ALL-1 gene rearrangements in DNA topoisomerase II inhibitor-related leukemia in children

We examined clinical, morphologic, and cytogenetic features and ALL-1 (MLL, Htrxl, HRX) gene rearrangements in 17 cases of secondary leukemia that occurred 11 months to 9 years from diagnoses of primary cancers in children who received topoisomerase II inhibitors or developed secondary leukemias typical of those associated with this therapy. Primary diagnoses included nine solid tumors and eight leukemias. Ten secondary leukemias were acute myeloid leukemia (AML), one was of mixed lineage, two were acute lymphoblastic leukemia (ALL), and four presented as myelodysplasia. Of 15 cases with 11q23 involvement, 11 (73%) were cytogenetically identifiable; four cases had molecular rearrangement only. By Southern blot, rearrangements within the ALL-1 gene were similar to sporadic cases. The results of this analysis suggest the following: (1) In most pediatric cases of topoisomerase II inhibitor-associated leukemia, there is disruption of the breakpoint cluster region of the ALL-1 gene at chromosomal band 11q23. (2) Exposure histories vary in secondary 11q23 leukemia, as the only topoisomerase II inhibitor was dactinomycin in one case, and, in another case, no topoisomerase II inhibitor was administered. (3) There is clinical, morphologic, cytogenetic, and molecular heterogeneity in pediatric secondary 11q23 leukemia. (4) There are some survivors of pediatric secondary 11q23 leukemia, but the outcome is most often fatal.     

Prognosis of prenatal uropathies: should fetal urine tests be continued?

Twenty percent of the children with end stage renal failure have severe obstructive uropathies. The assessment of fetal renal function and the degree of renal damage in utero is a critical factor in providing realistic counseling. The prediction of postnatal renal function is made by sonography, fetal urinary biochemistry and fetal serum for beta-2-microglobulin. Ultrasonography is a useful method including assessment of amniotic volume and ultrasonographic evaluation of the renal parenchyma. The analysis of fetal urine for the assessment of renal function leads to conflicting results. Some papers conclude that fetal urine electrolytes are not an accurate predictor of neonatal renal function, others conclude that they provide useful information. The number of studies dealing with the urinary beta-2-microglobulin levels in the assessment of prenatal renal function is too small for allowing definitive conclusions. The predictive value of fetal serum beta-2-microglobulin for neonatal renal function may be interesting but the results are yet preliminary. The studies of fetal urinary biochemistry should be continued within prospective research programs; the data are either too conflicting or too preliminary to use this methodology in commun practise.     

Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines

OBJECTIVE: Given concerns about use of psychotropic medication during pregnancy, the authors reviewed the literature regarding the effects of prenatal exposure to psychotropic medications on fetal outcome. METHOD: A MEDLINE search of all articles written in English from 1966 to 1995 was performed to review information on the effects of psychotropic drug use during pregnancy on fetal outcome. Where sufficient data were available and when methodologically appropriate, meta-analyses were performed to assess risk of fetal exposure by psychotropic medication class. RESULTS: Three primary effects are associated with medication use during pregnancy: 1) teratogenicity, 2) perinatal syndromes (neonatal toxicity), and 3) postnatal behavioral sequelae. For many drug classes there are substantial data regarding risk for teratogenicity. Tricyclic antidepressants do not seem to confer increased risk for organ dysgenesis. The available data indicate that first-trimester exposure to low-potency phenothiazines, lithium, certain anticonvulsants, and benzodiazepines may increase the relative risk for congenital anomalies. However, the absolute risk of congenital malformations following prenatal exposure to most psychotropics is low. CONCLUSION: Exposure to certain psychotropic drugs in utero may increase the risk for some specific congenital anomalies, but the rate of occurrence of these anomalies even with the increased risk remains low. Use of psychotropic medications during pregnancy is appropriate in many clinical situations and should include thoughtful weighing of risk of prenatal exposure versus risk of relapse following drug discontinuation. The authors present disorder-based guidelines for psychotropic drug use during pregnancy and for psychiatrically ill women who wish to conceive.     

Fetal origins of the TEL-AML1 fusion gene in identical twins with leukemia

The TEL (ETV6)-AML1 (CBFA2) gene fusion is the most common reciprocal chromosomal rearrangement in childhood cancer occurring in approximately 25% of the most predominant subtype of leukemia- common acute lymphoblastic leukemia. The TEL-AML1 genomic sequence has been characterized in a pair of monozygotic twins diagnosed at ages 3 years, 6 months and 4 years, 10 months with common acute lymphoblastic leukemia. The twin leukemic DNA shared the same unique (or clonotypic) but nonconstitutive TEL-AML1 fusion sequence. The most plausible explanation for this finding is a single cell origin of the TEL-AML fusion in one fetus in utero, probably as a leukemia-initiating mutation, followed by intraplacental metastasis of clonal progeny to the other twin. Clonal identity is further supported by the finding that the leukemic cells in the two twins shared an identical rearranged IGH allele. These data have implications for the etiology and natural history of childhood leukemia.     

