S-adenosylhomocysteine catabolism and basis for acquired resistance during treatment of T-cell acute lymphoblastic leukemia with 2'-deoxycoformycin alone and in combination with 9-beta-D-arabinofuranosyladenine.

A patient with refractory T-cell acute lymphoblastic leukemia was treated with eight courses of the adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF), over a 5-month period. After developing resistance to dCF, he responded to treatment with the combination of dCF and 9-beta-D-arabinofuranosyladenine (ara-A). We monitored the levels in plasma and urine of adenosine, 2'-deoxyadenosine, and ara-A as well as the accumulation of their nucleotide derivatives in erythrocytes and circulating lymphoblasts. We also monitored the activities of adenosine deaminase and S-adenosylhomocysteine (AdoHcy) hydrolase and the concentrations of AdoHcy and S-adenosylmethionine in lymphoblasts. Production of 2'-deoxyadenosine was related to both the duration of dCF infusion and the magnitude of cytolysis that occurred during treatment: much more 2'-deoxyadenosine was produced by dCF infusion when disease was active than by the same infusion given during remission. Resistance to dCF was associated with a decrease of greater than 90% in the amount of deoxyadenosine 5'-triphosphate accumulated by circulating lymphoblasts. Infusion of dCF resulted in increases of up to 20-fold in the concentration of AdoHcy in circulating lymphoblasts, causing a decrease in the S-adenosylmethionine:AdoHcy ratio (the "methylation index") from a pretreatment value of greater than 40:1 to less than 4:1. This ratio decreased to 2.5:1 during combined treatment with dCF and ara-A, which caused nearly complete inactivation of lymphoblast AdoHcy hydrolase. Decline in the methylation index was accompanied by inhibition of the methylation of newly synthesized lymphoblast RNA. Impaired ability to catabolize AdoHcy may have contributed to the cytolytic responses to dCF and ara-A, as well as to hepatic and central nervous system toxicity associated with their combined use.

Therapeutic considerations in childhood idiopathic thrombocytopenic purpura.

This monograph reviews the literature regarding therapy for childhood idiopathic thrombocytopenic purpura (ITP). The role and mechanism of action are discussed for corticosteroids, splenectomy, and intravenous gamma globulin. Alternative therapies with potent immunosuppressive agents are also mentioned. Guidelines for the management of children with ITP are presented.

Immunopathology of childhood idiopathic thrombocytopenic purpura.

Modern laboratory techniques have begun to elucidate the pathophysiology of chronic childhood ITP. Quantitative assays of PAIgG, complement, immune complexes, and platelet kinetic studies have all provided important information. Chronic ITP of childhood appears to be similar to adult ITP, with production of an antibody directed against platelets and megakaryocytes. Most of the antibody is produced in the spleen, but other parts of the RES can also produce antibody. Complement, immune complexes, and cell-mediated immunity may play a role in the pathogenesis. Sensitized platelets are cleared by the RES, particularly in the spleen. Platelet kinetic studies show that platelet turnover is usually rapid with compensatory increased thrombopoiesis, but there are some patients who have decreased thrombopoiesis. Acute ITP of childhood is a brief illness, characterized by abrupt onset of hemorrhagic symptoms and complete recovery. It often follows a viral illness, suggesting that immune complexes as well as antibodies are important in the pathogenesis. Both the spleen and liver may be important organs of immune clearance.

Treatment of platelet alloimmunization with intravenous immunoglobulin. Two case reports and review of the literature.

Two pediatric patients with severe aplastic anemia, elevated antiplatelet antibody levels, refractoriness to human lymphocyte antigen-matched platelet transfusions, and sustained bleeding problems were treated with intravenous immunoglobulin (IVIG), pH 4.25, for three to over nine months. Improved responses to platelet infusions and improved hemostasis were demonstrated in both patients. A review of the published literature analyzing the role of IVIG in the treatment of platelet alloimmunization is presented.

Efficacy of intravenous gamma globulin in autoimmune-mediated pediatric blood dyscrasias.

Sixteen pediatric patients diagnosed with a variety of autoimmune-mediated hematocytopenias were treated with one to 50 courses of intravenous gamma globulin (IVIG), pH 4.25, over the course of one to 30 months. Thirteen patients had immune thrombocytopenic purpura (ITP), two had autoimmune neutropenia, and one had autoimmune hemolytic anemia. In one patient, chronic ITP was associated with systemic lupus erythematosis, and in a second patient, acute ITP was the presenting manifestation of infection with human immunodeficiency virus. Initial therapy consisted of 400 mg/kg/dose daily for five days for the first seven patients treated, and 1,000 mg/kg/dose daily for two days for the remaining nine patients. In 15 of 16 patients, there was a response to IVIG therapy. In nine of 16 patients, maintenance IVIG therapy for two to more than 30 months was required. Minimal toxicity was experienced in four of 210 separate infusions. Data are presented to support the use of IVIG in the management of childhood autoimmune disorders.

