, or paraneoplastic syndrome including myasthenia gravis, pure red cell aplasia, or acquired hypogammaglobulinemia, and connective tissue disorders. Due to the limited number of cases, knowledge, and experience with thymoma in pediatric patients, the diagnosis and treatment are very challenging for this age group. In this article, we report 2 cases of thymoma in childhood and provide a comprehensive review and analysis of the reported pediatric cases in the past 30 years (total of 32 cases). We found that patients younger than age 10 years were predominantly male (M:F = 6:1) and had advanced tumor stage more frequent than patients older than age 10 (P = .03). There were also significant associations of male sex with more advanced tumor stage and less favorable outcome (P = .03). These findings suggest that age and sex may be additional potential prognostic contributors in pediatric patients with thymoma. The clinicopathologic features, differential diagnosis, and current therapeutic recommendations of this uncommon tumor in pediatric patients are also addressed.

Phase II study of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia.

PURPOSE: To determine the efficacy and safety of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia (AML). PATIENTS AND METHODS: A phase II, open-label, multicenter study was conducted with single-agent clofarabine in pediatric patients with refractory or relapsed AML. Clofarabine was administered intravenously over 2 hours at the pediatric maximum-tolerated dose (MTD) of 52 mg/m(2) daily for 5 consecutive days. Cycles were repeated every 2 to 6 weeks. Responses determined by an independent response review panel. RESULTS: The 42 patients treated on the study had a median age of 13 years (range, 2 to 22 years) and had received a median number of two (range, one to five) prior regimens. The response rate was 26% and included one complete response without platelet recovery and 10 partial responses. The median duration of response was 20 weeks (range, 2 to >or= 156 weeks). Six of 28 patients who were refractory to the immediately preceding therapy achieved response. Thirteen patients (31%), including seven responders, proceeded to hematopoietic stem-cell transplantation (HSCT) after treatment with clofarabine and survived between 24 to >or= 160 weeks. Five patients (12%) remain alive post-transplantation at >or= 63, >or= 71, >or= 86, >or= 114, and >or= 130 weeks. The most common grade 3 or greater adverse events without regard to causality were febrile neutropenia, catheter-related infection, epistaxis, hypotension, nausea, and fever. Transient elevation of liver enzymes and hypokalemia occurred frequently. Five patients died within 30 days of clofarabine administration secondary to progressive disease, and another five died as a result of an adverse event. CONCLUSION: Clofarabine is active in pediatric patients with multiply relapsed or refractory AML. Responses allowed several refractory patients to proceed to HSCT. The toxicity profile was expected in this patient population.

Successful intermittent prophylaxis with trimethoprim/sulfamethoxazole 2 days per week for Pneumocystis carinii (jiroveci) pneumonia in pediatric oncology patients.

OBJECTIVE: This study was conducted to determine the efficacy of dosing trimethoprim/sulfamethoxazole on 2 consecutive days per week for the prevention of Pneumocystis carinii (jiroveci) pneumonia in a pediatric leukemia and lymphoma population and to determine whether trimethoprim/sulfamethoxazole contributes to neutropenia during maintenance therapy. METHODS: Charts were reviewed for all pediatric patients with leukemia and lymphoma diagnosed between January 1, 1993, and December 31, 2002. Data were collected through April 1, 2004. RESULTS: A total of 575 charts were reviewed; 529 patients were included in the analysis. A total of 482 (345 leukemia, 137 lymphoma) patients were evaluated on trimethoprim/sulfamethoxazole dosed 2 consecutive days per week for 268074 patient-days. No breakthrough cases were documented in compliant patients; 2 noncompliant patients developed P. carinii pneumonia. A total of 238 patients who were on trimethoprim/sulfamethoxazole prophylaxis and 13 patients who were receiving an alternative medication prophylaxis were evaluated for neutropenia during maintenance therapy. The median number of maintenance days on trimethoprim/sulfamethoxazole was 605.5 days and on alternative drug was 617 days. The median number of neutropenic maintenance days on trimethoprim/sulfamethoxazole was 15.5 days and on the alternative drug was 16 days. The median proportion of neutropenic days per patient was 0.029 on trimethoprim/sulfamethoxazole and 0.022 on the alternative drug. CONCLUSIONS: Intermittent dosing of trimethoprim/sulfamethoxazole on 2 consecutive days per week is an effective alternative prophylactic regimen for P. carinii pneumonia in pediatric patients with leukemia and lymphoma. This analysis does not support a difference in neutropenia during maintenance therapy between patients who are treated with trimethoprim/sulfamethoxazole versus an alternative drug.