Fetal enterolithiasis and anhydramnios; due to in utero hepatorenal syndrome?

Enterolithiasis is a rare, prenatal ultrasonographic finding. Previously reported cases were invariably associated with major fetal malformations. We describe a case of fetal enterolithiasis and anhydramnios in an anatomically normal fetus who, at autopsy, showed end-stage fetal liver disease. Fetal hepatorenal syndrome is the most probable cause of this in utero sonographic combination.     

Allogeneic peripheral blood progenitor cells for treatment of relapse after bone marrow transplantation

Donor leukocyte infusions (DLI) are an effective therapy for patients who relapse with leukemia after bone marrow transplantation (BMT). Severe graft-versus-host disease and prolonged periods of pancytopenia compromise the success of this treatment in a substantial number of patients. We used filgrastim-mobilized peripheral blood progenitor cells (PBPCs), in some cases preceded by cytoreductive therapy, to circumvent some of the problems associated with DLI. Eleven patients (median age 41 years) received a total of 20 donor cell infusions. Their diagnosis was CML in hematological (two patients) or cytogenetic relapse (two patients), six patients suffered from acute myeloid leukemia (AM; n = 5) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL Ph+). One patient had multiple myeloma (MM). All six patients with acute leukemias received cytoreductive therapy prior to PBPC infusions; three patients with CML were pretreated with IFN alpha. Four of four patients with CML responded to PBPC infusions and currently are in complete clinical and molecular remission for time periods between 1 and 12 months. Six of six patients with acute leukemias achieved a complete remission. All of them relapsed after a median remission duration of 24 weeks (range 11-49 weeks). Three patients relapsed at extramedullary sites (CNS, testes, skin). Four of six acute leukemia patients received further cytoreductive therapy. All patients responded again and are in complete remission for time periods between 14 and 615 days. Two patients with acute leukemias have died due to dissemination of the disease. The patient with MM did not respond and is alive with disease. Severe (grade III) acute GVHD developed in two of 11 patients, three patients developed grade II disease, six patients did not show any signs of GVHD. Extensive chronic GVHD has developed in two cases to date. Patients with chemotherapy prior to PBPC infusion developed neutropenia and thrombocytopenia with a maximum duration of 20 and 14 days, respectively; prolonged periods of neutropenia did not occur. Two patients developed long-lasting thrombocytopenia in spite of PBPC infusion, in one case followed by leukemic relapse. Repeated courses of chemotherapy and PBPC infusion were generally tolerated well; no early deaths due to treatment-related toxicity or GVHD were observed. We conclude that the use of allogeneic PBPC instead of DLI in patients with relapse after BMT is technically feasible and safe. The efficacy of PBPC infusions seems comparable to DLI in patients with CML. Patients with acute leukemias also achieved complete albeit transient remissions. Aggressive chemotherapy followed by PBPC infusions resulted in only limited duration of cytopenia. The usage of PBPC infusion instead of non G-CSF-mobilized donor cells for treatment of relapse after BMT may reduce pancytopenia-related complications and merits further investigation.     

Oncogenesis in utero: fetal death due to acute myelogenous leukaemia with an MLL translocation

The incidence of translocations involving the 11q23 gene MLL is markedly increased in leukaemias that occur in infants <1 year of age. Epidemiological and molecular data have demonstrated that at least some of these translocations occur in utero. In this report we describe a case of fetal death at 36 weeks of gestation. At autopsy the fetus was found to have widely disseminated acute myelogenous leukaemia (AML), FAB subtype M5. Molecular cytogenetic studies of nuclei recovered from paraffin-embedded tissue sections demonstrated that the leukaemic cells contained an MLL translocation. This is the first detailed report, to our knowledge, of fetal death due to acute leukaemia, and directly demonstrates oncogenesis in utero.     

