Primary hemophagocytic lymphohistiocytosis in Turkish children.

Nineteen children with hemophagocytic lymphohistiocytosis (HLH) were studied in the Department of Pediatric Hematology, Hacettepe University. Patients were divided into two groups. Group 1: Thirteen patients were classified as having a genetic etiology (7 familial, 6 presumed familial) on the basis of an affected sibling and consanguinity. There was a history of consanguineous marriage in 13 of the families. Seven of them had a history of a sibling with HLH. Group 2: Six patients were diagnosed with sporadic HLH. The age at presentation for familial patients was 0.7-84 months (mean 21.9 +/- 24.9 months), and for sporadic cases it was 2.5-48 months (mean 22.7 +/- 19.8 months). The clinical and laboratory data of these two groups were similar at diagnosis. Thirteen cases were diagnosed premortem by bone marrow aspiration. Splenic biopsy was performed in 2 patients. Four patients were diagnosed by postmortem examination. Elevated LDH levels were found in all patients tested. No significant differences for clinical and laboratory data were found between the two groups.

Evaluation of children with myelodysplastic syndrome: importance of extramedullary disease as a presenting symptom.

Thirty-three children diagnosed with primary myelodysplastic syndrome (MDS) in a single institution over an 8 year period were evaluated with special emphasis on children who presented with extramedullary disease (EMD). EMD was present at diagnosis in 12 (36%) of the 33 children with MDS. Three patients with juvenile myelomonocytic leukemia (JMML) and 2 patients with chronic myelomonocytic leukemia (CMML) presented with pleural effusion. Pericardial effusion was present in 3 of these patients, two of whom also had thrombosis. Pyoderma gangrenosum, relapsing polychondritis were the initial findings in another two cases with JMML. Lymphadenopathy (n=1), gingival hypertrophy (n=2), orbital granulocytic sarcoma (n=1) and spinal mass (n=1) were the presenting findings in 5 patients with refractory anemia with excess of blasts in transformation. Since high-dose methylprednisolone (HDMP, 20-30 mg/kg/day) has been shown to induce differentiation and apoptosis of myeloid leukemic cells in children with different morphological subtypes of acute myeloid leukemia in vivo and in vitro, 25 children with de novo MDS were treated with combined HDMP and cytotoxic chemotherapy. Dramatic improvement of EMD and decrease in blast cells both in the peripheral blood and bone marrow were obtained following administration of short-course HDMP treatment alone as observed in children with AML. HDMP, combined with low-dose cytosine arabinoside and mitoxantrone were used for the remission induction. Remission was achieved in 8 (80%) of 10 children who presented with EMD and in 9 (60%) of 15 children without EMD. Long-term remission (>6 years) was obtained in 4 (two with JMML and two with CMML), three of whom presented with EMD. In conclusion EMD can be a presenting finding in childhood MDS as observed in adults. In addition, the beneficial effect of HDMP combined with more intensive chemotherapy should be explored as alternative therapy in children with MDS not suitable for bone marrow transplantation.

The analysis of eosinophil and lymphocyte phenotype following single dose of high-dose methylprednisolone in two siblings with marked hypereosinophilia.

The effect of single high-dose methylprednisolone (HDMP) on eosinophil and lymphocyte phenotype in two siblings with marked hypereosinophilia was investigated. Since conventional dose steroids failed to produce a haematological and clinical response in case one, both children were given HDMP (20 mg/kg/day). Eosinophils and lymphocytes showed an activated state before treatment, characterized by marked expression of CD11b, CD18, CD45RO on eosinophils and increased HLA-DR, CD95, CD18, CD38 on lymphocytes. Twenty-four hours after administration of HDMP a dramatic reduction in peripheral blood eosinophil count was observed in both patients associated with phenotypic changes characterized by decreased expression of CD11b, CD18, CD13 and increased CD95 expression in one. Furthermore, HDMP treatment induced a drop in the expression of CD95 and CD18 on lymphocytes. These changes may suggest a suppressive role for HDMP on eosinophil and lymphocyte activation which may have contributed to the haematological and clinical response.