Posttransplant Hodgkin lymphoma preceded by polymorphic posttransplant lymphoproliferative disorder: report of a pediatric case and review of the literature.

Epstein-Barr virus-mediated posttransplant lymphoproliferative disorder (PTLD) is a well-recognized complication of immunosuppression in transplant patients and has broad clinical manifestations and pathologic features ranging from reactive lymphoid proliferation to malignant lymphoma. The category of Hodgkin lymphoma and Hodgkin lymphomalike PTLD is an uncommon variant of PTLD. Development of Hodgkin lymphoma subsequent to other subtypes of PTLD in the same patient is even more unusual, especially in pediatric patients. In this report, we describe a pediatric case of Epstein-Barr virus-associated posttransplant Hodgkin lymphoma developing several years after the patient was diagnosed with polymorphic PTLD and review the literature of the previously reported cases in children to further help characterize the clinical features, histopathologic appearances, biology, and treatment strategies of this uncommon entity.

Population pharmacokinetics of micafungin in pediatric patients and implications for antifungal dosing.

The echinocandins potentially have an important role in treatment of infections caused by Candida spp. and Aspergillus spp. in immunocompromised children. However, there are no population pharmacokinetic models of the echinocandins for pediatric patients. The safety and descriptive pharmacokinetics of micafungin in children were recently reported. However, a population pharmacokinetic model in children is needed in order to accurately determine the dosage of micafungin that produces an equivalent magnitude of drug exposure to that observed in adults. In order to explore the effect of weight on micafungin pharmacokinetics, a standard two-compartment pharmacokinetic model, a linear model, and an allometric power model were developed. For all three models, the fit to the data was excellent, with comparable measures of precision and bias. However, the superior log-likelihood value of the allometric power model suggested that it best reflected the data and was therefore chosen for a more detailed analysis of the magnitude and pattern of drug exposure which develop following the administration of micafungin. The allometric power model suggested that clearance in smaller children is higher than that predicted on the basis of weight alone. Consequently, a degree of dosage increase is required in smaller children to ensure comparable levels of drug exposure to those observed in larger children and adults. The allometric power model developed in this study enables identification of pediatric dosage regimens of micafungin which, based upon Monte Carlo simulations, result in equivalent drug exposures to those observed in adults, for which antifungal efficacy has been established.

Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia.

PURPOSE: To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: In a phase II, open-label, multicenter study, 61 pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m2 intravenously over 2 hours daily for 5 days, every 2 to 6 weeks. The median age was 12 years (range, 1 to 20 years), and the median number of prior regimens was three (range, two to six regimens). RESULTS: The response rate was 30%, consisting of seven complete remissions (CR), five CRs without platelet recovery (CRp), and six partial remissions. Remissions were durable enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT) after clofarabine. Median CR duration in patients who did not receive HSCT was 6 weeks, with four patients maintaining CR or CRp for 8 weeks or more (8+, 12, 37+, and 48 weeks) on clofarabine therapy alone. The most common adverse events of grade > or = 3 were febrile neutropenia, anorexia, hypotension, and nausea. CONCLUSION: Clofarabine is active as a single agent in pediatric patients with multiple relapsed or refractory ALL. The toxicity profile is as expected in this heavily pretreated patient population. Studies exploring rational combinations of clofarabine with other agents are ongoing in an effort to maximize clinical benefit.

Primary ocular adnexal lymphoma in pediatric patients: report of two cases and review of the literature.

Primary ocular adnexal lymphoma (POAL) is a rare extranodal lymphoma. The mucosa-associated lymphoid tissue (MALT) subtype predominates and primarily occurs after the sixth decade of life. Most studies of ocular adnexal lymphoma are from the adult population. The data and experience in pediatric patients with POAL are limited to a few cases reported in the literature. Here we describe two pediatric cases of POAL and review the literature to further help characterize the clinical features and histopathologic appearance of this uncommon lymphoma.