Edythe A. Albano

Population Pharmacokinetics of Micafungin in Pediatric Patients and Implications for Antifungal Dosing

ABSTRACT 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.

Infectious Complications in Childhood Acute Leukemias

Infectious complications in children with acute leukemias are reviewed as to incidence, predisposing factors, microbiologic etiologies and treatment. Principles of antimicrobiologic therapy are presented for bacterial, fungal, viral, and protozoal infections seen in children with cancer. Prevention of infection is also discussed.

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.

Pattern of recurrence in children with midline posterior fossa malignant neoplasms.

Background. Surveillance imaging of the brain and spinal neuraxis in patients with posterior fossa malignant tumors is commonly performed, with the assumption that early detection of tumor recurrence will improve outcome. However, the benefit of this imaging has not been proven.¶Purpose. To evaluate the usefulness of spinal surveillance imaging in children with nonmetastatic (at diagnosis, M0) posterior fossa ependymoma and medulloblastoma.¶Materials and methods. This retrospective study included 65 children (3 months to 16 years, mean 5.7 years) treated between 1985 and 1997 for ependymoma (22) and medulloblastoma (43). Medical records were reviewed for pathology and treatment data. Serial imaging of the head and spine was reviewed for evidence of tumor recurrence.¶Results. Twenty-four patients (37 %) had tumor recurrence, including 13 with ependymoma and 11 with medulloblastoma. Of the 17/24 recurrent patients initially diagnosed as M0 (6 medulloblastoma and 11 ependymoma), 13 (76 %) had a cranial recurrence only, and 4 (24 %) presented with concomitant cranial and spinal recurrence. No M0 patient presented solely with spinal metastases at recurrence.¶Conclusion. This study suggests that spinal surveillance imaging in patients with posterior fossa ependymoma or medulloblastoma initially staged as M0 may not be useful, as these patients initially recur intracranially. Thus, until an intracranial recurrence is detected, these patients may be spared the time, expense and sedation risk necessary for spinal imaging.

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.

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.

The evolving population of immunocompromised children.

The immunocompromised host was first defined around the host abnormalities and consequent infections that were associated with congenitally acquired deficiencies. Although the impact of the deficiency on the affected child was considerable, the numbers of such children remained small. With the advent of immunosuppressive therapy and cytotoxic regimens for the effective treatment of cancers and autoimmune diseases, an increasingly larger number of children became immunocompromised and thus subject to serious infectious complications. More recently a new population of immunocompromised children have emerged, those infected with the human immunodeficiency virus; over the next several years this group of patients threatens to become the predominant group of “immunocompromised hosts” in pediatrics. Regardless of whether the immunodeficiency is a genetically transmitted immunodeficiency or results from cytotoxic therapy or from infection with human immunodeficiency virus, the incidence and pattern of the infections that occur parallel the targets of the immune system that are adversely affected or destroyed. In some cases, this may represent only a single component of the immune system whereas in others, multiple aspects of the immune matrix have been altered or perturbed. Two goals apply to the management of the immunocompromised child: (1) to identify the basis for the immunodeficiency and to develop methods to restore or replenish it; (2) to define the spectrum of infectious complications that can occur in association with the immunocompromised state and to develop regimens to treat or prevent them, at least until the underlying defects can be dealt with in a more definitive manner. Although there have been enormous insights into the genesis and etiology of many childhood immunodeficiency states, there have been few opportunities to reverse either congenital or acquired immunodeficiency. The recent progress in bone marrow transplantation, the prospect for gene therapy and the availability of immunoregulatory compounds offer hope for future progress. Although these modalities find their place in the clinical armamentarium, effective supportive care remains an important and vital part of the management scheme. Accomplishments in supportive care have included the recognition of the pathogens responsible for infection if different immunodeficiency states and awareness that the spectrum of these pathogens may change over time; the importance of organized empirical antibiotic therapy with broad spectrum agent(s) when the hosts phagocytic defenses are quantitatively or qualitatively depleted (efforts which have been aided by the significant developments in new antimicrobial agents); the recognition that multiple infections can occur in a single host, particularly during prolonged periods of neutropenia and that multiple interventions may be essential; and the fact that certain pathogens can be prevented with prophylactic therapy. It is also apparent that in spite of the best available supportive management, immunosuppressed children can still succumb to infection. Methods to bolster or reconstitute the altered immune defect(s) are therefore particularly appealing. These have included the use of autologous, syngeneic or allogeneic transplantation and, more recently, the use of mismatched transplantation, the replacement of missing components of the immune system (e.g. passive immunization) and the correction of genetic deficiencies (e.g. adenosine deaminase). Currently the use of antiretroviral therapy with azidothymidine is showing promise in overcoming some of the defects associated with human immunodeficiency virus infection in children with acquired immunodeficiency syndrome. In the near future the use of granulocyte- macrophage colony-stimulating factor, interleukins or interferons may also be used, singularly or in combination, to either provide adjunctive therapy to patients already infected or reconstitutive therapy to minimize or prevent infectious complications in immunocompromised children.

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 conditions 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.

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.