Tetrasomy 8 as a primary chromosomal abnormality in a child with acute megakaryoblastic leukemia. a case report and review of the literature.

Tetrasomy 8 is a relatively rare chromosomal abnormality in hematological disorders, and is mostly associated with myeloid malignancies and poor prognosis. In a number of cases, tetrasomy 8 has been reported as an accompanying anomaly with other chromosomal changes. In this report, we describe a 14-year-old girl with acute megakaryoblastic leukemia associated with tetrasomy 8 (primary) and trisomy 6, 19 and 20. She died 6 months after diagnosis, suggesting a relatively poor prognosis for AML with tetrasomy 8. To the best of our knowledge, this is the first report of a tetrasomy 8 abnormality associated with subtype FAB M7. Interestingly, this abnormality has not been previously reported in childhood AML patients.

Effect of short-course, high-dose steroid therapy in a child with myelodysplastic syndrome.

High-dose methylprednisolone (HDMP) has been shown to induce differentiation of myeloid leukemic cells with a remarkable antileukemic effect in children with various subtypes of acute myeloblastic leukemia (AML). Here the beneficial effect of short-course HDMP therapy in a child with myelodysplastic syndrome (MDS) is reported. Oral methylprednisolone sodium succinate (Prednol-L) was administered at a single daily dose of 30 mg/kg for 5 days to a 4-year-old girl with refractory anemia with excess of blasts and hypocellular bone marrow before the initiation of chemotherapy. In addition to dramatic clinical improvement, the patient's white blood cell count increased from 2.3 x 10(9)/L to 5.0 x 10(9)/L, and peripheral blood blast cells disappeared 4 days after HDMP treatment. Repeated bone marrow aspirate 1 week after the initiation of HDMP disclosed increased cellularity with no blasts. Furthermore, short-course HDMP treatment stimulated the increase in the number of peripheral blood lymphocytes and CD3+, CD4+, CD8+, CD19+, CD34+, and NK cells. Results obtained with HDMP from the previous studies and the present case suggest that high-dose methylprednisolone is a promising agent in the treatment of AIDS and it is recommended as an initial treatment especially for MDS children with hypocellular bone marrow at presentation.

Allogeneic bone marrow transplantation for children with myelodysplastic syndrome.

Six children with myelodysplastic syndrome underwent allogeneic bone marrow transplantation (BMT) from their HLA-identical siblings. Ages ranged from six to 16 years. French-American British (FAB) diagnosis was refractory anemia with excess blasts (RAEB) in three, RAEB in transformation (RAEB-t) in one and chronic myelomonocytic leukemia (CMML) in two cases. Two patients had progressed to leukemia before BMT. All patients received busulfan and cyclophosphamide as a conditioning regimen. Antithymocyte globulin (ATG) was administered to two of them due to the multiple transfusion history. Graft versus host disease (GvHD) prophylaxis consisted of cyclosporine-methotrexate. Engraftment was documented in all patients except one who underwent a second infusion of bone marrow cells. She died in the early post-transplant period with pancytopenia and veno-occlusive disease of the liver. Two patients died from disease recurrence. Three patients are alive > 12 months post-transplant, two are in remission and one just relapsed at +16 months and is now being prepared for a second bone marrow transplant. The only significant factor for favorable outcome was short duration between diagnosis to transplant in the two patients in remission.

CD34/CD117 co-expression in childhood acute leukemia.

CD117 protein is expressed by the primitive CD34 positive haemopoietic stem cells and also demonstrated on the blasts of 30-100% of AML cases, but rarely on lymphoblasts. Therefore several investigators have used CD117 expression to exclude lymphoblastic origin of blasts. However, conflicting results exist in the literature. We investigated CD34 and CD117 status at initial presentation of 232 children with acute leukemia. CD34 was commonly expressed in all types of acute leukemias, whereas CD117 molecule seemed to be a more specific marker for leukemia of myeloid origin being demonstrated on > 5% of blasts in 60 out of 73 cases of AML patients, but rarely detected in ALL (9/140 patients). Moreover, co-expression of CD34/CD117 was extremely rare on lymphoblasts with only 3/140 ALL patients demonstrating > 5% co-expression of CD34 and CD117, and therefore we suggest that it should be used in the exclusion of ALL.