Venous thrombosis in a family with defective release of vascular plasminogen activator and elevated plasma factor VIII/von Willebrand's factor.

A family is described in which venous thrombosis developed in five members as early as 14 years of age. Routine coagulation studies, plasma antithrombin III, factor V, plasminogen, beta-thromboglobulin, fibrinopeptide A, prothrombin fragment F1+2, and thrombin-antithrombin III complex were all within normal limits. However, defective release of vascular plasminogen activator was observed on several occasions in all five subjects as compared with a control population of 125 persons (0.04 Committee on Thrombolytic Agents [CTA] units/ml plasma as compared with 0.21 CTS units/ml). In addition, levels of factor VII/von Willebrand's factor were significantly elevated above the normal range in this pedigree.

Mortality in children and adolescents with sickle cell disease. Cooperative Study of Sickle Cell Disease.

A study of the natural history of sickle hemoglobinopathies was begun in March 1979. By August 1987, a total of 2824 patients less than 20 years of age were enrolled. There have been 14,670 person-years of follow-up. Seventy-three deaths have occurred. Most of the deaths were in patients with hemoglobin SS. The peak incidence of death was between 1 and 3 years of age, and the major cause in these young patients was infection. Cerebrovascular accidents and traumatic events exceeded infections as a cause of death in patients greater than 10 years of age. There was limited success in identifying risk factors for death. Comparison of this study's overall mortality of 2.6% (0.5 deaths per 100 person-years) with previous reports indicates improvement of survival in US patients less than 20 years of age with sickle hemoglobinopathies. This improvement is most likely due to parental education and counseling about the illness and the early institution of antibiotics in suspected infections.

Successful treatment of varicella pneumonia with prolonged extracorporeal membrane oxygenation in a child with leukemia.

A 5-year-old boy with acute lymphoblastic leukemia in complete continuous remission developed life-threatening varicella pneumonia and acute respiratory insufficiency (ARI). The child recovered after 92 hours of partial venoarterial perfusion with a membrane oxygenator. Functional asplenia developed. Serial pulmonary function tests after perfusion indicate moderately severe restrictive lung disease which has slightly improved during an 18 month period.

9p- in a girl with acute lymphocytic leukemia and sickle cell disease.

A 4 year old girl with sickle cell disease developed acute lymphocytic leukemia null cell type. The bone marrow karyotype was 46,XX,del(9)(p13). This girl is among the few patients with acute lymphocytic leukemia and abnormalities of #9 to have an isolated 9p-.

The adolescent with sickle cell anemia.

Adolescence is a time of intense change and turmoil. Helping patients with sickle cell disease have a smooth transition from the pediatric to adult health care environment is an important and meaningful experience. Facilitating the patient's transition, however, takes time and effort. Pediatricians must compile accurate medical summaries transmitting the details and nuances of the patient's history and care. Effort must be expended to ensure that details related to alloimmunization are not omitted. The pediatrician must be careful that the transfer does not create feelings of rejection and abandonment in the patient and the family. Physicians accepting the patient in transfer must devote time to educating and counseling the new patient. A relationship of trust and respect must be built. The physician should work with the patient to explore feelings of distrust and to uncover any concerns and fears, which should be dealt with proactively to avoid major conflicts later. Working closely with the adolescent patient can have many rewards, including helping the patient through a difficult period of adjustment. Helping the patient negotiate this difficult period can have many positive consequences. It is essential that both the pediatrician and internist work closely with the patient and family during the transfer process. Failure to do so can have disastrous consequences. When the collaboration is successful, however, the rewards for patients, families, and providers are great.

Treatment of trilateral retinoblastoma with vincristine and cyclophosphamide.

Current therapy for patients with trilateral retinoblastoma, consisting primarily of surgical intervention and radiotherapy, has resulted in no long-term survivors. The use of adjuvant chemotherapy has not improved this outcome. After observing a tumor response to cyclophosphamide in a patient with suprasellar retinoblastoma, we treated a subsequent patient with trilateral retinoblastoma with both vincristine and cyclophosphamide. Objective tumor regression resulted. Although the tumor ultimately progressed in both patients, these findings suggest that vincristine and cyclophosphamide are active in patients with intracranial (trilateral) retinoblastoma.

The spectrum of brain MR abnormalities in sickle-cell disease: a report from the Cooperative Study of Sickle Cell Disease.

PURPOSE: To define the spectrum of abnormalities in sickle-cell disease, including infarction, atrophy, and hemorrhage, that are identified by brain MR imaging. METHODS: All MR studies included T1, T2, and intermediate pulse sequences. Images were interpreted without knowledge of the clinical history or neurologic examination findings. Brain MR imaging was performed in 312 children with sickle-cell disease. RESULTS: Seventy patients (22%) had infarction/ischemia and/or atrophy, infarction/ischemia was noted in 39 children (13%) who had no history of a stroke (the "silent" group). The prevalence rates for silent lesions were 17% for sickle-cell anemia and 3% for hemoglobin sickle-cell disease. For patients with sickle-cell anemia and a history of cerebrovascular accident, infarction/ischemia lesions typically involved both cortex and deep white matter, while silent lesions usually were confined to deep white matter. Within the age range studied, the prevalence of infarction/ischemia did not increase significantly with age, although older patients with lesions had more lesions than did younger patients with lesions. CONCLUSIONS: Brain MR imaging showed infarction/ischemia in the absence of a recognized cerebrovascular accident in 13% of patients. The prevalence of these lesions did not increase significantly between the ages of 6 and 14 years, suggesting that lesions are present by age 6. However, the increase in the average number of lesions per patient with age may indicate progressive brain injury.