Obstetric outcome after RhD and Kell testing

The study was conducted to report on the use of molecular biology methods and pregnancy outcome in women sensitized to either Rhesus D (RhD) or Kell 1 (K1) antigens. Paternal RhD genotype was determined by DNA amplification of an RhD-specific sequence from single sperm cells. Paternal Kell phenotype was determined by serologic assays using peripheral blood samples, and the fetal RhD or Kell-type status were established by the polymerase chain reaction (PCR) with amniotic cells. Thirteen women (14 pregnancies, one with twins) sensitized to RhD and four sensitized to K1 antigens, comprised the study group. All had paternal heterozygosity to either D or K1 antigens. Nine fetuses were RhD positive and five were RhD negative. An additional woman underwent early spontaneous abortion. The nine RhD-positive fetuses underwent a total of 41 invasive procedures. One fetus with hydrops fetalis died in utero after intrauterine blood transfusion. All the remaining RhD-positive fetuses were delivered after 33 weeks gestation, and all those who were RhD negative were delivered at term. Four women were sensitized to the K1 antigen; in three, the fetus was found to be K1 negative, and in one, K1 positive, necessitating intrauterine blood transfusion. In all cases, the results of RhD or K1 genotype analyses from amniotic fluid were compatible with fetal/neonatal red blood cell RhD or Kell phenotypes. In conclusion, the use of molecular biology techniques represents a major advance in the clinical management of RhD and Kell alloimmunization.     

Prenatal diagnosis

The enormous progress witnessed in the field of prenatal diagnosis during the past two decades is likely to continue into the future. Improved imaging techniques are likely to enhance the resolution of noninvasively obtained fetal images considerably over their current excellent quality. Although this undoubtedly will be true for ultrasonography, the increased speed of magnetic resonance equipment may offer a new realm of imaging possibilities. Computerized image processing, analysis, and three-dimensional reconstructions all should make interpretation of fetal images easier and more understandable to the nonspecialist. Advances in molecular genetics will continue to accelerate, greatly expanding the range and accuracy of prenatal diagnosis. The alert pediatrician who is sensitive to genetic issues may, by early detection of pediatric disorders and careful family history assessment, be in a position to identify families at risk for serious genetic conditions and provide the opportunity to make informed decisions on reproductive options that avert a major tragedy. The pediatrician, working with obstetric colleagues, should be part of a team effort to support families going through prenatal testing. Familiarity with these rapidly changing technologies will make it far easier to support the family needing additional explanation about prenatal diagnosis issues.     

Transplacental cocaine exposure: a mouse model demonstrating neuroanatomic and behavioral abnormalities

Between 10% and 15% of infants born in urban America today have been exposed to cocaine in utero. Clinical studies have suggested that impairment of brain growth is the single best marker of significant prenatal cocaine exposure, and postnatal developmental compromise seen in a subset of affected children as a consequence of that exposure. We have developed an animal model, in mice, of prenatal cocaine exposure that has allowed us to dissociate the direct effects of cocaine in altering fetal development from the indirect effects associated with cocaine-induced malnutrition. We find that transplacental cocaine exposure independently impairs fetal brain and body growth and results in behavioral deficits and permanent alterations in neocortical cytoarchitecture in exposed offspring.     

History of maternal fetal loss and increased risk of childhood acute leukemia at an early age. A report from the Childrens Cancer Group

BACKGROUND: Maternal reproductive history of fetal loss previously has been reported to be associated with an increased risk of leukemia in subsequent offspring. Data from a Childrens Cancer Group (CCG) case-control study were analyzed to test the hypothesis that this association was dependent on the number of previous fetal losses and age at leukemia diagnosis. METHODS: A case-control study using a large Childrens Cancer Group database examined maternal history of fetal loss as a risk factor for childhood leukemia in subsequent offspring. One thousand seven hundred fifty-three patients with childhood acute leukemia were compared with 839 community control subjects s and 2081 nonleukemia cancer control subjects. RESULTS: A modest increase in risk was found to be associated with a history of fetal loss. Stratification by age at diagnosis of leukemia showed that this association was significant only for those patients diagnosed before 4 years of age and most significant in those patients diagnosed before 2 years of age. When comparing community controls with patients acute lymphocytic leukemia diagnosed before 2 years of age, one previous fetal loss was associated with a five-fold increased risk (P < 0.001) whereas two or more fetal losses were associated with a relative risk of 24.8 (P < 0.001). Similarly, patients with acute myelocytic leukemia diagnosed before 2 years of age demonstrated 5-fold and 12-fold increased risks associated with the previous fetal loss and 2 or more previous fetal losses, respectively. CONCLUSIONS: Childhood acute leukemia occurring at younger ages may be associated with an underlying genetic abnormality or chronic environmental exposure, which can be either lethal to the developing fetus or mutagenic and result in the development of acute leukemia.     

Transition from fetal to extrauterine circulation

In utero, there is increased pulmonary vascular resistance favoring minimal pulmonary blood flow and right-to-left shunting of blood through the ductus arteriosus and foramen ovale. Delivery initiates a series of complex biochemical and structural changes whereby the neonate assumes those processes critical to survival. This article reviews fetal circulation, the characteristics of the fetal cardiopulmonary system, and the transition from fetal to neonatal circulation. It also discusses the consequences of disrupted transition to extrauterine life and the relationship between fetal cardiopulmonary anatomy and congenital heart disease.     

