Treatment of stage I, IIA, IIIA1 pediatric Hodgkin disease with doxorubicin, bleomycin, vincristine and etoposide (DBVE) and radiation: a Pediatric Oncology Group (POG) study.

PURPOSE: The objectives of this study were to evaluate the feasibility of reducing therapy, while maintaining treatment efficacy, in the context of a cooperative group clinical trial that allowed for clinical staging in early stage Hodgkin disease (HD). PATIENTS AND METHODS: Between August 1992 and December 1993, 51 eligible children < or =21 years of age, 31 male and 20 female, were enrolled in this study which was designed for low stage (IA, IIA, IIIA1) HD. Laparotomy and surgical staging was optional. Five postpubertal patients with Stage IA and IIA disease received only involved-field radiation therapy. The other 46 patients, who form the basis of this report, received combined modality therapy consisting of four courses of doxorubicin, bleomycin, vincristine, and etoposide (DBVE) followed by 2,550 cGy involved-field irradiation. RESULTS: With a median follow-up of 8.4 years, the 6-year overall and event-free survival rates for the 46 patients treated with combination therapy were 98 +/- 2% and 91 +/- 5%, respectively. All patients achieved remission after completion of therapy. There have been four recurrences and a remission death due to gunshot wound. Combined modality therapy was well tolerated. Predominant side effects were gastrointestinal and hemopoietic. There have been no clinically significant cardio-pulmonary side effects so far. CONCLUSION: In clinically staged children with early-stage HD, DBVE and low-dose involved-field irradiation was effective therapy with tolerable side effects and reduced potential for long-term adverse events.

Successful use of ReFacto continuous infusion in two paediatric patients with severe haemophilia A undergoing orthopaedic surgery.

In this report we describe the successful use of B-domain-deleted recombinant factor VIII (ReFacto) administered by continuous infusion during orthopaedic procedures in two children with severe haemophilia A. Both patients underwent ankle synovectomy and in patient 2, a medial patello-femoral ligament repair was performed in the same operative session. Patient 2 developed septic arthritis A in his knee joint and arthroscopic joint irrigation and debridement was performed 2 weeks after the initial procedure. Surgical cover was initiated with a bolus dose of ReFacto 50 IU kg(-1) followed by continuous infusion at 3.3-4.8 IU kg(-1) h(-1) which was maintained for up to 9 days postoperatively. Patient 2 received an additional bolus dose of 15 IU kg(-1) during the infusion period. All procedures were performed without haemostatic complications and long-term orthopaedic outcomes were good in both patients.

Clinical presentation of rhabdoid tumors of the kidney.

PURPOSE: We designed this study to differentiate the clinical presentation, particularly the incidence of hematuria, of a rhabdoid tumor of the kidney (RTK), a rare but highly malignant tumor, from a Wilms tumor. PATIENTS AND METHODS: We reviewed patient flow charts from the National Wilms Tumor Study Group and queried participating hospitals to obtain additional information regarding presenting symptoms and laboratory data for fifty patients. Patient ages ranged from 2 days to 3.5 years with a mean of 11 months. We documented the presence of gross and microscopic hematuria, fever, and hypercalcemia. RESULTS: Whereas 75% of children with rhabdoid tumor of the kidney (RTK) had stage III (44%), IV (27%), or V (4%) tumors, 67% of children with Wilms tumors had stage I (41%) or II (26%) tumors. Either gross or microscopic hematuria was present in 84.4% (27/32) of the patients with RTK. Gross hematuria was present in 59% (22/37) of children with RTK compared with 18% previously reported with Wilms tumor. Microscopic hematuria was present in 76% (22/29) of children with RTK compared with 24% previously reported with Wilms tumor. Fever was found in 44% (16/36) of children with RTK, compared with 22% of children previously reported with Wilms tumor. Hypercalcemia was seen 26% (6/23) of children with RTK. CONCLUSION: Although diagnosis of any renal mass still must be confirmed with histopathologic features, a distinct clinical presentation with fever, hematuria, a young age, and high-tumor stage at presentation suggests the diagnosis of RTK.

Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group.