Role of child and maternal processes in the psychological adjustment of children with sickle cell disease.

In this study, 64% of children aged 7-12 years with sickle cell disease were found to have a parent-reported behavior problem, and 50% met the criteria for a Diagnostic and Statistical Manual of Mental Disorders (3rd ed.) diagnosis based on a structural clinical interview of the child. Internalizing types of behavior problems and diagnoses were the most frequent. Support was provided for a transactional stress and coping model in delineating the processes associated with child adjustment. In particular, maternal anxiety accounted for 16%-33% of the variance in mother-reported internalizing and externalizing behavior problems, respectively, and child pain-coping strategies accounted for 21% of the variance in child-reported adjustment problems.

Psychological adjustment of children with sickle cell disease: stability and change over a 10-month period.

Rates of poor psychological adjustment of children with sickle cell disease remained relatively constant over initial and follow-up assessment points. However, there was relatively little stability in the classification of the adjustment of individuals, low congruence in specific behavior problem patterns and diagnoses in accordance with the Diagnostic and Statistical Manual of Mental Disorders (3rd ed.; American Psychiatric Association, 1980), and less stability in child adjustment by child report than by mother report. With initial levels of adjustment controlled, children's strategies for coping with pain accounted for a significant increment in child-reported symptoms (19%) and mother-reported internalizing behavior problems (8%) at follow-up beyond the contribution of illness and demographic parameters and follow-up interval. The findings suggest that children's coping strategies are a salient intervention target for enhancing adjustment.

Diagnosis and management of common bile duct stones in patients with sickle hemoglobinopathies.

Nine of 35 patients with sickle hemoglobinopathies and cholelithiasis were found to have concomitant common bile duct (CBD) stones. We describe the diagnosis and management of these patients with CBD stones. Historical information, physical examination, and routine laboratory tests were unable to identify accurately the patients with CBD stones. Similarly, ultrasonography of the hepatobiliary system was an insensitive method for detecting CBD stones, as only 3 of 8 patients were correctly identified. In contrast, both an intraoperative cholangiogram and endoscopic retrograde cholangiopancreatography were sensitive procedures for detection of CBD stones. We conclude that CBD stones are relatively common in patients with sickle cell disease and cholelithiasis, and clinicians should have a high index of suspicion for their presence.

Successful surgical outcome in children with sickle hemoglobinopathies: the Duke University experience.

BACKGROUND/PURPOSE: Surgery in patients with sickle hemoglobinopathies can be problematic because of the potential for sickling events in the perioperative and postoperative period. The authors and others have previously reported successful surgical outcomes using an aggressive erythrocyte transfusion regimen, designed to alleviate anemia and to reduce the percentage of sickle hemoglobin to below 30%. Recently, a randomized trial compared this aggressive regimen with a more conservative transfusion regimen and found no differences in perioperative complications. The incidence of complications, however, was very high in each group (31% to 35%). METHODS: The authors therefore analyzed retrospectively their surgical experience in children with sickle hemoglobinopathies over the past 10 years to determine the efficacy of an aggressive transfusion regimen and skilled perioperative care in their patient population. RESULTS: A total of 130 surgical procedures were performed on 92 children including 54 cholecystectomies (42%), 23 splenectomies (18%), 12 ENT procedures (9%), 11 central line placements and removals (8%), 7 herniorrhaphies (5%), 7 appendectomies (5%), and 16 miscellaneous operations (13%). The mean age of the children was 10 years (range, 1 to 22 years), and the mean weight was 32.1 kg (range, 9.9 to 76.8 kg). The average hemoglobin (mean +/- 1 SD) at the time of surgery was 11.2+/-1.3 g/dL, and the average percent hemoglobin S was 21+/-11%. CONCLUSIONS: Relatively few transfusions were required to achieve these endpoints, and the complications resulting from transfusions were minimal. Similarly, the number of perioperative and postoperative events was very low.

Retinoblastoma metastatic to bone marrow. A case with florid spread.

A 28-month-old white male, 7 months status postenucleation for retinoblastoma, presented with lethargy, irritability, anemia, and thrombocytopenia. Bone marrow examination revealed almost total replacement of marrow elements with clumps of small round basophilic cells. Electron microscopic study of the marrow revealed clumps of cohesive tumor cells with intermediate junctions, establishing a diagnosis of metastatic retinoblastoma.