Myelodysplastic syndrome associated with monosomy 7 in a child with Bloom syndrome.

Bloom syndrome is a genomic instability syndrome associated with predisposition to development of various types of malignancy. In this report, we described a 7-year-old boy with Bloom syndrome (BS) and myelodysplastic syndrome (MDS) associated with monosomy 7 and loss of the Y chromosome. To our knowledge, this was the first case with BS showing monosomy 7 and MDS during the early childhood period.

Loss of maternal allele in a child with myelodysplastic syndrome and monosomy 7.

Monosomy 7 or partial deletion of the long arm of chromosome 7 is frequently described in children with myelodysplastic syndrome and acute myeloblastic leukemia. Parental origin of chromosome 7 in children with sporadic monosomy 7 has been examined very rarely. To investigate if monosomy 7 shows parent-of-origin, we have studied a female child with monosomy 7 and de novo myelodysplastic syndrome by a series of polymorphic polymerase chain reaction markers. We found loss of maternal allele and discussed the results with the previous reports.

Differentiation of leukemic cells induced by short-course high-dose methylprednisolone in children with different subtypes of acute myeloblastic leukemia.

Differentiation of myeloid leukemic cells to mature granulocytes by high-dose methylprednisolone (HDMP, 20-30 mg/kg/day) with a favorable antileukemic effect has previously been demonstrated in children with acute promyelocytic leukemia and acute myeloblastic leukemia (AML) M4. In the present study, three children with other morphological subtypes of AML (two AML M1, one AML M2) were given methylprednisolone (30 mg/kg/day) orally in a single dose. After a short-course (3 or 7 days) of HDMP treatment alone, a striking decrease in blast cells associated with an increase in maturing and abnormally nucleated polymorphonuclear-like cells some containing Auer rods were detected in all patients in peripheral blood or bone marrow smears. During HDMP treatment, in parallel to morphological improvements, marked increases in the percentage of cells expressing granulocytic antigen (CD15) were observed. The increase of CD15 expression on myeloid cells, together with the steady expression of CD34 and CD117 antigens in Casel(AML M1) , is suggestive of aberrant CD34 + CD117 + CD15 + cells, which may indicate the leukemic origin of the maturing myeloid cells. These results suggest that HDMP treatment may induce differentiation of myeloid leukemic cells in some children with different morphological subtypes of AML, and that the differentiation-inducing effect of HDMP should be explored in other malignant diseases.

Effects of methylprednisolone on human myeloid leukemic cells in vitro.

We have demonstrated previously that high-dose methylprednisolone treatment induces differentiation and apoptosis of leukemic cells in patients with different morphological subtypes of acute myeloblastic leukemia (AML) in vivo. In the present study, we investigated the in vitro effects of high (10(-3) M) and low (10(-6) M) concentrations of methylprednisolone (MP) on freshly isolated bone marrow leukemic cells from nine newly diagnosed patients with AML by light and electron microscopy (EM) and agarose gel electrophoresis. A marked increase in MP-induced apoptosis of leukemic cells, with a maximum effect at 24 hr of exposure to both low and high concentrations of MP (10(-6) M and 10(-3) M), was demonstrated by light microscopy in cultures of four (three with AML-M1 and one with AML-M7) of the nine patients. In three cases, the increase in the number of apoptotic cells induced by high-concentration MP was approximately twice that observed when the lower concentration was used. A few apoptotic cells were detected in the cultures from the other five patients. However, a typical DNA ladder pattern of apoptosis was observed on gel electrophoresis of MP-treated leukemic cells from one patient (AML-M1) after 2 hr of incubation with both high- and low-MP concentrations. In two patients, a nonspecific DNA smear was observed only when high-concentration MP was used. The increase in differentiated leukemic cells induced by MP was also dose dependent, and was observed in cultures from all but one patient. Morphological features of apoptosis and differentiation were also confirmed by EM studies. The results of the present study, together with our previous clinical experience, suggest that MP, especially at high doses, could have a significant role in the treatment of some AML patients by inducing apoptosis and differentiation of leukemic cells.

