Background. Intrathecal chemotherapy, radiation therapy, and systemic chemotherapy are used for both prophylaxis and treatment of central nervous system (CNS) disease in hematologic malignancies. Twenty‐three cases of myelopathy that occurred in patients who received intensive CNS‐directed therapy were evaluated to identify the determinants of this severe CNS toxicity. Methods. Nine cases treated by the authors and 14 collected from the literature are discussed. Twelve had Burkitt's leukemia/lymphoma. Patient ages ranged from 3 to 30 years (median, 15 years). The dose intensity of CNS‐directed therapies, including intrathecal cytosine arabinoside (ara‐C), intrathecal methotrexate (MTX), systemic high dose (HD) MTX, systemic HD ara‐C, systemic thiotepa, and CNS radiation, was evaluated by the determination of single drug doses and cumulative total drug or irradiation doses over elapsed treatment durations. Results. Central nervous system treatment was prophylactic in 10 cases; active CNS disease was being treated in 13 cases. One patient received only intrathecal ara‐C before toxicity occurred; others received intrathecal ara‐C and varying combinations of intrathecal MTX, HD ara‐C, HD MTX, CNS radiation, and systemic thiotepa. Eight patients died of toxicity, of whom 6 had autopsy‐proven cord necrosis; 3 were ventilator‐dependent; 10 had persistent paraplegia or paraparesis; and 2 recovered completely. Conclusion. Both highly intensive, short CNS treatment sequences and lower intensity, long term cumulative treatments may result in this rare but severe myelopathy. The cause is multifactorial, with systemic chemotherapy, intrathecal chemotherapy, and radiation therapy contributing to toxicity. Multiple intrathecal ara‐C and/or MTX doses given at frequent (daily) intervals should be avoided. Concurrent intrathecal ara‐C and systemic HD ara‐C also appear to be especially toxic. Intrathecal hydrocortisone given with intrathecal ara‐C does not protect against myelopathy. Multiple, frequently spaced courses of CNS‐directed therapies must be avoided, especially in patients who have received prior CNS radiation.
The use of high-dose therapy (HDT) and autologous hematopoietic cell transplantation (AHCT) for children and adolescents with primary refractory and relapsed Hodgkin's disease is increasing. The purpose of this retrospective analysis was to: (1) evaluate the outcome of HDT and AHCT in pediatric patients with Hodgkin's disease, and (2) identify factors that predispose patients to the development of transplantation-related complications. We describe the experiences of 34 pediatric patients from a single institution with primary refractory or relapsed Hodgkin's disease. HDT regimens consisted of cyclophosphamide and etoposide combined with either carmustine, chloroethylcyclohexylnitrosurea, or fractionated total body irradiation. Kaplan-Meier survival predicts that 67% (95% confidence interval [CI] 47%-87%) of patients will be alive and disease-free at 5 years. Nine patients had disease recurrence, of whom 5 relapsed after 1 year (1.5-6.3 years). Five patients succumbed to treatment-related toxicities, of whom 4 died of pulmonary failure. Fifteen patients (44%) developed post-AHCT idiopathic diffuse lung injury syndrome: acute alveolitis (n = 2); diffuse alveolar hemorrhage (n = 2); acute respiratory distress syndrome (n = 2); delayed interstitial pneumonitis (n = 8); and bronchiolitis obliterans (n = 1). The following factors did not predict for the development of a diffuse lung injury syndrome in univariate analysis: prior treatment with bleomycin, pre-HDT pulmonary function tests, and prior thoracic irradiation. Of the patients in our cohort, 44% had a history of atopy (allergic rhinitis and/or asthma). Multivariate logistic analysis revealed that a preexisting history of atopy was highly predictive of idiopathic pulmonary complications (P = .0001, odds ratio = 21, CI 3.6-125). Our experience shows that HDT followed by AHCT results in durable remissions in two thirds of pediatric patients with refractory and relapsed Hodgkin's disease, and a history of atopy is associated with post-AHCT pulmonary complications.
Catecholamines, acting via the alpha-1 adrenergic receptor, have been demonstrated to influence adult rat hepatocyte DNA synthesis in primary culture and in vivo during liver regeneration following partial hepatectomy (PHX). Earlier investigations have suggested that the alpha-1 effect on DNA synthesis is significant only during the first day following PHX. We examined receptor binding at several early and late time points after surgery, and we observed a significant loss of specific [3H]-prazosin binding to cells isolated from rat livers 48 and 72 hr after PHX. In contrast, the ability of norepinephrine to stimulate inositol phosphate production in isolated cells prelabeled with [3H]-myo-inositol was transiently reduced between 8 and 16 hr, when alpha-1 binding capacity was virtually unchanged. This uncoupling of phosphoinositide turnover from binding was preceded by a drop in hepatic membrane ras p21 content, as assayed by liquid competition radioimmunoassay. The loss of immunoreactive p21 from membranes was significant by 2 hr after PHX. These findings suggest a role for alpha-1 receptors and ras protein in the early events of liver regeneration.
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