A retrospective data collection was performed on 29 children diagnosed with neuroblastoma and opsoclonus-myoclonus between 1983-1993 from Pediatric Oncology Group institutions. The aim was to describe neurologic outcome in children with neuroblastoma and opsoclonus-myoclonus. Age at diagnosis ranged from one month to 4 years (median age, 18 months). The duration of opsoclonus-myoclonus symptoms prior to the diagnosis of neuroblastoma ranged from 6 days to 17 months (median duration, 6 weeks). There was a prevalence of low stage disease according to the POG staging system: stage A (n = 18), stage B (n = 3), stage C (n = 7), stage D (n = 1). There was a predominance of paraspinal primary tumors. There was no case of Nmyc amplification (0/17), and 2/8 cases were diploid. Treatment for neuroblastoma consisted of surgery alone in 19/29 (18 stage A, 1 stage C in thorax), and surgery plus chemotherapy in 10/ 29. No patient received radiotherapy. Treatment for opsoclonus-myoclonus ranged varied. Six children received no treatment for opsoclonus-myoclonus. The following agents were used ACTH (n = 14), prednisone (n = 12), IV IgG (n = 6), immuran (n = 2), depakote (n = 1), and inderal (n = 1). Eighteen of 29 children (62%) had resolution of opsoclonus-myoclonus symptoms. The range of time for recovery was a few days to 3 years. However the majority recovered over several months. Twenty of 29 children (69%) had persistent neurologic deficits including speech delay, cognitive deficits, motor delay, and behavioral problems. Of the 9 children who had complete recovery of opsoclonus-myoclonus without neurologic sequelae, age at diagnosis and duration of symptoms were not different from the entire group. Interestingly, 6/9 children with complete recovery received chemotherapy as part of their treatment. In conclusion, persistent neurologic deficits are characteristic for children with neuroblastoma and opsoclonus-myoclonus. Treatment with chemotherapy may improve the neurologic outcome.

Analysis of megakaryocyte ploidy in fetal bone marrow biopsies using a new adaptation of the feulgen technique to measure DNA content and estimate megakaryocyte ploidy from biopsy specimens.

Platelet counts in newborns are similar to those of adults and children. However, newborn infants admitted to intensive care nurseries have a high prevalence of thrombocytopenia. The mechanisms responsible for the increased susceptibility to thrombocytopenia are not known. In addition, some studies have documented functional abnormalities in newborn platelets. In an effort to understand differences between platelets in newborns and in adults, we examined megakaryocyte ploidy in bone marrow from fetuses and compared it with bone marrow from adults, using a modified Feulgen stain to measure DNA of individual megakaryocytes. Faced with small fixed tissue samples, we developed a technique for use on bone marrow biopsies to estimate megakaryocyte ploidy and compared the results obtained with this method to those obtained from bone marrow aspirates. This study demonstrated that the overall mean ploidy of fetal megakaryocytes is decreased compared with adults. Additionally, fetal megakaryocyte ploidy increases as megakaryocyte maturation increases, but not to the same extent that adult megakaryocyte ploidy increases with megakaryocyte maturation. Over the gestational period studied, there was no relationship between gestational age and mean ploidy. The small size, shift to a less mature population, and decreased ploidy of fetal megakaryocytes indicate that there are differences in the post mitotic phase of megakaryocyte development in the fetus. Such differences may be related to quantitative and qualitative platelet abnormalities in the newborn. Understanding the physiology and regulation of megakaryocytopoiesis in the fetus and newborn will be valuable in determining the pathophysiologic basis of platelet dysfunction in the newborn.

Effect of chronic erythropoietin administration on plasma iron in newborn lambs.

