Search

The experience with immune tolerance (IT) induction therapy for haemophilia patients with inhibitors, instituted during 1990-97 at 17 haemophilia treatment centres in the western United States, was reviewed. IT was instituted in 104 of 139 (75%) of all identified haemophilia A and haemophilia B patients with inhibitors. Doses and schedules for IT varied but most patients were treated with a daily administration of 25-200 units kg-1 day-1. Successful immune tolerance (defined as Bethesda Unit titres < 1.0) was achieved in 57 of 81 (78%) patients who completed therapy. IT success was significantly greater for those patients with historic titres < 100 BU (P < 0.0003) and those with titres of < 10 BU at initiation of IT (P < 0.0001). IT success was uniformly achieved in 16 patients with low to moderate responding inhibitors. IT in infants < 2 years of age was problematic due to the presence of high titre inhibitors and complications of venous access. Frequent complications of IT included increased bleeding during intravenous access device insertion (20%) and infections associated with venous access devices (64%). IT is widely accepted as a treatment modality for haemophilia patients with inhibitors. Patient participation in IT regimens and management during therapy is facilitated greatly by the efforts of treatment centre nurse coordinators who are knowledgeable about haemophilia and its complications. Additional clinical trials will be necessary to define better initial dose, schedule, dose adjustment and success/failure criteria for IT.

Pharmacokinetic and pharmacodynamic data on adrenergic agents in children have revealed wide ranges of plasma clearance rates and hemodynamic responses in patients with critical illnesses or myocardial dysfunction. In order to more clearly elucidate the underlying pharmacologic processes, graded i.v. dobutamine infusions of 0.5, 2.5 and 5.0 micrograms/kg/min were sequentially administered to healthy children and adolescents. Plasma dobutamine concentrations and hemodynamic responses, including echocardiographic measures of systolic and diastolic function, were determined at each infusion rate. Pharmacodynamic data were evaluated by both threshold modeling and mean hemodynamic responses to each infusion rate. Mean plasma dobutamine clearance was 115 +/- 63 ml/kg/min, with an intersubject variability greater than 5-fold. These data establish that the previously published wide variability in dobutamine clearance is not due simply to underlying disease states. Dobutamine clearance was linear over the dosage range evaluated. Dobutamine improved systolic function even at plasma concentrations attained with infusion rates as low as 1 to 2 micrograms/kg/min. The improved systolic function was at least partially due to inotropic effects. In addition, dobutamine improved diastolic function and reduced afterload. Chronotropic effects were observed in only two subjects and only at higher plasma concentrations than the other hemodynamic effects. Individualized threshold modeling effectively described the log-linear relationship between plasma dobutamine concentration and hemodynamic response beyond the threshold concentration.

Doxorubicin is an effective anticancer chemotherapeutic agent known to cause acute and chronic cardiomyopathy. To develop a more sensitive echocardiographic screening test for cardiac damage due to doxorubicin, a cohort study was performed using dobutamine infusion to differentiate asymptomatic long-term survivors of childhood cancer treated with doxorubicin from healthy control subjects. Echocardiographic data from the experimental group of 21 patients (mean age 16 +/- 5 years) treated from 1.6 to 14.3 years (median 5.3) before this study with 27 to 532 mg/m2 of doxorubicin (mean 196) were compared with echocardiographic data from 12 normal age-matched control subjects. Graded dobutamine infusions of 0.5, 2.5, 5 and 10 micrograms/kg per min were administered. Echocardiographic Doppler studies were performed before infusion and after 15 min of infusion at each rate. Dobutamine infusion at 10 micrograms/kg per min was discontinued after six studies secondary to a 50% incidence rate of adverse symptoms. The most important findings were that compared with values in control subjects, end-systolic left ventricular posterior wall dimension and percent of left ventricular posterior wall thickening in doxorubicin-treated patients were decreased at baseline study and these findings were more clearly delineated with dobutamine stimulation. End-systolic left ventricular posterior wall dimension at baseline for the doxorubicin-treated group was 11 +/- 1.9 mm versus 13.1 +/- 1.5 mm for control subjects (p less than 0.01). End-systolic left ventricular posterior wall dimension at the 5-micrograms/kg per min dobutamine infusion for the doxorubicin-treated group was 14.1 +/- 2.4 mm versus 19.3 +/- 2.6 mm for control subjects (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

