The ochsner experience with acute lymphoblastic leukemia in childhood.

Pediatricians at Ochsner Clinic and Alton Ochsner Medical Foundation have treated children with acute lymphoblastic leukemia for the past 17 years with excellent results. Although a single institution, and small in comparison to the national cooperative groups, we have achieved results comparable to the most successful national groups. In collaboration with the Dana-Farber Cancer Institute in Boston, MA, we have pursued several themes of study, including the comparison of various drugs, doses, and schedules of administration in the context of an investigational window in previously untreated patients. Schedules and dosages of radiation for prevention of relapse of leukemia in the central nervous system have also been studied with interesting results.

Nutritional status of children with leukemia.

Children with cancer represent a high-risk group for protein-energy malnutrition due to side effects associated with treatment. Assessment of nutritional status at the time of diagnosis and during treatment is, therefore, essential for planning nutritional intervention. We studied the nutritional status of 25 children with leukemia [9 newly diagnosed/relapsed (D/R) leukemic patients and 16 children with leukemia in remission (REM)]. Plasma proteins (prealbumin, PA; albumin, Alb; transferrin, Tr; retinol-binding protein, RBP) and acute phase-reactant proteins (alpha 1-acid glycoprotein, AGP; C-reactive protein, CRP; ceruloplasmin, CER) were measured by radial immunodiffusion. Results show that there were no significant deficits in anthropometric measurements among leukemic children. In contrast, the mean levels of all plasma proteins, especially PA (P < 0.005), were significantly lower in the D/R group than in the REM group. All D/R children, compared to 59% of those in remission, had PA levels < 20 mg/dl. Only the D/R group had abnormal levels of RBP, Tr, and Alb. Children who were treated with prednisone had significantly higher mean levels of PA, RBP, and AGP than those who were not receiving prednisone. The mean levels of acute phase-reactant proteins in these leukemic children were comparable to those of healthy children. We conclude that mild/moderate malnutrition is common in leukemic patients at D/R and that PA seems to be the most sensitive indicator of visceral protein status.

Epidemiologic features of pain in pediatric cancer patients: a co-operative community-based study. North Central Cancer Treatment Group and Mayo Clinic).

The prevalence, etiology, and management of pain in pediatric cancer patients seen at the Mayo Clinic and member institutions of the North Central Cancer Treatment Group were assessed. Participating centers, including both primary care and referral institutions, surveyed all patients seen during a 1-week period (Monday through Friday); procedure-related pain was excluded. Of the 160 children surveyed, 28 reported pain of which 57.8% was related to a side effect of anticancer treatment, 21.1% was unrelated to the malignancy, and 21.1% arose directly from the cancer. Pain intensity assessment was performed by both health-care professional and patient using a variety of measurement tools. Correlation between assessors was close except in young children. The predominance of treatment-related rather than cancer-related pain differs from results in series in adult cancer patients.

Gallium-67 scans as an adjunct to computed tomography scans for the assessment of a residual mediastinal mass in pediatric patients with Hodgkin's disease. A Pediatric Oncology Group study.

This study determines the utility of gallium-67 (Ga-67) scintigraphs as an adjunct to computed tomography (CT) scans for the assessment of residual mediastinal masses in children and adolescents with advanced-stage Hodgkin's disease. At diagnosis 42 patients with CT scan-documented mediastinal disease had a Ga-67 scan performed. Thirty-four of 42 patients (81%) had gallium-avid mediastinal lesions, whereas in eight (19%), the Ga-67 scan was negative. At the completion of eight cycles of therapy of Mustargen (mechlorethamine), Oncovin (vincristine), procarbazine, prednisone (MOPP) alternating with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), 21 of 34 patients with initially positive Ga-67 scans had them repeated; 18 of 21 converted to negative results, and three remained positive. In 11 of 18 patients, the loss of gallium avidity was consistent with a negative mediastinal CT scan. In seven, although the gallium scan was negative, the CT scan remained positive; all seven patients had a mediastinal biopsy of suspected residual disease and in all seven the biopsy results were negative for Hodgkin's disease. These preliminary results in a small cohort of patients demonstrate that Ga-67 scans may be of benefit in evaluating residual mediastinal masses in patients with Hodgkin's disease.

Primary extracranial neuroblastoma with central nervous system metastases characterization by clinicopathologic findings and neuroimaging.