Erythropoietin, the primary stimulator of erythropoiesis, represents an important potential therapy for the anemia of prematurity. Enhancement of the therapeutic benefit of recombinant human erythropoietin (rhEp) in very-low-birth-weight infants will require a better understanding of rhEp's pharmacodynamic effects including its interaction with iron in stimulating erythropoiesis. The purpose of this study was to determine the effects of chronic rhEp administration on plasma iron levels and hematopoiesis using a twin lamb model. Nine pairs of twin lambs in which one twin was randomized to receive rhEp, and the other saline, were studied during a 1-week baseline and a subsequent 4- to 5-week treatment period. The effects of therapy on plasma iron levels and erythropoiesis were measured by integrating the areas under the concentration-time curves (AUC) of the study variables. During the rhEp treatment period, significantly greater negative daily AUCs were observed in the rhEp-treated lambs for plasma iron concentration (p = 0.0008), while significantly greater positive daily AUCs were observed for hemoglobin concentration (p = 0.04) and reticulocyte count (p = 0.02). In the rhEp-treated group, pretreatment iron concentrations were directly associated with the magnitude of the iron response during treatment such that the greater the pretreatment iron, the greater the daily AUC below the plasma iron concentration-time plot (r = -0.66, p = 0.05). For the placebo-treated group, this association tended toward, but did not achieve, statistical significance (r = -0.52, p = n.s.). These observations suggest that treatment of rapidly growing newborn lambs with rhEp results in increased iron utilization due to increased erythropoiesis and depends on iron status at the initiation of rhEp treatment. Use of the term neonatal lamb model offers advantages over studies in human infants for more detailed or invasive examinations of the interaction of iron and rhEp treatment.

Neuroblastoma-associated opsoclonus-myoclonus treated with intravenously administered immune globulin G.

An 18-month-old black girl had progressive truncal ataxia, opsoclonus, and multifocal myoclonus associated with a nonresectable abdominal ganglioneuroblastoma. Before chemotherapy, she received intravenously administered IgG, 1 gm/kg, for 2 days; within 48 hours of the first dose, there was significant improvement of the opsoclonus-myoclonus and ataxia. She required a 1 gm/kg maintenance dose every 4 to 6 weeks for a total of 12 doses, but is now free of symptomatic after 2 years with no therapy.

Thrombocytopenia and absent radii syndrome: defective megakaryocytopoiesis-thrombocytopoiesis.

Thrombocytopenia and absent radii (TAR) syndrome is a congenital defect with osseous abnormalities and thrombocytopenia. It is inherited as an autosomal recessive trait, but the mechanism of thrombocytopenia in this disorder is not clear. We have had the opportunity to study the mechanism of thrombocytopenia in an infant with TAR syndrome. The infant had normal levels of thrombopoietin and megakaryocyte colony-stimulating activity in spite of marked thrombocytopenia. However, the megakaryocyte progenitor cells in the bone marrow produced abnormal colonies with increased numbers of megakaryocytes per colony and small megakaryocytes similar to the small megakaryocyte seen in vivo. These findings suggest that the TAR syndrome in this infant is due to a failure in the production of thrombopoietin or to an abnormal progenitor cell with a maturational defect.

Bone marrow transplantation improves survival for acute lymphoblastic leukemia in relapse: a preliminary report.

Acute lymphoblastic leukemia of childhood is the most common malignant disease in children greater than 1 year of age. Chemotherapy has improved the survival of children with this disorder. More than 95% of children will achieve a remission with chemotherapy. However, 30% of children with acute lymphoblastic leukemia who achieved a remission will have a relapse sometime after successful remission-inducing chemotherapy. Although a second remission can be induced in most of these children, in 10-40% a remission cannot be induced or they relapse shortly thereafter and develop refractory leukemia. We present in this preliminary report the early results of therapy for refractory leukemia with an intensive preparative regimen for bone marrow transplantation including etoposide, cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Transplantation was done in twenty-three patients with refractory leukemia. Projected survival at 917 days after transplantation in these patients is 43.4% +/- 11%. The survival of these patients so far is similar to the survival of children with acute lymphoblastic leukemia transplanted in second remission. All patients treated with this regimen who had transplantation in relapse were free of leukemia 27 days after transplantation. The results of this preliminary report suggest that an intensive preparative regimen can improve the outlook of refractory leukemia and may rescue some patients who otherwise would have died of their disease.

Acute megakaryocytic leukemia (M7) in children.

We analyzed the clinical and laboratory features of eight children (median age, 20 months; range, 13 months to 11 years) with acute megakaryocytic leukemia (M7) and compared the findings with those reported in the literature. The diagnosis was supported by ultrastructural examination for platelet peroxidase or immunophenotyping for glycoprotein IIb/IIIa or the von Willebrand factor protein. Two patients had Down's syndrome. Initial findings included anemia (in all patients), thrombocytopenia (in six), myelofibrosis (in three), lytic bone lesions (in two), and pronounced leukocytosis (in one). Stem cell culture studies of peripheral blood specimens revealed an aberrant phenotype of the megakaryocytes in one patient and reversal to a normal pattern after successful therapy. Remission was achieved in seven of the eight patients after aggressive chemotherapy, and four patients remained in remission 27 to 57 months after diagnosis. Three of these four patients underwent allogeneic bone marrow transplantation. M7 leukemia is not infrequent in children younger than 3 years of age, especially in those with Down's syndrome. The availability of monoclonal antibodies specific to restricted antigens of the megakaryocytic lineage has made the diagnosis of M7 leukemia both possible and practical.

