Lymphomatous presentation of childhood acute lymphoblastic leukemia. A subgroup at high risk of early treatment failure.

Multivariate analyses of the clinical course of 1537 children with acute lymphoblastic leukemia (ALL) identified a subgroup which experienced short remission duration and a high incidence of extramedullary relapse. The patients differed from other ALL patients by the presence at diagnosis of two or more of a constellation of clinical and laboratory features: organomegaly or mass disease, E-rosette positivity, hemoglobin level greater than 10 g/dl, leukocyte count greater than 50,000/microliters, male predominance, and older age. This type of presentation of ALL is referred to as the "lymphoma syndrome" (LS) since such patients exhibit a pattern of several clinical and laboratory features which were observed repeatedly but in differing combinations, and some of which clinically resemble lymphoma. A subsequent database from 2231 patients was analyzed. Patients with a mediastinal mass, massive splenomegaly, or massive adenopathy, alone or in combination, had a worse outcome when the patient also had either leukocytosis, E-rosette-positive lymphoblasts, or a normal or near normal hemoglobin (Hb) level at diagnosis. Similarly, the above three laboratory features alone or in combination did not predict less than 40% disease-free survival (DFS) unless they were accompanied by at least one of the clinical features of mass disease. When at least one clinical feature and at least one laboratory feature were present, the overall DFS was 36% 6 years after diagnosis versus 64% for all other patients. The association of these features with poor prognosis remained significant after adjusting for the level of leukocyte count at diagnosis, age at diagnosis, and sex of the patients. Patients with this recurrent syndrome of features do not represent a homogeneous biologic entity but they constitute a subgroup of patients with ALL having a high risk of treatment failure using current therapies, including failure to achieve remission, early relapse, and increased frequency of relapse in extramedullary sites. They deserve early recognition at diagnosis and selection of treatment strategies appropriate for very high risk ALL.

Transient myeloproliferative disorder of the Down type in the normal newborn.

Two infants with congenital nonlymphoblastic leukemia were discovered to have mosaicism for trisomy 21. Both infants achieved durable spontaneous remissions. Trisomy was apparently restricted to the leukemic clone and could be detected in neither phytohemagglutinin-stimulated peripheral blood cells or bone marrow in either patient nor in myeloid progenitor cells from the second patient after resolution of the transient myeloproliferative disorder. We conclude that spontaneous remission of congenital leukemia is not confined to infants with partial or complete systemic trisomy 21 but can occur in genetically normal newborns whose leukemic cells contain a third chromosome 21.

Attenuation of asparaginase-induced hyperglycemia after substitution of the Erwinia carotovora for the Escherichia coli enzyme preparation.

L-asparaginase, an enzyme with established antileukemic activity, increases the induction rate and duration of remission of acute lymphoblastic leukemia when added to vincristine and prednisone for induction therapy. Enzymes derived from two different bacterial sources (Escherichia coli and Erwinia carotovora) are in common use. These enzymes may be associated with toxic reactions of differing frequency and severity. Specifically, the complication of enzyme-induced hyperglycemia may be seen more frequently after exposure to the E. coli product. The authors present two patients in whom it was necessary to substitute the Erwinia enzyme for the E. coli enzyme because of the occurrence of severe allergic reactions to the E. coli enzyme. Hyperglycemia induced by the first product improved after the substitution, suggesting that the Erwinia enzyme may be less diabetogenic than the E. coli enzyme.

Interleukin 1-dependent paracrine granulopoiesis in chronic granulocytic leukemia of the juvenile type.

Marrow and peripheral blood cells from nine children with juvenile chronic granulocytic leukemia (JCGL) demonstrated intense (94 +/- 16% maximum) spontaneous granulocyte/macrophage colony growth but cells from five children with the adult variety of CGL did not. This unusual pattern of colony growth depended upon a stimulatory protein(s) produced by mononuclear phagocytes. No GM-CSA activity was found in any chromatofocused fraction of JCGL monocyte-conditioned media but an activity that induced GM-CSA in umbilical vein endothelial cells was detected at pI 6.9-7.2. Moreover, the CSA-inducing monokine was neutralized by an anti-IL-1 antibody in vitro and, in the one case so tested, the same antibody also inhibited "spontaneous" colony growth. Therefore granulocyte/macrophage colony growth in JCGL is characteristically abnormal and distinguishes JCGL from the adult form of the disease. This abnormality depends upon the production, by mononuclear phagocytes, of IL-1 which, in turn, stimulates the release of high levels of colony stimulating activity by other cells. The high proliferative activity of CFU-GM we found in JCGL patients, and the high levels of GM-CSA found in their serum are compatible with the view that the in vitro abnormality reflects a similar abnormality in vivo.

Unsuspected non-Hodgkin's lymphoma of the tonsils and adenoids in children.

