Pathologically proven cavernous angiomas of the brain following radiation therapy for pediatric brain tumors

Lesions consistent with cavernous angiomas (CAs) of the brain are sometimes seen on MRI scans of the brains of patients who received radiation therapy for brain tumors as children. The lesions appear years later within brain tissue that was included in radiation fields. It is unclear whether these MRI-detected lesions are true CAs or a pathological variant. This study reports the clinical, radiographical, and pathological findings in 3 cases of radiation-induced CAs of the brain. From 1995 to 1997, 3 patients previously treated with radiation therapy (45-55 Gy) for pediatric brain tumors (medulloblastoma, ependymoma, and a presumed midbrain astrocytoma) underwent resections of symptomatic and enlarging lesions that were consistent with a CA of the brain. All of the lesions occurred within fields of prior irradiation. None of the patients had received chemotherapy as part of their cancer treatment. CA-presenting symptoms included seizures, cranial nerve deficits, and headaches. The lesions appeared 7-19 years after radiation therapy and slowly enlarged on subsequent imaging studies. MRI scans of the lesions revealed characteristics typical of CA. The lesions became symptomatic 1-5 years after they were initially noted. Surgical resection was performed 1-2 years after symptoms began. The age at resection ranged from 15 to 23 years (10-21 years after radiation therapy). Pathological analysis of the three lesions showed typical CA characteristics. Some CAs may be caused by radiation therapy for pediatric brain tumors. They are radiologically and pathologically similar to sporadically occurring CAs of the brain and may enlarge over time and become symptomatic. CAs can be safely resected using standard microsurgical techniques.     

High dose methotrexate therapy of solid tumors: observations relating to clinical toxicity

In clinical studies performed during 111 infusions of high dose methotrexate (MTX) we have evolved a clinical and laboratory protocol which permits such therapy without prohibitive risk to the patient. The plasma MTX data obtained indicate that pharmacokinetic disposition is dose related during these infusions and that such data are useful in identifying patients at risk from serious toxicity.     

Short- and long-term complications of radiation therapy for pediatric brain tumors.

Brain tumors are the second most common malignancy of childhood after acute lymphocytic leukemia. Improvements in therapy have led to increased survival. It is estimated that by the year 2000 there will be approximately 200,000 survivors of childhood cancer. A proportion of these will have survived a central nervous system malignancy. As more children survive, complications of treatment are increasingly recognized. This paper reviews the spectrum of radiation-induced complications, both short- and long-term. Their frequency and characteristics will be reviewed as well as suggestions made to decrease their incidence.     

Risk of venous thromboembolism in pediatric patients with brain tumors

BACKGROUND: Venous thromboembolism (VTE) is a common event in adults with malignant brain tumors approaching 24% throughout the course of the disease. The high morbidity and mortality of this complication yielded several protocols for prevention of the disease in adults undergoing neurosurgery for brain tumors and possible primary prevention afterwards. We investigated the incidence and complications of VTE in pediatric neuro-oncology patients. PROCEDURE: We analyzed, retrospectively, the files of all consecutive patients under the age of 18 years who were hospitalized for the treatment of brain tumors between the years 1990 and 2003 in two leading, closely related, Israeli neuro-oncology centers. RESULTS: A total of 462 children were analyzed. Three hundred eighty-four patients underwent surgery and 78 were treated medically. Only three (0.64%) of the patients developed clinical episodes of VTE that were treated conservatively. Two of these patients developed intracranial bleeding while on secondary prevention for the disease. CONCLUSIONS: Although this study has considerable limitations in terms of retrospective design, heterogeneous group of patients and diagnoses, the changing awareness for thrombosis over the last 14 years and the inclusion of symptomatic VTE events only, our surprising data suggest that, as opposed to adults, the risk of clinically significant VTE in children with brain tumors may be exceedingly low. These findings set the stage for future forthcoming evaluations in view of the prospective studies that were done in adults and the possible significant implications for the prevention and possible etiologies of the disease.     

High dose methotrexate therapy of solid tumors: observations relating to clinical toxicity.

In clinical studies performed during 111 infusions of high dose methotrexate (MTX) we have evolved a clinical and laboratory protocol which permits such therapy without prohibitive risk to the patient. The plasma MTX data obtained indicate that pharmacokinetic disposition is dose related during these infusions and that such data are useful in identifying patients at risk from serious toxicity.     

