Secondary hemophagocytic lymphohistiocytosis induced by malaria infection in a child with Langerhans cell histiocytosis.

Since the first description of infection-associated hemophagocytosis (IAHS), the list of precipitating infectious agents causing hemophagocytic syndrome has grown. A lymphohistiocytic proliferation with hemophagocytosis may develop as a result of macrophage activation, viral or bacterial infection, parasitic infestations, or malignancy. The authors report on a 3-year-old boy with Langerhans cell histiocytosis (LCH), who developed IAHS during malaria infection. Hemophagocytic syndromes may complicate the course of LCH and cause diagnostics problems. Malaria is one of many infections that can precipitate secondary hemophagocytic lymphohistiocytosis.

Cost-effectiveness of cefepime + netilmicin or ceftazidime + amikacin or meropenem monotherapy in febrile neutropenic children with malignancy in Turkey.

Infection remains the major cause of morbidity and mortality in immunocompromised children with malignancy. In addition, the economic impact of antibiotic treatment should always be evaluated, especially in developing countries. In our center between January 1998 and January 1999, 73 children with hematological malignancies [acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML)]; 9 children with solid tumors (rhabdomyosarcoma, neuroblastoma) had 87 febrile neutropenic episodes (related to chemotherapy). These children were randomized prospectively into three treatment groups. The first group (n: 28) received cefepime plus netilmicin, while the second group (n: 29) was treated with ceftazidime plus amikacin and the third (n: 30) with meropenem as monotherapy. The aim of the study was to compare the success rates and cost of fourth generation cephalosporin plus aminoglycoside and monotherapy of meropenem with ceftazidime plus amikacin, which is the standard therapy for febrile neutropenia. Microbiologically documented infections were 29.9%, clinically documented infections were 9.2% and 60.9% of the febrile neutropenic episodes were considered to be FUO. Gram-positive microorganisms were the most commonly isolated agents from blood cultures [MRSA (Methicillin Resistant Staphylococcus aureus) in 6 patients and MSSA (Methicillin Sensitive Staphylococcus aureus) in 4 patients]. The success rates were 78.5%, 79.3% and 73.3 % for the 1st, 2nd and 3rd groups respectively. In 4 patients (4.5%) fever responded only to amphotericin-B therapy. There was no statistically significant difference between the three treatment regimens with respect to efficacy, safety and tolerance (chi2 test, p>0.05), but while the third and fourth generation cephalosporins + aminoglycosides were comparable for cost, the monotherapy regimen was the most expensive. The main determining factors for the choice of treatment of febrile neutropenic children, especially in a developing country, are cost, presence of indwelling catheter and the bacterial flora of the unit, as well as efficacy.

Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of relapsed or poor risk childhood acute leukemia.

The prognosis of relapsed acute leukemia or chronic leukemia in acute blast crisis is poor and new chemotherapeutic regimens could be useful for these patients. Six relapsed acute lymphoblastic leukemia (ALL), nine relapsed acute myeloblastic leukemia (AML), one chronic myelomonocytic leukemia (CMML) and one chronic myeloid leukemia (CML) in acute blast crisis between three to 18 years (median 10 years) received fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) chemotherapy (CT). Five of the AML relapses were after bone marrow transplantation (BMT) and four were recurrent relapses. At the end of the second course only three patients (2 AML, 1 ALL) were in complete remission (CR). Of the three patients in CR, one patient with AML had her first donor lymphocyte transfusion (DLT) on the 7th day of the second FLAG-IDA course and she is disease-free on the 30th month of the second remission. The remaining two patients were transplanted from unrelated donors in a BMT center abroad on the 5th and 8th month of the last remission and both died with BMT-related complications. Out of 25 courses, seven resulted in fatal infections. The regimen was ineffective in B-cell ALL as in acute blastic crisis of CMML and CML. We could not evaluate the remission-inducing effect accurately in most of the patients due to induction failure. FLAG-IDA appears to be a myelotoxic therapy for relapsed or poor risk leukemia in a developing country. It is not cost-effective; dose modifications or a regimen without IDA may be tried if there is an available marrow donor.

Is AML1/ETO gene expression a good prognostic factor in pediatric acute myeloblastic leukemia?