Six children with lymphoreticular malignancy arising in the pharyngeal tonsils or adenoids are presented. Early clues to the possible malignant nature of the enlargement of tonsils and adenoids in this series include: asymmetric and persistent enlargement, the absence of such manifestations of infection as fever or pain, and the association of atypical adenopathy. Lack of clinical suspicion brings with it the risk of delayed diagnosis and possible compromise of optimal therapy.

Enhanced lymphocyte response to PHA among leukemia patients taking oral lithium carbonate.

Seven children receiving maintenance therapy for acute lymphoblastic leukemia (in remission) were given oral lithium carbonate for 12 weeks. Hematologic values, serum immunoglobulin levels, and responsiveness of peripheral blood mononuclear cells to mitogen stimulation were studied during the lithium treatment period, and compared to measurements made during a 12-week period when no lithium was administered (children served as their own controls). Changes attributable to treatment with lithium carbonate included increases in total white blood cell count, circulating neutrophil count, and response to phytohemagglutinin-P. No important toxicity to lithium carbonate was observed.

Significance of X granules in histiocytosis X: an ultrastructural study.

Histiocytosis X is characterized by the presence of cytoplasmic rod structures called Langerhans' cell granules or X granules (XG). It has been speculated that histiocytosis X is a Langerhans' cell disorder. This ultrastructural study was performed to quantitate the number of XG containing histiocytes in the histiocytosis X lesions. Twenty-four specimens from 22 patients with histiocytosis X were studied: 4 from skin, 5 from lymph node, 11 from bone, 2 from lung, 1 from gingiva, and 1 from cheek. The majority of the histiocytes in histiocytosis X lesions do not contain X granules. The majority of the histiocytes in histiocytosis X lesions do not contain X granules. The percentage of histiocytes with XG in a lesion has no relation to the age of the patient or the organ from which it was obtained, except for skin, where they were quite numerous. The relative percent-age of histiocytes with granules does not correlate significantly with the prognosis of these patients.

T-lymphocyte--mediated granulopoietic failure. In vitro identification of prednisone-responsive patients.

To identify patients with T-lymphocyte--mediated granulopoietic failure, we compared clonal growth of unfractionated bone-marrow cells with that of autologous marrow cells from which T lymphocytes had been removed, in a group of 234 patients. We also attempted to identify prednisone-responsive patients by culturing both unfractionated and T-depleted cells with and without glucocorticoids in vitro. Ninety-three patients were treated with prednisone for two to four weeks. Neutropenia resolved in 24 of 25 patients whose colony growth was enhanced by glucocorticoids in vitro, but in none of 68 whose cultures showed no response (P = 10(-10). Hemopoietic inhibitory T cells were found in 21 of the 24 prednisone-responsive patients. When these 21 patients were restudied during steroid treatment, the hemopoietic inhibitory cells were undetectable in steroid-responsive patients but were present in steroid-resistant patients. T lymphocytes can mediate granulopoietic failure in a variety of conditions, and in vitro studies identify most of the patients with these conditions. Hemopoietic inhibitory T cells are often steroid-sensitive, and in vitro study accurately predicts responses to steroid therapy.

Aleukemic leukemia cutis: juvenile chronic granulocytic leukemia presenting with figurate cutaneous lesions.

We report a 3 1/2-year-old girl who developed a figurate cutaneous eruption. Distinctive findings in her skin biopsies, as well as unusual red cell characteristics, in the presence of a normal peripheral smear and bone marrow biopsy, led us to suspect the diagnosis of preleukemic juvenile type chronic granulocytic leukemia. This is the first case we know of in which this diagnosis was suspected prior to abnormal findings in the peripheral smear or bone marrow.

Prolonged second remissions in childhood acute lymphocytic leukemia: a report from the Childrens Cancer Study Group.

To date, median duration of second and subsequent remissions in childhood acute lymphocytic leukemia (ALL) has been short, with most studies reporting median remission duration less than 6 months. In May 1979, the Childrens Cancer Study Group (CCSG) undertook a pilot study to assess the efficacy of a vincristine, methotrexate, and L-asparaginase regimen (modified Capizzi) for maintenance in children with ALL in second or subsequent remission. Thirty patients were treated with this maintenance regimen. By life table analysis, predicted median duration of hematologic remission was 57 weeks. Ten patients (33%) were in continuous hematologic remission at 1 year and three (10%) continue in remission greater than 2 years from maintenance onset. Major toxicity included leukoencephalopathy in four patients, three of whom had experienced at least one central nervous system relapse prior to study entry. Allergic reactions to Escherichia coli L-asparaginase were common. Nine of 30 patients experienced at least one CNS relapse during therapy. We conclude that a modified Capizzi regimen is the most effective regimen reported to date for maintaining second and subsequent remission in childhood ALL. CCSG is currently utilizing this regimen in an ongoing open study.