Expression of the Neural RNA-binding protein Musashi1 in pediatric brain tumors

Musashi1 (MSI1) is an evolutionarily conserved RNA-binding protein, selectively expressed in neural stem cells (NSCs) and considered a versatile marker for normal NSCs and tumor cell diagnosis. Here, we examined MSI1 expression in primary pediatric brain tumors, medulloblastomas and ependymomas, by double immunostaining with lineage phenotypic markers (Lin). These tumors highly express MSI1 and are heterogeneous, containing both MSI1+/Lin- tumor cells in regions of relatively high cellularity and proliferative activity and MSI1+/Lin+ tumor cells in regions of lower cellularity. These findings suggest that MSI1 may be a useful marker for characterizing tumor heterogeneity and for examining in situ the analogy between normal NSCs and MSI1+ cells in pediatric brain tumors. This test could be easily applied to routine clinical diagnosis.     

New technologies in radiation therapy for pediatric brain tumors: the rationale for proton radiation therapy

BACKGROUND: Pediatric brain tumors are frequently treated with radiation therapy and often cured. The long-term side effects of treatment with high-energy X-rays (photons) can be substantial. Proton radiation therapy may limit these late effects. PROCEDURE: The physical difference between photon and proton irradiation is compared. The clinical benefits of the superior physical properties of proton beam radiation therapy are explained for children with brain tumors. RESULTS: At biologically equivalent doses, proton radiation therapy offers tumor control similar to photon radiation therapy. The superior physical properties of proton beams make this mode of radiation therapy less likely to cause late effects. CONCLUSIONS: For many children with brain tumors, proton beam radiation therapy may limit the late effects of radiation therapy and therefore offer an advantage over techniques using photons.     

Efficacy of the "8 drugs in a day" protocol in brain tumors in children

In the present study, the "8 drugs in 1 day" regimen was tested in 54 children: 27 relapses (brain and/or spinal and/or meningeal sites), 10 refractory progressive diseases, 13 macroscopic residual tumors after partial excision and/or radiotherapy; in 4 cases, this regimen was prescribed as first line treatment. The response rate (complete and partial remission) was 46%. Results were very encouraging in medalloblastomas with a response rate of 76.5% whereas in brain stem gliomas it was only 23% and 33% in other astrocytomas. Immediate toxicity, mainly hematological, was very moderate. These results justify to propose this regimen as adjuvant chemotherapy, mostly in medulloblastomas and to plan other similar trials, using the most active drugs which seem presently to be alkylating and platinum-derived agents.     

Delay in the diagnosis of pediatric brain tumors

The interval from the onset of symptoms to the diagnosis in 79 children with primary brain tumors was compared with that in 45 children with Wilms' tumor and 123 children with acute leukemia. The patients with brain tumors had a significant delay from symptom onset to diagnosis. Only 38% of primary brain tumors were diagnosed within the first month after the onset of symptoms. In contrast, 84% of Wilms' tumors and 80% of cases of acute leukemia were diagnosed within one month of the onset of symptoms. Early detection of brain tumors is important as it may have a significant bearing on clinical outcome.     

Differential responsiveness among "high risk" pediatric brain tumors in a pilot study of dose-intensive induction chemotherapy

BACKGROUND: These factors have been predictive for progressive disease on therapy (PDOT) among pediatric brain tumors: >1.5 cm(2) unresectable tumor, glioblastoma, supratentorial primitive neuroectodermal tumor, and metastatic medulloblastoma (MBL). This pilot study sought to correlate cytoreductive response with progression free survival. PROCEDURES: Four courses of cisplatinum, cyclophosphamide, etoposide, and vincristine preceded hyperfractionated radiotherapy (RT). Maintenance chemotherapy consisted of eight cycles of carboplatin, etoposide, and vincristine. Biopsy specimens were immunohistochemically studied for labeling index, hypoxia, and multidrug resistance proteins. RESULTS: Twenty newly diagnosed patients [nine primitive neuroectodermal tumors/MBL, one choroid plexus carcinoma, eight malignant gliomas, and two anaplastic ependymomas] were treated. Ten patients, who required neuraxis irradiation, constituted the "PNET" group. These demonstrated five complete and one partial response (PR), with an estimated median progression free survival of 44 months and median survival in excess of 53 months. Patients treated with involved field irradiation were designated the "Glioma" group. Induction chemotherapy produced partial and minor responses (MRs) among 5/10. Their estimated median progression free survival was 6.9 months (P = 0.035 relative to the PNET) with a median survival of 10.7 months (P = 0.04). Age, labeling index, the presence of hypoxia, and Pgp/MDR1 expression failed to discriminate between the two groups. CONCLUSIONS: This induction regimen produced a cytoreductive response in 6/10 and achieved a significant improvement in progression free survival among 7/10 in the PNET group. Unfortunately, responses among Glioma patients did not translate into durable control. Expression of the biologic factors was similar between both groups and did not correlate with diagnosis or response.     