Autoimmune hemolytic anemia with warm antibodies in children: retrospective analysis of 51 cases.

In this paper, research based on 51 children with a positive antiglobulin test is presented. Eighteen of the children had acute anemia and 33 had chronic anemia. Two clinical patterns were distinguished: an acute transient type and a prolonged chronic type. Corticosteroid therapy was effective in all acute cases but its results were variable in the chronic cases. The acute form was more frequent in young children, while chronic autoimmune hemolytic anemia (AIHA) occurred mainly among children at puberty. In the chronic form of the disease, it was sometimes necessary to add immunosuppressive drugs and in two cases to perform a splenectomy.

Biphenotypic characteristics, cell size and prognosis in childhood acute myeloblastic leukemia.

In order to determine the prognostic significance of cell size together with expression of biphenotypic markers in childhood acute myeloblastic leukemia (AML), we evaluated the cell size of children with AML, 12 with and 21 without biphenotypic markers. The patients were followed up for at least 12 months. The cells which were stained with FITC conjugated surface marker antibodies were divided into small, middle or large cell groups according to their mean channel number of forward scatter by flow cytometry. Nine of 12 biphenotypic and 15 of 21 non-biphenotypic children either died or relapsed within the first 12 months. The percentages of the small, middle and large cells were similar in children and in deceased patients, regardless of whether or not they expressed biphenotypic markers. We believe that biphenotypic marker expression is a poor prognostic factor regardless of cell size.

Myelodysplastic syndrome associated with Griscelli syndrome.

Myelodysplastic syndrome (MDS) in children has been reported to be associated with various constitutional anomalies; however, it has not been described previously in patients with Griscelli syndrome (GS). In this report, we present a case with GS and refractory anemia with an excess of blasts. We believe that careful evaluation of peripheral blood and bone marrow could increase the number of patients who are found to have GS-associated MDS.

Dramatic resolution of pleural effusion in children with chronic myelomonocytic leukemia following short-course high-dose methylprednisolone.

High-dose methylprednisolone (HDMP) which can induce--differentiation and -apoptosis of myeloid leukemic cells has been shown to be very effective in the treatment of extramedullary infiltration (EMI) of children with acute myeloblastic leukemia (AML). In the present study 2 children with chronic myelomonocytic leukemia (CMML) who had pleural effusions were given a single daily dose of oral methylprednisolone (20 mg/kg or 30 mg/kg). In addition to dramatic improvement of respiratory symptoms, pleural effusions disappeared in four days in both patients possibly due to apoptotic cell death induced by HDMP treatment. Further studies are needed to determine whether high-dose corticosteroids are also effective on the resolution of pleural effusions associated with other malignant disease.

Retrospective analysis of 78 children with chronic idiopathic thrombocytopenic purpura: follow-up from 1976 to 1996.

In this retrospective study of 20 years, 78 children with chronic idiopathic thrombocytopenic purpura (ITP) were analyzed. Patients were followed for 1-17 years (median 2.7 years). Every application that required therapy was accepted as an "attack." Seventy-eight patients received therapy in 236 attacks. Immediate platelet responses to high-dose methylprednisolone (HDMP), prednisone, and splenectomy were 69.3% (in 53 patients), 48.3% (in 35 patients), and 84.6% (in 29 patients) of attacks, respectively. Because 31 patients were lost to follow-up, the rate of remission was calculated on the basis of 47 patients. The remission rates for patients who underwent remission spontaneously, after steroid therapy, and after splenectomy were 29.78, 6.38, and 14.89%, respectively. Of 78 adolescent patients, 11.5% had intracranial hemorrhage (ICH), being after splenectomy. One patient died because of ICH. These data indicate that chronic ITP is still a serious problem during adolescence and splenectomy still seems to be a current choice of therapy.