The authors report the clinicopathologic and neuroimaging findings in ten children with primary abdominal or thoracic neuroblastoma who relapsed in the central nervous system (CNS) without evidence of concurrent intracranial extension from adjacent bone, dura, or dural sinus metastases. At diagnosis, the patients ranged in age from 0.3 to 4.5 years (median, 2 years). Their times to CNS relapse ranged from 2 to 34 months from diagnosis. In seven patients the relapse occurred from 1 to 14 months after elective discontinuation of therapy. In four patients, the CNS relapse was the primary (isolated) adverse event. Four patients could not be treated at the time of relapse, and they died within 7 days of progressive CNS disease. In the remaining group, craniospinal irradiation with or without administration of a platinum compound and an epipodophyllotoxin caused complete CNS remissions lasting 4, 5, 16, and 62+ months. Neuroimaging and autopsy findings indicated that cerebrospinal fluid is the major pathway for neuraxis dissemination by neuroblastoma cells. There was no evidence of dural penetration in any patient. The possibility of relapse in the neuraxis should be considered for any patient with neuroblastoma who had neurologic deterioration. A combination of craniospinal radiation and administration of a platinum compound and an epipodophyllotoxin will induce complete responses in some patients with neuraxis involvement by neuroblastoma, but the risk of subsequent failure outside the CNS remains high.

Postoperative treatment of nonmetastatic visible residual neuroblastoma: a Pediatric Oncology Group study.

The Pediatric Oncology Group (POG) evaluated in a prospective study the hypothesis that patients who had localized, visible residual neuroblastoma without regional lymph node involvement after surgery (POG stage B) have a favorable prognosis when treated with moderate intensive chemotherapy. Eligible patients were initially treated with five courses of Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co., Evansville, IN) and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) followed by surgery (CY/AD +/- surgery). Those patients not achieving a complete remission (CR) crossed over to five courses of cisplatin and teniposide (PL/VM) +/- surgery. Radiation therapy (XRT) was given to selected patients who still were not in CR after the crossover therapy. Of the 61 eligible patients, 38 (62%) patients achieved CR after CY/AD proven by clinical (31) or surgical (seven) evaluation. One (2%) patient in clinical partial remission (PR-C) entered CR without further therapy. Nineteen (31%) patients achieved CR with the following salvage therapies: surgery (five), PL/VM +/- surgery (five) followed by XRT (three) or autologous bone marrow transplant (ABMT) (one) and further courses of CY/AD +/- PL/VM instead of courses of PL/VM (five). The overall CR rate was 95% (58 of 61). Four patients had recurrence of the disease. The probability of being disease-free at 3 years after initial or salvage therapy was estimated at 84% (SE, 5%). The overall prognosis of children older than 1 year and younger than 1 year was similar (P = .26). If, however, the three remission deaths (all younger than 1 year) were censored, there was only one other failure in 32 children younger than one versus seven of 29 children older than 1 year (P = .018). These results confirm the excellent prognosis for patients with POG stage B neuroblastoma and indicate that most patients are curable with CY/AD +/- surgery, and those not achieving CR with this therapy are curable with alternate therapy.

Isolated CNS involvement in Ewing's sarcoma.

Ewing's sarcoma, an uncommon malignant neoplasm of bone, represents about 10% of all the malignant primary bone tumors. The assumption that subclinical metastases are already present in patients with apparently localized tumor indicates the need for systemic therapy as an integral part of primary treatment. The usual sites of metastases are the lungs and skeletal system. Central nervous system (CNS) involvement is rare and is usually seen only in disseminated and fairly advanced disease. We report two patients in whom, after aggressive adjuvant chemotherapy, disease developed in the CNS without local recurrence. In one patient, meningeal involvement with malignant cells was identifiable in the cerebrospinal fluid; in the second patient, who presented with a space-occupying lesion, a diagnosis of arachnoid involvement was made histologically.

Pernicious anemia and juvenile-onset diabetes mellitus in an adolescent: a case report.

We report a case of a 15-year-old black boy who developed juvenile-onset pernicious anemia in association with insulin-dependent diabetes mellitus. He had both intrinsic factor and parietal cell antibodies in addition to anti-islet cell surface antibodies. The existence of pernicious anemia and diabetes mellitus in such a young child makes this an unusual case.

Neutrophil agglutinins in idiopathic chronic neutropenia of early childhood.

Twelve patients with chronic neutropenia, ranging in age from 7 to 27 months, were studied for circulating antineutrophil autoantibodies. Absolute neutrophil counts ranged from 0 to 500/cu mm. None of the patients was transfused or had a history of prior drug ingestion. Edetic acid-microagglutination was employed to detect leukocyte antibodies. Sera from six of 12 patients contained antineutrophil antibodies, four reacting with neutrophils from the father and two from the mother. Patient sera also reacted with neutrophils of several unrelated normal volunteers. Four of the six patient sera with antineutrophil antibodies also reacted with autologous neutrophils. The duration of neutropenia was seven months in one patient with antibody whose neutropenia resolved. Patients with neutrophil autoantibody did not clinically differ from those without demonstrable antibody. The coexistent fall in leukoagglutinin titer and rise in neutrophil counts in one patient suggested an etiologic role for this antibody. Detection and proper diagnosis have important therapeutic implications.