A 7-month-old girl with acute biphenotypic leukemia [t(4;11)] had accompanying anemia, thrombocytopenia, and a white blood cell count of 535,000/microL with 98% blasts. Before instituting chemotherapy, therapeutic leukapheresis was done to reduce the threat of complications from leukostasis. Using a Cobe Spectra blood cell separator primed with modified blood, we processed 1,395 mL of her blood, removing 201 mL of the buffy coat containing 5.8 x 10(10) white blood cells. This reduced the WBC count to 301,000/microL. Only a single procedure was done, without significant complications. The rationale of this preparatory cytoreduction is discussed critically. Subsequent chemotherapy resulted in a long-lasting remission.

Serial determinations of the absolute granulocyte and platelet counts were performed in 40 infants with severe neonatal necrotizing enterocolitis. Fourteen of the 38 infants had absolute granulocyte counts less than 1,500 nm3, the mean absolute granulocyte count was significantly lower in the group of infants who died during the acute episode of NEC as compared to that of the infants who survived. Thrity-five of 40 infants had nadir platelet counts less than 150,000/nm3, clinical bleeding occurred in 12 of the thrombocytopenic infants. Fourteen thrombocytopenic infants were evaluated for disseminated intravascular coagulation by additional coagulation studies; six were noted to have laboratory evidence of DIC. We conclude that (1) a low absolute granulocyte count in severe NEC is associated with a poor prognosis and (2) thrombocytopenia is a significant problem in severe NEC and may occur with or without evidence of fulminant intravascular coagulation.

The hematologic manifestations and clinical course are described for six children and adolescents with bone marrow monosomy 7. One child with secondary acute myelogenous leukemia had monosomy 7 plus a marker chromosome; the remaining patients had marrow monosomy 7 as the only karyotypic abnormality. The hematologic abnormalities were diverse, but the majority of patients had a smoldering preleukemic or myeloproliferative phase. Leukemic blasts were either undifferentiated or demonstrated evidence of myeloid differentiation. All patients responded poorly to antileukemic therapy. Bone marrow monosomy 7 was observed in one patient with severe marrow hypoplasia. Antileukemic therapy in another patient with greater than 30 per cent marrow blasts was associated with the development of a bone marrow myeloproliferative disorder with persistence of the monosomy 7 karyotype. We speculate that monosomy 7 may be a specific marker for a pluripotent hematopoietic stem cell abnormality that is associated with either blastic leukemia or a myeloproliferative disorder.

Serum varicella-zoster (VZ) antibody titers were determined by a simple, indirect immunofluorescent antibody technique in 50 children with leukemia or non-Hodgkin's lymphoma. Sixteen children had initial antibody titers that were not detectable at a serum dilution of 1:8 and were considered to be susceptible to varicella. Thirty-one patients had initial serum VZ antibody titers of 1:16 or greater, while three had levels of 1:8. The serum antibody titer was 1:8 or greater in 16 children with a history of varicella. Seven episodes of localized herpes zoster were observed in children whose VZ titer was 1:8 or greater prior to onset. Two nonfatal infections with primary varicella developed in children with leukemia in remission whose initial titers were less than 1:8 and were associated with a convalescent rise in VZ antibody to levels greater than 1:16. Three susceptible children received zoster immune plasma or zoster immune globulin for varicella exposure, causing a transient rise in serum VZ titer. The assessment of serum VZ titer by this immunofluorescent antibody technique combined with the prior varicella history is useful in defining the population of children with leukemia and non-Hodgkin's lymphoma who are susceptible to primary varicella.