Selenium and vitamin E sufficiency in premature infants requiring total parenteral nutrition.

A randomized prospective study of LBW infants was undertaken to evaluate the effect of parenteral lipid infusions upon their antioxidant systems. Ten babies received a parenteral nutrition regimen with lipid emulsion, and ten received a regimen without lipid. Although the addition of lipid emulsion to the total parenteral nutrition regimen led to a rise in vitamin E levels, the selenium levels fell in both groups. Neither group showed evidence of deficient antioxidant systems by the peroxide hemolysis test or thiobarbituric acid test. There did not seem to be any adverse effect of the lipid infusion upon the clinical course of the infants except for hyperlipidemia. There was a better weight gain in infants receiving lipid.

Vincristine in the etiology of toxicity of high-dose methotrexate therapy.

A 14-year-old received a six-hour infusion of methotrexate (71/2 g/M2) with vincristine (2 mg) and citrovorum rescue according to a standard protocol for adjunctive chemotherapy of osteogenic sarcoma. Signs of mild vincristine toxicity occurred from 2-5 days following the infusion; these including jaw pain, decreases in deep tendon reflexes, and a transient ileus. Clearance of serum methotrexate was delayed during the period of ileus and severe methotrexate toxicity was observed.

Juvenile chronic granulocytic leukemia: emphasis on cutaneous manifestations and underlying neurofibromatosis.

Five patients with juvenile chronic granulocytic leukemia are described. Two patients had multiple cafe-au-lait spots compatible with von Recklinghausen's neurofibromatosis, and three had cutaneous xanthomata. Recurrent cutaneous leukemic infiltrates were noted in two patients. The clinical course of all five patients was characterized by recurrent respiratory symptoms and pulmonary infiltrates that responded to antileukemic therapy in three. Chemotherapy controlled the symptoms but did not influence the eventually fatal outcome.

Congenital mesoblastic nephroma and polyhydramnios.

Polyhydramnios and premature delivery complicated the pregnancies of three women whose infants were born with renal tumors. In each case the tumor was a mesoblastic nephroma. The liquid of polyhydramnios enhances detection of masses in the fetal abdomen by ultrasound. In the future, mesoblastic nephroma may, therefore, be diagnosed antenatally. Tumors in these infants, which have proved in most cases to be benign, are usually cured by surgical removal. Occasionally, local infiltration and adhesions prevent removal. The fate of the infant with residual tumor is not known.

Contribution of angiography to the diagnosis, staging and assessment of radiation and chemotherapy of solid abdominal malignancies in children.

Sequential angiographic studies were done in six children to stage and assess the results of radiation and/or chemotherapy of solid abdominal malignancies: one bilateral Wilms' tumor, two neuroblastomas, two hepatoblastomas and one hepatocarcinoma. Angiography was of value in demonstrating the tumor, its location, extent and vascular characteristics, as well as its regression and recurrence. Wilms' tumor and neuroblastoma responded and well to radiation and chemotherapy with substantial decrease in tumor size and regression or disappearance of tumor neovasculature. Resceted tumors revealed this to be due to tumor necrosis, hemorrhage and/or cystic degeneration. Hepatoblastoma and hepatocarcinoma did not respond as well to chemotherapy, with only mild decrease in size and neovasculature of the tumor.

Experience with incompatible maternal donors for bone marrow transplantation.

Marrow transplantation in aplastic anemia and leukemia has generally been limited to siblings who have been histocompatible at both the serological (A and B) and lymphocyte determined (D or MLC) loci of the HLA system. We studied three male patients, two with aplastic anemia and one with acute myelogenous leukemia, who received transplants from their histoincompatible mothers. MLC studies between donors and recipients showed varying degrees of stimulation. Definite engraftment occurred in one patient and transient engraftment in another. Engraftment in the third patient could not be evaluated. In the patient with sustained engraftment, there was clinical evidence of severe graft versus host disease (GVHD) however, this was not substantiated by histologic findings. This preliminary study suggests that MLC incompatibility may be more of an indicator of the risk of GVHD than of bone marrow rejection. If more effective control of GVHD can be accomplished, marrow transplantation between MLC-reactive individuals may become feasible.

Angiography in the diagnosis of liver disease in children.

75 angiographic examinations were done in 64 children aged 1 day to 16 years; 41 with various liver diseases and 23 with normal lives. The angiographic diagnosis was accurate in 95% of 44 patients where proof was established by surgery and/or biopsy. Properly used hepatic angiography is a reasonably safe procedure of great value in diagnosing and planning the surgical management of liver masses. It is also a useful tool in the diagnosis of diffuse hepatic processes of neoplastic, inflammatory or degenerative origin.