Current concepts in radiologic assessment of pediatric brain tumors during treatment,part 1

Pediatric Radiology - Pediatric brain tumors differ from those in adults by location, phenotype and genotype. In addition, they show dissimilar imaging characteristics before and after treatment....     

Pharmacokinetics of enfuvirtide in pediatric human immunodeficiency virus 1-infected patients receiving combination therapy

BACKGROUND: Enfuvirtide is the first of a new class of antiretroviral agents, the fusion inhibitors. OBJECTIVES: The primary objective of this analysis was to evaluate the pharmacokinetics of 2.0 mg/kg enfuvirtide in human immunodeficiency virus 1 (HIV-1)-infected children and adolescents when administered in combination with at least 3 other antiretrovirals. METHODS: Twenty-five HIV-1-infected pediatric patients (5-16 years of age) enrolled in an ongoing phase I/II study were included in this analysis. Patients received enfuvirtide 2.0 mg/kg sc twice daily (bid) for at least 7 days. Blood samples were collected on day 7, and plasma concentrations of enfuvirtide and its metabolite were measured by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetics measures [Cmax, tmax, Ctrough, and area under the concentration time curve time 0 to 12 hours (AUC12 hours)] were calculated from plasma concentration-time data by standard noncompartmental methods. RESULTS: There was no significant difference between children and adolescents for enfuvirtide Cmax (6.43 versus 5.88 microg/mL), Ctrough (2.87 versus 2.98 microg/mL) and AUC12 hours (56.1 versus 52.7 hours . microg/mL). Similarly no significant differences were found when the pharmacokinetic measures were compared based on sexual maturity stages. A post hoc regression analysis based on AUC12 hours showed that body weight-adjusted dosing of enfuvirtide provides drug exposure that is independent of age group, body weight and body surface area. CONCLUSIONS: Body weight-adjusted dosing of enfuvirtide, at a dose of 2.0 mg/kg sc bid, in HIV-1-infected pediatric patients at least 5 years of age, provides drug exposure comparable with that previously observed in HIV-1-infected adults after 90 mg sc bid dosing. Drug exposure in children and adolescents is independent of age group, body weight, body surface area and sexual maturity stage.     

Characteristics of growth hormone therapy for pediatric patients with brain tumors in the National Cooperative Growth Study (NCGS) and from a survey of pediatric endocrinologists

Pediatric patients with brain tumors may have significant short stature secondary to growth hormone deficiency (GHD). This occurs as a result of impaired hypothalamic function due to tumor location, radiation therapy, surgery, or chemotherapy. The use of GH replacement therapy in this patient population is variable and somewhat unpredictable. We analyzed patient data from the National Co-operative Growth Study (NCGS) database and a survey completed by 19 members of the Pediatric Endocrine Alliance for Neuro Oncology Patients (PEANOP) to identify patterns of GH use in pediatric patients following treatment for brain tumors. From the NCGS database, we present demographic, dosing, and safety data. The PEANOP survey was examined to determine the percentage of patients receiving GH and the likelihood of treating these patients with GH following tumor treatment. The time to initiating GH replacement therapy was evaluated in 14 tumor types, as well as the contributing impact of the extent of tumor resection.     

Tacrolimus dosage requirements after initiation of azole antifungal therapy in pediatric thoracic organ transplantation

Azole antifungals inhibit the metabolism of tacrolimus mediated by CYP3A4. Upon initiation of azole therapy, the required dose reduction of tacrolimus is unknown. We reviewed our experience with azole antifungals in our pediatric thoracic transplant population receiving tacrolimus. Tacrolimus levels and dosage requirements were compared before and during azole therapy. Thirty-one patients received both tacrolimus and an azole antifungal (fluconazole = 9, itraconazole = 22). The tacrolimus dose was empirically reduced by approximately one-third when azole therapy was initiated. Mean tacrolimus dose requirements decreased by 68% within the first month of therapy (pre-azole: 0.27 +/- 0.14 mg/kg/day; 30 day post-azole: 0.087 +/- 0.069 mg/kg/day; p < 0.001). Despite a mean decrease in tacrolimus dose from baseline of 33, 42, and 55% on day 1, 2, and 4 of azole therapy, respectively, there was still an unintended 38% increase in tacrolimus levels during the first month of azole therapy. A calculated dose-reduction protocol of 50% on day of azole initiation, 70% on day 3, and 75% on day 14 should result in minimal mean changes in the tacrolimus levels. There was no difference in tacrolimus dose reduction between fluconazole and itraconazole groups. Azole antifungals markedly decrease tacrolimus requirements within the first few days of therapy. An initial reduction in tacrolimus dose by one-third is insufficient, and dose reduction of at least 50% upon azole initiation seems warranted. Once azole antifungal therapy is initiated, frequent therapeutic drug monitoring is required.