Serial echocardiographic studies were performed on 48 children who received chemotherapy with doxorubicin hydrochloride (Adriamycin). For the group as a whole, no correlation could be made between the cumulative dose of doxorubicin administered and left ventricular systolic function as measured by the fractional shortening of the left ventricle (delta s). Two asymptomatic patients, however, demonstrated depressed delta s and abnormal results from radionuclide studies at cumulative doxorubicin doses of less than 430 mg/sq m. Differentiation of the echoderived curve of left ventricular minor axis dimension indicated that these two patients had abnormalities in both diastolic and systolic function. Good correlation was demonstrated between echocardiographic and radionuclide studies in eight patients, including the two with depressed function. Inherent variability limits the sensitivity of echocardiographic functional studies, but serial studies are helpful in the evaluation of cardiac function in children who receive doxorubicin.

Ten patients with AML refractory to anthracyclines and cytosine arabinoside were treated with vincristine 1.4 mg/m2 and methotrexate (MTX) 2.5 gm/m2 by intravenous (IV) bolus on day 1 [citrovorum factor (CF) rescue began 24 h later], BCNU 80 mg/m2, and cyclophosphamide 900 mg/m2 IV 36 h after MTX and MGBG 300 mg/m2 IV over 1-2 h on days 3, 4, and 5. Bone marrow aplasia was achieved in all patients by day 12. Five patients (50%) achieved complete remission (CR). Two patients died of sepsis during induction. The median duration of remission was 24 weeks (range 8-38). Maintenance therapy was employed in three patients (high-dose MTX-CF in 2 and MGBG plus BCNU in 1), but did not appear to significantly increase the duration of remission. Nausea and vomiting occurred in eight patients. Five patients developed moderate stomatitis and one developed a moderately severe cutaneous reaction. This pilot experience demonstrates that patients with refractory AML can achieve CR after aggressive treatment with so-called second-line drugs. and may indicate that collateral sensitivity to MTX exists in cells which have become resistant to anthracyclines, a situation we previously described in an experimental cell line.

This report describes an 11-7/12-year-old girl with leiomyosarcoma of the stomach metastatic to liver who was treated with surgical resection and combination chemotherapy, which included adriamycin. She remains well 52 months after diagnosis and 27 months after cessation of chemotherapy. The favorable course of this patient suggests that aggressive adjuvant chemotherapy should be considered for patients with leiomyosarcoma who have poor prognostic features.

Neutrophil (PMN) bactericidal activity, phagocytosis, and nitroblue tetrazolium (NBT) reduction were evaluated in 18 children with untreated or relapsing acute leukemia and 20 children in hematologic remission. Half of the patients in relapse demonstrated abnormal PMN bactericidal activity, while remission patients had essentially normal PMN bactericidal activity. Phagocytosis of Staphylococcus aureus was normal in relapse and remission subjects. NBT reduction by PMN's of leukemic patients was significantly lower than that of controls, but there was no correlation between decreased NBT-reductase activity and decreased bactericidal power. Six patients in remission had received intensive chemotherapy for more than 4 years, and all demonstrated normal PMN functions. Among relapse patients with abnormal PMN bactericidal activity 63% eventually developed severe bacterial infections. By comparison, 20% of the relapse patients with normal PMN bactericidal activity subsequently developed severe infections. The PMN dysfunction observed in relapse patients suggests that abnormal PMN bactericidal activity may contribute the increased susceptibility to bacterial infections during leukemic relapse.

Spontaneous mitoses in the blood of 67 patients with acute leukemia were enumerated and their identity determined by cytogenetic methods. Most patients were children with acute lymphoblastic leukemia. Simultaneous 16- to 20-hour cultures of blood leukocytes (Bu) and of bone marrow (BM) cells were performed without phytohemagglutinin (PHA). Blood leukocytes were also cultured with PHA for 72 hours (BPHA). Mitoses in Bu cultures were counted, and karyotypic analysis performed on cells from the three culture types. In 21 control subjects, Bu cultures usually yielded no mitoses. Relapse and remission patients both displayed significantly more Bu mitoses than the controls. The karyotypes of Bu, BPHA, and BM mitoses in remission patients were normal. Fifty percent of relapse patients displayed cytogenetically abnormal leukemia cell lines; the percentage of their abnormal karyotypes was significantly higher in BM cells than in Bu or BPHA cells. The majority of the mitotic cells in Bu cultures from both relapse and remission patients appear to be of a nonleukemic origin. The number of mitoses could not be correlated with type of leukemia, hematologic parameters, or prognosis.