To assess the clinical significance of AML1/ETO gene detected by nested reverse transcriptase polymerase chain reaction, the outcome of 7 patients with acute myeloblastic leukemia between 3 and 14 years of age were presented. All patients had complete remission (CR) at the end of induction (AML-MRC 10 protocol) and 4 underwent unpurged autologous, 2 allogeneic (from matched siblings) non-T-cell-depleted bone marrow transplantations (BMT) in first CR. One patient died due to allogeneic BMT-related complications, and 4 patients relapsed at 13, 17, 18, and 26 months. Only one patient achieved second CR. All relapsed patients died between 18 and 36 months with resistant disease (n = 3) or infection during salvage chemotherapy (n = 1). Two patients who had autologous BMT are alive and disease free at 44 and 50 months. Although statistical significance could not be shown, event-free survival and overall survival rates of AML1/ETO-positive patients (28.57 and 28.57%, respectively) at 3.5 years were even lower than those of AML1/ETO-negative patients. The results confirm some previous reports that AML1/ETO gene in children and adolescents is not a favorable prognostic factor.

Results of rhabdomyosarcoma treatment in a developing country.

Fifty-one children (median age: 4.5 years; 4 months-16 years) diagnosed with rhabdomyosarcoma were treated in our center between 1980-1999. The primary sites were head and neck in 31.4%, the genito-urinary system in 21.6%, and extremities in 9.8% of the patients. The histopathologic subtypes were embryonal in 80.4%, alveolar in 9.8%, and undifferentiated in 9.8%. The majority of the patients were considered group III (47%) and group IV (25.5%) according the criteria of the Intergroup Rhabdomyosarcoma Study (IRS). Primary total tumour resection was performed in only 27.5% of the patients. The patients were treated with assigned regimens of IRS II and IRS III protocols. Radiotherapy was applied to 92.1% of the patients. Thirty-four patients (66.7%) were lost to follow up, and of the remaining 17 patients, 7 patients (41.2%) died, relapse occurred in 9 patients (52.9%) and 10 patients (58.8%) are alive. The percentage of cases lost to follow up during the first 10 years and the following 9 years of the study were 77.4% and 50%, respectively. In compliance with cancer treatment remains a major problem in developing countries.

Prognostic significance of wilms tumor 1 gene in childhood acute Lymphoblastic Leukemia.

Wilms tumor 1 (WT1) gene is a tumor supressor gene, expressed in malignant and normal hematopoietic progenitor cells. Prognostic significance of this gene in childhood acute lymphoid leukemia (ALL) is not clear. We evaluated the presence of WT1 expression in bone marrow samples of 28 children with de novo ALL at diagnosis by two step RT-PCR. Expression of WT1 gene was detected in 78.5% of patients. There was no correlation between WT1 gene expression and age, sex, FAB type, leukocyte count, and presence of t(4;11) and t(9;22). All patients were treated with modified BFM 86 protocol. There was no difference in the complete remission (CR) rate between WT1 positive and negative patients. Event free survival (EFS) and overall survival (OS) of WT1 positive and negative patients were also not significant. We conclude that expression of WT1 gene is not associated with specific characteristics of ALL blast cells and is not a prognostic factor for CR, remission duration and overall survival.

Detection of BCR/ABL transcripts by reverse transcriptase polimerase chain reaction in pediatric acute Lymphoblastic Leukemia: incidence and clinical eatures.

BCR/ABL expression, which is the molecular equivalent of the Philadelphia chromosome, is an independent poor risk factor in acute lymphoblastic leukemia (ALL). We used a two-step (nested) reverse transcriptase polimerase chain reaction (RT-PCR) assay to examine BCR/ABL expression in the diagnostic bone marrow specimen of children with ALL, prospectively. Among 75 de novo ALL patients, 4 (%5.3) were found to be BCR/ABL- ositive, whereas 4 of 17 relapsed patients (23.5%) were positive. This preliminary study in Turkish children showed an incidence similar to reports from Europe and the U.S.A. More intensive chemotherapies and allogeneic bone marrow transplantations (BMT) uring the first remission were planned if a donor was available. Out of 8 BCR/ABL-positive patients, complete remission (CR) was achieved in 7 patients and partial remission (PR) was achieved in 1 patient. Three patients underwent allogeneic BMT during the first CR and 1 under went autologous BMT during the first PR. The Kaplan-Meier estimate of vent-free survival (EFS) of BCR/ABL negative de novo ALL patients was 78.36% at 3 years, whereas the EFS of positive patients was 31.25% at 26 ± 6.4 months. Molecular screening for the Philadelphia chromosome should become a part of the routine diagnostic panel in ALL patients in order to predict which patients have a poor prognosis and need tailored therapy.

