Noriko Esumi

High serum ferritin level as a marker of malignant histiocytosis and virus-associated hemophagocytic syndrome

Serum ferritin level was measured serially in three malignant histiocytosis (MH) and five virus‐associated hemophagocytic syndrome (VAHS) patients. Serum ferritin levels were greater than 1000 ng/ml at the early phase of disease. When disseminated intravascular coagulation (DIC) developed in patients, serum ferritin levels elevated further to greater than 12,000 ng/ml. MH patients were treated by combination chemotherapy, and VAHS patients were given prednisone. Each MH and VAHS patient died within 1 week from the onset of DIC, without decrease of serum ferritin level. One MH patient with continued high serum ferritin levels for 3 months after DIC also died. The remaining patients with decreased serum ferritin values less than 1000 ng/ml at 3 months after DIC are now alive with normal serum ferritin levels. These results suggest that serum ferritin level in histiocytic proliferative disorders is a useful indicator of disease activity in both neoplastic and reactive conditions rather than only a marker of malignant process.

Hyperferritinemia in Malignant Histiocytosis, Virus-Associated Hemophagocytic Syndrome and Familial Erythrophagocytic Lymphohistiocytosis.: A Survey of Pediatric Cases

ABSTRACT. Data on 28 patients with malignant histiocytosis (MH), fourteen patients with virus‐associated hemophagocytic syndrome (VAHS) and two patients with familial erythrophagocytic lymphohistiocytosis (FEL) were collected from 21 hospitals in Japan to study the serum ferritin levels and clinical features. At diagnosis, the serum ferritin values were a median of 3000 ng/ml (range, 59–270000 ng/ml) in MH and 10500 ng/ml (range, 44–68600 ng/ml) in VAHS/FEL. Clinical signs and symptoms were not substantially different between MH and VAHS/FEL. Thus, serum ferritin markedly increased in the majority of MH/VAHS/FEL patients and should be a useful marker of disease activity in either neoplastic or reactive histiocytic proliferative disorders.

Malignant histiocytosis in childhood: Clinical features and therapeutic results by combination chemotherapy

Ten children, four males and six females, with malignant histiocytosis were treated from July 1980 to July 1984. None of them had an affected sibling with a similar disorder. Septic-type fever, hepatosplenomegaly, lymphadenopathy, pulmonary infiltration, and disseminated intravascular coagulation were common signs and symptoms, and convulsion occurred in four cases. The diagnosis was made from bone marrow smears in all cases. In five cases, biopsy or autopsy specimens confirmed the diagnosis. In five cases studied, proliferating histiocytes in lymph nodes were demonstrated to be S100 protein-positive. All patients were treated with adriamycin, cyclophosphamide, vincristine, and prednisone (ACOP). Complete response was achieved in four patients after two to three courses of ACOP, and another case attained complete remission after further drug treatment. The five complete responders are now alive without evidence of disease after 23-48 months from the onset. Among partial and no responders, four died within 3 months and one has been alive with disease for 2 months. Bone marrow aspiration is useful for prompt diagnosis, and early treatment with intensive combination chemotherapy improves the prognosis of malignant histiocytosis in childhood.

Etoposide and cytosine arabinoside combination chemotherapy for refractory acute lymphocytic leukemia in childhood.

Eighteen children with refractory acute lymphocytic leukemia (ALL) who had been heavily pretreated, were treated with combination etoposide and cytosine arabinoside (ara-C) chemotherapy. Seventeen of these 18 patients were in their first to third relapses; the remaining patient had never responded to induction therapy. The drug combination of etoposide followed by ara-C was administered as an intravenous (IV) infusion twice a week for two consecutive weeks, a total of four doses. The dosage was 150 mg/m2/dose for each drug. Seven (39%) of the 18 patients attained a complete remission (CR) and three (17%) attained a partial remission (PR). Complete response was obtained in two of eight patients in first marrow relapse, and in five of nine patients in second and third relapse. Five patients achieved a CR after one course of therapy and two achieved a CR after two courses of therapy. Of three patients who had previously received teniposide, two attained a CR with this combination. The duration of these responses was brief with a median of 1 month, ranging from 0.5 to 3 months, with the exception of one case, which has been in remission for 2.5 + months. Although myelosuppression was observed, none of the patients died from infection or bleeding. Allergic reaction with fever and rash was observed in two patients. The efficacy of the etoposide and ara-C combination for refractory childhood ALL is encouraging in several current reinduction regimens.

Procoagulant Activity of Human Neuroblastoma Cell Lines, in Relation to Cell Growth, Differentiation and Cytogenetic Abnormalities

Procoagulant activity (PCA) was investigated in relation to cell growth, differentiation, and cytogenetics in seven human neuroblastoma cell lines. Before 5‐bromodeoxyuridine (BrdUrd) treatment, PCA was notably heterogeneous, with the highest activity in NCG (S‐type in morphology) 40‐to 100‐fold greater than the lowest activity in SK‐N‐D2 (N‐type). PCA was not related to 1p abnormalities. After BrdUrd treatment at 5 μg/ml for 6 days, PCA increased 6.8‐fold in GOTO and 2.7‐fold in SK‐N‐DZ with associated growth inhibition and morphological changes (I‐type morphology converted to S‐type in GOTO and N‐type converted to an advanced N‐type in SK‐N‐DZ). In contrast, only growth suppression was observed in 2 other cell lines, and no changes in PCA, growth or morphology were induced in the remaining 3 cell lines.