Last ICRU recommendations for the prescription, recording and reporting of external bean therapy]

There is increasing epidemiological evidence in humans which associates low birth weight with later cardiovascular and metabolic disorders including hypertension, insulin resistance, hyperlipidaemia and death from ischaemic heart disease. The molecular mechanisms underlying this link are unknown but fetal glucocorticoid exposure may play a role. In adult mammals, glucocorticoid hormones are involved in control of several physiological processes that maintain homeostasis including coordination of responses to stress. During development, glucocorticoids have important regulatory functions to prepare the organism for metabolic adaptations necessary for extrauterine life. Fetal glucocorticoid load is, in part, regulated by placental and fetal 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) which catalyses a rapid breakdown of maternal and fetal glucocorticoids into inert products. Supraphysiological doses of glucocorticoids retard fetal growth, and human intrauterine growth retardation is associated with elevated cortisol levels. Recent studies have shown that exposing rats to excessive glucocorticoids in utero reduces birth weight and causes permanent hypertension and hyperglycaemia in the adult offspring. These observations show that glucocorticoids could be the link between low birth weight and later disease. Understanding of the molecular details involved in prenatal glucocorticoid action may provide novel insights into the pathogenesis of common cardiovascular and metabolic disorders.     

A case report on drug screening of nail clippings to detect prenatal drug exposure

In a case of a sudden infant death syndrome-related death of a 3-month-old infant, nail clippings were positive for cocaine by gas chromatography-mass spectroscopy analysis that revealed a prenatal exposure to the drug substance. In utero exposure to drugs has been investigated using amniotic fluid, neonatal urine, meconium, and hair samples. Nail analysis offers some advantage over hair analysis because of its continuous growth and persistence after delivery. Nail material is easy to sample in suitable amounts. Currently, the cocaine finding cannot be related to the underlying cause of death. However, this observation indicates that nail analysis may be a new and valuable tool to screen newborns for intrauterine drug exposure. In addition, it can help collect information on the prevalence of possible embryotoxic effects and the link to postnatal manifestations of different dysfunctions in infants who are born by drug abusing mothers.     

Correction of congenital diaphragmatic hernia in utero VIII: Response of the hypoplastic lung to tracheal occlusion

Most fetuses with congenital diaphragmatic hernia (CDH) diagnosed before 24 weeks' gestation die despite optimal postnatal care. In fetuses with liver herniation into the chest, prenatal repair has not been successful. In the course of exploring the pathophysiology of CDH and its repair in fetal lambs, the authors found that obstructing the normal egress of fetal lung fluid enlarges developing fetal lungs, reduces the herniated viscera, and accelerates lung growth, resulting in improved pulmonary function after birth. They developed and tested experimentally a variety of methods to temporarily occlude the fetal trachea, allow fetal lung growth, and reverse the obstruction at birth. The authors applied this strategy of temporary tracheal occlusion in eight human fetuses with CDH and liver herniation at 25 to 28 weeks' gestation. With ongoing experimental and clinical experience, the technique of tracheal occlusion evolved from an internal plug (two patients) to an external clip (six patients), and a technique was developed for unplugging the trachea at the time of birth (Ex Utero Intrapartum Tracheoplasty [EXIT]). Two fetuses had a foam plug placed inside the trachea. The first showed dramatic lung growth in utero and survived; the second (who had a smaller plug to avoid tracheomalacia) showed no demonstrable lung growth and died at birth. Two fetuses had external spring-loaded aneurysm clips placed on the trachea; one was aborted due to tocolytic failure, and the other showed no lung growth (presumed leak) and died 3 months after birth. Four fetuses had metal clips placed on the trachea. All showed dramatic lung growth in utero, with reversal of pulmonary hypoplasia documented after birth. However, all died of nonpulmonary causes. Temporary occlusion of the fetal trachea accelerates fetal lung growth and ameliorates the often fatal pulmonary hypoplasia associated with severe CDH. Although the strategy is physiologically sound and technically feasible, complications encountered during the evolution of these techniques have limited the survival rate. Further evolution of this technique is required before it can be recommended as therapy for fetal pulmonary hypoplasia.     

Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain

Programmed cell death (apoptosis) occurs during normal development of the central nervous system. However, the mechanisms that determine which neurons will succumb to apoptosis are poorly understood. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors for only a few hours during late fetal or early neonatal life triggered widespread apoptotic neurodegeneration in the developing rat brain, suggesting that the excitatory neurotransmitter glutamate, acting at NMDA receptors, controls neuronal survival. These findings may have relevance to human neurodevelopmental disorders involving prenatal (drug-abusing mothers) or postnatal (pediatric anesthesia) exposure to drugs that block NMDA receptors.