Parvovirus B19 infection in patients receiving cancer chemotherapy: the expanding spectrum of disease.

Initial reports have suggested that human parvovirus B19 infection in immune-compromised individuals may cause prolonged or chronic bone marrow suppression. We report four children receiving cancer chemotherapy who developed atypical patterns of cutaneous and hematologic disease associated with parvoviral infection. B19 infection was demonstrated by specific serologies. This report suggests that patients undergoing myelosuppressive or immunosuppressive therapy may have unusual manifestations of infection and be at risk for complications associated with this common and widespread pathogen.

Megakaryocyte colony-stimulating factor (Mk-CSF): its physiologic significance.

Megakaryocyte colony-stimulating activity (Mk-CSA) is required for in vitro megakaryocyte colony formation. Its in vivo significance in megakaryocytopoiesis is unknown. We studied 12 patients undergoing bone marrow transplantation (BMT) at our institution. The bone marrow megakaryocyte progenitor cells (CFU-Mk), the serum level of Mk-CSA, and the platelet count on the 28th day after BMT were studied. Patients with elevated Mk-CSA levels had less CFU-Mk in their bone marrow than did patients with a normal or decreased Mk-CSA (p less than 0.01). Animal experiments using murine models have documented that several purified molecules including erythropoietin, multi-CSF and GM-CSF possess Mk-CSA. The in vitro Mk-CSF of WEHI-3-conditioned medium is multi-CSF. The in vivo significance for megakaryocytopoiesis of these factors is not clear. In the human system, Mk-CSA is increased in conditions with decreased bone marrow megakaryocytes. Recombinant human or primate CSFs have in vitro Mk-CSA utilizing both human and murine cells as targets. However, the presence of these activities does not fully explain the Mk-CSA in human serum rich in Mk-CSA. The precise regulation of human blood cell levels and the studies discussed suggest that there is a specific Mk-CSF that responds to in vivo changes in megakaryocyte numbers. Proof of its physiologic role awaits the isolation of a pure factor.

Miliary pulmonary neuroblastoma. A risk of autologous bone marrow transplantation?

A case of miliary pulmonary neuroblastoma is described which occurred 8 months after autologous bone marrow transplantation for Stage IV neuroblastoma. The patient, a 4-year-old boy had pulmonary symptoms at this time. Disseminated metastatic disease was found, but there was no tumor at the primary site. This unusual pattern of relapse suggests that the patient's disseminated disease was related to infusion of malignant cells at the time of transplantation.

Pattern of response of megakaryocyte colony-stimulating activity in the serum of patients undergoing bone marrow transplantation.

Bone marrow transplantation has become an accepted form of therapy for several malignant, hematologic, and genetic disorders. Platelet recovery is delayed after bone marrow transplantation. To better understand the mechanisms involved in platelet recovery we studied 23 patients undergoing bone marrow transplantation for the presence of megakaryocyte colony-stimulating activity (Mk-CSA) in their serum. Shortly after beginning the pretransplant preparative regimen the Mk-CSA level in the serum of these patients increased. This increase was transient, and the level returned to baseline, to later increase again. The second increase in Mk-CSA level occurred during the second week after bone marrow transplantation at the time of hematopoietic recovery. Most patients who failed to engraft did not show a rise in Mk-CSA during the second week after transplantation. All patients showing engraftment had an Mk-CSA rise during the second week after transplantation. The difference between these two groups was highly significant (p = 0.0007). The biphasic response of Mk-CSA after bone marrow transplantation is similar to the response seen in a rat model after lethal irradiation. We postulate that the first elevation in Mk-CSA is due to tissue injury and nonspecific response whereas the second elevation of Mk-CSA is a physiologic response to marrow aplasia and associated with effective bone marrow engraftment.