Therapeutic effects of human leukocyte interferon on chronic active hepatitis B in children

Seven children with chronic active hepatitis (CAH) and one child with persistently abnormal results of liver function tests due to hepatitis B virus (HBV) infection were treated with human leukocyte interferon (Hu-IFN). Five of them were positive for eAg and two of the three who were measured for DNA polymerase (DNAP) activity in sera showed moderate elevations of its levels. Hu-IFN was injected intramuscularly daily or once weekly at doses of 0.05–1 x 106 IU. The total dose per patient varied from 10.5–54 x 106 IU. After administration of Hu-IFN, rapid loss of eAg was observed in two of the five eAg patients, and DNAP activity reverted to normal ranges in the two patients with moderate elevations of its levels. One of the patients who lost eAg has retained normal serum glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase levels for more than 2 years after therapy with Hu-IFN. Serial hepatic biopsies were performed in only one patient. In the second biopsy, 3 months after therapy with Hu-α-IFN, infiltration of inflammatory cells in the portal region was improved compared with earlier findings. Immediate and/or prolonged adverse side effects were not observed during or after administration of Hu-α-IFN. For the present, we propose these six conditions for use of Hu-α-IFN in children with HBV infection. Children should: (a) be more than 1 year old; (b) have abnormal liver function for more than 6 months; (c) have a liver biopsy demonstrating CAH; (d) have moderate elevation of DNAP activity; (e) be eAg positive; and (f) be unresponsive to other treatments.

Distinct mechanism of human neuroblastoma cell adhesion to fibronectin

We investigated the adhesion of three morphologically distinct human neuroblastoma cell lines (NCG, GOTO and SK-N-DZ) to intact fibronectin, central cell binding domain fragment (CBF) and CS peptide-IgG conjugates in the fibronectin molecule. Each cell line was found to express different integrin fibronectin receptors (α3β1,α4β1 and α5β1), although similarly attached on intact fibronectin. To CBF, NCG attached well, while GOTO moderately and SK-N-DZ poorly attached. Only GOTO adhered to CS1-IgG. RGDS inhibited the spreading of NCG and SK-N-DZ on intact fibronectin, but it barely inhibited that of GOTO. The analysis by fluorescence-activated cell sorting (FACS) revealed that NCG expressed abundant α3β1 and α5β1, but little α4β1, while GOTO expressed a large amount of α4β1 as well as α5β1. SK-N-DZ was undetectable in any of these molecules, but expressed αvβ1, which was identified by immunoprecipitation and immunoblotting. Polyclonal antibody to αvβ3 inhibited the adhesion of SK-N-DZ but not that of NCG or GOTO on intact fibronectin. These results suggest the existence of a distinct mechanism of cell adhesion to fibronectin among human neuroblastoma cell lines. It remains to be determined if such heterogeneous adhesion properties are related to the unique metastatic character of human neuroblastoma.

Abnormal serum phenylalanine-tyrosine ratio and hyperferritinemia in malignant histiocytosis

Nine cases of childhood malignant histiocytosis (MH) showed an abnormally high serum phenylalanine (Phe)/tyrosine (Tyr) ratio (3.47 +/- 1.32) coincident with hyperferritinemia (50,800 +/- 33,600 ng/ml). Lactate dehydrogenase activity was also increased in these patients. These values were compared with data on sera from two groups of patients, acute leukemia cases (n = 14) and measles cases (n = 13), and with control values from normal healthy children (n = 38). The Phe/Tyr ratio was 1.57 +/- 0.54 for the acute leukemia (p less than 0.01) and 2.58 +/- 1.46 for the measles cases (NS), serum ferritin was 245 +/- 124 ng/ml for acute leukemia (p less than 0.01) and 167 +/- 117 ng/ml for measles (p less than 0.01). Accordingly, the concurrence of both abnormalities is considered to be characteristic for MH. It was also found that both serum Phe/Tyr ratio and ferritin levels reflect the disease activity, indicating that these two factors are useful prognostic indicators in the treatment of patients with MH.

Hyperphenylalaninemia in Malignant Histiocytosis and Virus-Associated Hemophagocytic Syndrome

It has been known for more than 2 decades that amino acid changes accompany various forms of infectious diseases. In some of these infections, an elevation in the phenylalanine/tyrosine ratio has been reported (1–4). Similar amino acid changes have also been described in protein calorie malnutrition (5) and chronic renal insufficiency (6). So far, however, such changes have not been clearly described in patients with hematologic neoplasias, especially for proliferative disorders of mononuclear macrophages. Nor has the actual occurrence of hyperphenylalaninemia in association with infectious or neoplastic disorders been reported. Recently, we encountered 2 patients with malignant histiocytosis (MH) (7) and a case of virus‐associated hemophagocytic syndrome (VAHS) (8). In all three patients the disease took a very rapid and fatal course with multiple organ dysfunction associated with hyperphenylalaninemia (>400 μmol/l) and an increased serum phenylalanine/tyrosine (Phe/Tyr) ratio (>4.00) (Table 1).