The clinical and histopathological findings in 26 children with non-Hodgkin's lymphoma without initial marrow involvement are reviewed. A marked male predominance similar to that observed in previous series was noted. Biopsy material was classified according to the recommendations of Rappaport in 22 cases. All have diffuse lymphomas, and 16 of 22 patients had involvement of the mediastinum as part of their initial presentation. Of these 12, 5 developed lymphomatous involvement of the central nervous system prior to the development of leukemic transformation of the bone marrow. This observation suggests that prophylactic therapy against CNS relapse be considered for children with mediastinal non-Hodgkin's lymphoma, even in the absence of initial marrow involvement.

Children with neuroblastoma whose opsomyoclonus recurs or persists after initial surgery should be carefully evaluated for tumor. If no tumor is detectable, therapy with ACTH should be considered in patients whose symptomatology is severe enough to compromise normal development.

This investigation was designed to evaluate echoes of patients who received a course of doxorubicin (225-550 mg/m2) by two sensitive indicators of myocardial fibrosis: (1) M-mode scans of thickening-thinning curves of the left ventricular posterior wall (LVPW), and (2) two-dimensional qualitative evaluation of LVPW contraction at three levels of the LV short axis (leaflet, chordal, and papillary). These were compared to standard M-mode shortening fraction (delta S). Eighteen children with cancer were evaluated; 11 had received doxorubicin and 7 were treated with other agents. Echocardiographers were unaware of the treatment category. All controls and 10 of 11 doxorubicin patients had normal delta S. An M-mode echocardiogram of the expanded LVPW was digitized and wall thickness was evaluated by determining if diastolic relaxation had the normal two phases or only one; six of ten doxorubicin patients and no controls had abnormal relaxation. Qualitative evaluation of LVPW and septal contraction toward the center of the ventricle showed that seven of eleven patients who received doxorubicin and one control (a postthoracotomy patient) had contraction deficits. Six of seven with contraction deficit were the same patients with slowed relaxation. The greatest contraction deficit occurred in the LVPW behind the posterior mitral leaflet. Patients with more extensive involvement had an additional contraction deficit extending to the apex. These tests are more sensitive for detection of doxorubicin toxicity than delta S.

A 22-month-old girl developed a rapidly fatal erythrophagocytic syndrome associated with evidence of acute EB viral infection. The association of hemophagocytic syndromes with viral, bacterial, and parasitic infections is discussed. All cases diagnosed as histiocytic medullary reticulosis should include attempts to detect possible association with infectious agents in addition to the assessment of host response.

Two children who presented initially with a lymphoid malignancy were noted to develop recurrences with myeloid features late in the course of their disease. In both cases, evidence of lymphoid differentiation was present in the myelogenous cells that were Ph1 chromosome negative. The first patient had acute myelogenous leukemia and developed a recurrence with morphologic features of acute myelogenous leukemia. Terminal transferase was present in the myelogenous blasts. The second patient initially had a diffuse lymphoblastic non-Hodgkin lymphoma. During the course of her illness she developed a myeloproliferative disorder characterized by basophilic meningitis, splenomegaly, and hypereosinophilia. Lymphocyte T-cell (E-rosette) markers were present on the eosinophils. These observations lend further support to the hypothesis of varying lymphoid and myeloid differentiation in certain cases of leukemia.

The diagnosis and treatment of cancer in adolescents produce changes in their activities, relationships, and concerns. This case study explores these changes and formulates an approach to help such adolescents live meaningfully as they experience their illness.

A growing literature supports the concept that some cases of neuroblastoma are hereditary. To this we add the first known case, to our knowledge, of neuroblastoma in a parent and child. Various factors, such as the remarkable tendency for this tumor to regress spontaneously, as well as its frequent fatal outcome, have reduced the number of observed familial cases. It is important that siblings and progeny of patients with neuroblastoma be examined to detect possible subclinical neuroblastoma.