Cobalamin malabsorption in three siblings due to an abnormal intrinsic factor that is markedly susceptible to acid and proteolysis.

Three siblings presented in their second year of life with megaloblastic anemia that responded to parenteral cobalamin (Cbl). Schilling tests were less than 1%, correcting to 5 to 15% after addition of hog intrinsic factor (IF). Gastric acid analysis and gastric biopsies were normal by light and electron microscopy. Gastric juice contained less than 3 pmol/ml of Cbl-binding ability due to IF (normal, 10-34 pmol/ml) and less than 2 pmol/ml of IF when measured with a radioimmunoassay (RIA) using normal human IF-[57Co]Cbl and rabbit anti-human IF serum (normal, 17-66 pmol/ml). However, RIA employing rabbit anti-hog IF serum gave values of 4-13 pmol/ml of IF (normal, 11-33 pmol/ml). This material had an apparent molecular weight of 40,000 (normal IF = 70,000). The IF from gastric biopsies appeared normal in terms of Cbl-binding ability, ileal binding, molecular weight, and both RIAs. This IF differed from normal mucosal IF, in that it lost its Cbl-binding ability when incubated at 37 degrees C at acid pH or in the presence of pepsin or trypsin. This loss was retarded when [57Co]Cbl was bound to the IF before these incubations. The stabilizing effects of neutralization and Cbl were also demonstrated in vivo. Schilling tests for the siblings of 0.4, 0.5, and 1.0% increased to 2.7, 5.7, and 4.3% (P less than 0.05), respectively, when the Schilling tests were repeated with the addition of NaHCO3 and cobinamide (which allows Cbl to bind immediately to IF). We conclude that Cbl malabsorption in these children is due to an abnormal IF that is markedly susceptible to acid and proteolytic enzymes which cause a decrease in its molecular weight and Cbl-binding ability and a loss of antigenic determinants that are recognized by the anti-human IF serum.

Thermostable erythrocyte rosette-forming lymphocytes in hereditary hemochromatosis. I. Identification in peripheral blood.

Although the immunoregulatory role of iron has been demonstrated in vitro, evidence for a similar role in vivo is controversial. We have, therefore, studied certain functional and structural properties of lymphocytes in hereditary (idiopathic) hemochromatosis (HH), a disease characterized by iron overload. T- and B-lymphocyte percentages in peripheral blood, serum immunoglobulin levels, and proliferative responses of peripheral blood mononuclear cells (PBM) to lectins were comparable with those of controls. Furthermore, HH serum with elevated iron concentrations did not significantly alter proliferative responses of normal lymphocytes to mitogens. In contrast to those normal findings was the identification of a subset of T lymphocytes in HH that formed rosettes with sheep red blood cells (SRC) at 37 degrees C in abnormally high numbers. Those lymphocytes that formed thermostable erythrocyte rosettes (TE-R) were not immature thymocytes, activated T lymphocytes, or an artifact of passive attachment of anti-SRC antibodies to the HH lymphocyte surface. Their presence did not correlate with a concentration of iron in the serum, the length of treatment, or the presence of the HLA antigen, A3. We conclude that the cellular expression of HH may be detected not as an immunological abnormality, but rather as an abnormality in receptor expression.

Thermostable erythrocyte rosettes in chronic renal failure and allograft rejection.

Rejection of an allograft usually is preceded by activation of T lymphocytes, in which state such cells may be identified by their ability to form thermostable rosettes with sheep erythrocytes (TE-R). The objective of the present work, therefore, was to determine whether or not enumeration of TE-R in the peripheral blood was of any value in the diagnosis of rejection. The results showed no significant differences between TE-R (mean +/- SEM) in normal subjects (9.9 +/- 1.3; n = 25), renal allograft recipients without rejections (13.5 +/- 1.7; n = 5) and in patients who suffered from acute tubular necrosis in the posttransplant period (12.4 +/- 2.5; n = 8). In contrast, recipients who had rejection episodes showed a marked rise in TE-R levels (43.0 +/- 4.0; n = 11) about two to seven days prior to the diagnosis of rejection by clinical and chemical criteria. Furthermore, TE-R remained high if the rejection episodes turned out to be irreversible after therapy (42.2 +/- 3.7) but fell if the episodes were reversible (19.9 +/- 3.2). TE-R values were elevated in patients with chronic renal failure on maintenance hemodialysis (45.7 +/- 4.9; n = 23). Neither acute dialytic runs or acute infections altered TE-R values. In conclusion, those results show that enumeration of TE-R may be helpful in the early diagnosis of allograft rejection, before clinical and chemical stigmata are apparent.