Adverse effects of intrathecal methotrexate in children with acute leukemia in remission

A toxic syndrome characterized by fever, headache, and vomiting, lasting 2-5 days, occurred in 61% of 39 children with acute leukemia in complete remission, receiving central nervous system prophylaxis with intrathecal methotrexate, and in 14% of 34 children receiving the same plus cranial radiation. The syndrome was accompanied by pleocytosis with lymphocytes, monocytoid cells, and neutrophils. There was evidence of cumulative Mtx toxicity, since the toxic syndrome occurred mostly after the third and fourth dose and did not recur with longer intervals between doses. The incidence of the syndrome was significantly reduced by the use of Elliott's B solution as Mtx diluent, rather than water or normal saline. The occurrence of pleocytosis and toxic clinical syndrome was also significantly reduced in patients receiving concomitant cranial radiation, probably due to the lympholytic action of radiotherapy and the depressed cellular response of irradiated tissues. The use of Elliott's B solution as diluent for IT Mtx and an appropriate interval between Mtx doses are suggested for prevention of this toxic syndrome.     

Role of right ventricular endomyocardial biopsy in infants and children with suspected or possible myocarditis.

OBJECTIVES--To assess the diagnostic yield, sampling errors, risks, and therapeutic implications of right ventricular endomyocardial biopsy in children with suspected or possible myocarditis. DESIGN--Retrospective study. SETTING--Tertiary referral centre for paediatric cardiology, cardiac surgery, heart transplantation, and mechanical circulatory support. PATIENTS AND METHODS--Review of clinical and histological findings among 63 consecutive children with possible myocarditis undergoing right ventricular endomyocardial biopsy. Review of cardiac histology at subsequent necropsy or after explantation at time of transplantation. RESULTS--From January 1980 to December 1992, 76 biopsies were performed in 63 children (2 weeks to 18 years of age). In 41 cases, the biopsy was performed for evaluation of dilated cardiomyopathy. The median interval from onset of symptoms was one month. Eight children (20%; all with a history of less than six weeks duration) had biopsy proved myocarditis. Five of the eight children made a full recovery, including four who presented in cardiogenic shock. By contrast, only three of 33 children without evidence of myocarditis showed recovery of ventricular function. The whole heart was available for histological examination in 23 patients. Myocarditis was confirmed in one patient, and no evidence of myocarditis was found in the remaining 22 (all with negative biopsies). One procedure related death occurred in a 2 week old infant with dilated cardiomyopathy. In 22 cases, biopsy was performed for the evaluation of arrhythmia. Only one biopsy showed myocarditis. CONCLUSIONS--The diagnostic yield of a biopsy is low in children with arrhythmias. In children presenting with profound ventricular dysfunction, a diagnosis of acute myocarditis may avoid premature consideration of transplantation as this group has an important potential for full recovery. In less critically ill patients and in those with a longer duration of symptoms the justification for biopsy is not as clear and the procedure is not without risk.     

Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2

We assessed somatic alleles of six receptor tyrosine kinase genes mutated in lung adenocarcinoma for oncogenic activity. Five of these genes failed to score in transformation assays; however, novel recurring extracellular domain mutations of the receptor tyrosine kinase gene ERBB2 were potently oncogenic. These ERBB2 extracellular domain mutants were activated by two distinct mechanisms, characterized by elevated C-terminal tail phosphorylation or by covalent dimerization mediated by intermolecular disulfide bond formation. These distinct mechanisms of receptor activation converged upon tyrosine phosphorylation of cellular proteins, impacting cell motility. Survival of Ba/F3 cells transformed to IL-3 independence by the ERBB2 extracellular domain mutants was abrogated by treatment with small-molecule inhibitors of ERBB2, raising the possibility that patients harboring such mutations could benefit from ERBB2-directed therapy.     

Troponin--past, present, and future

Cardiac troponin is the analyte of choice for the diagnosis of cardiac injury. It is highly specific for the heart and much more sensitive than prior biomarkers. Because of this increased sensitivity, clinicians have had to struggle with elevations in novel clinical situations. We have developed new understandings about coronary artery disease but also have begun to appreciate that many other entities as well can result in cardiac injury. As assays have increased in sensitivity over time, this trend has, if anything, accelerated. This review attempts to put the past, the present, and the future into a clinical perspective that will help clinicians.