Acute lymphoblastic leukemia: dental health of children in maintenance therapy.

The dental health of 41 children aged 4-16 years who were in maintenance therapy from acute lymphoblastic leukemia (ALL) was examined in relation to the period of time in maintenance. There was no significant difference in dental experience and salivary flow rate between the control group and patients with leukemia. Performed treatment index (PTI) and required treatment index (RTI) scores reflected that children, who were in maintenance therapy had insufficient dental care and needed more dental treatments. A statistically significant difference in salivary pH was found between the children, who were in maintenance therapy for 12-24 months and less than 12 months and also the control group; but the pH scores of all groups were observed in normal limits.

Immunologic status in children with brain tumors and the effect of therapy.

The cellular and humoral immunological parameters (leucocyte, granulocyte, lymphocyte, total T, T4, T8 lymphocyte counts, lymphoproliferative response to PHA [LP-PHA], natural killer cell activity [NKCA], IgG, IgM and IgA levels) of 20 pediatric brain tumor patients were investigated before and after chemo-(CT) and radiotherapy (RT) administered according to the UIOI-PBT-91 protocol. The T4 and T8 cell percentages and the LP-PHA values before therapy were found to be significantly diminished in comparison to values obtained from 12 healthy children (p < 0.05). In patients receiving postoperative CT, all cellular immunity parameters except T8 cell number and NKCA; IgG and IgA levels were significantly decreased after two courses of CT (p < 0.05). In 7 patients given postoperative RT, a depression in all cellular immunity parameters was observed (p < 0.05). In 6 patients treated with 2 courses of postoperative CT followed by RT administered concomitantly with low dose CDDP, there was a decrease in all cellular and humoral immunity parameters, which was not found to be significant. In 5/18 patients infectious episodes in mild to moderate severity were observed, none causing mortality. It was concluded that the UIOI-PBT-91 protocol caused cellular immunosuppression both after CT and after RT and some humoral immunosuppression after CT, but was found to be tolerable in regard to acute immunological side effects.

Primary osteosarcoma of the cervical spine: a pediatric case report and review of the literature.

A 4 1/2-year-old girl with a primary osteosarcoma of the seventh cervical vertebra, treated by surgery and chemotherapy, and who is off therapy for 24 months with no evidence of disease is presented and the literature reviewed.

Epidural metastasis in Wilms' tumor: a case report and review of the literature.

Spinal canal involvement is not a common pattern of metastasis in Wilms' tumor. Although early detection and treatment can achieve improvement of neurological deficit, mortality remains high. We present a 5-year-old girl who had an epidural metastasis while she was receiving chemotherapy for stage IV Wilms' tumor. Within 2 months following laminectomy, total removal of tumor, radiotherapy, and adjuvant chemotherapy some of the neurological signs improved.

Non-midline endodermal sinus tumor in the head and neck region: a case report.

Germ cell tumors, in particular teratomas, are some of the most commonly found tumors in childhood. Six percent of all germ cell tumors are located in the head and neck region. Endodermal sinus tumors (yolk sac tumors) of the head and neck, exclusive of the central nervous system, are rare. This study reports a 20-month-old girl with a mass of 5 x 5 cm on the left temporal area and with bone destruction on CT. The histopathological examination of the excised mass revealed an endodermal sinus tumor. The serum AFP and the LDH levels were elevated at diagnosis. The patient was treated by the BEP protocol (bleomycin, etoposide, and cisplatin), six cycles every three weeks. Partial response was attained after the first and complete response after the fourth cycle. The patient, who is being followed up, has been in remission for five months.

The molecular basis of beta-thalassemia in Turkey.

By using oligonucleotide hybridization, restriction endonuclease analysis and direct sequencing of amplified genomic DNA, we have been able to characterize 18 different mutations in the beta-globin genes of 161 beta-thalassemia homozygotes and 107 beta-thalassemia heterozygotes from Turkey (429 beta-thalassemia chromosomes). Previous studies dealing with beta-thalassemia in Mediterranean countries have shown that, in most Mediterranean populations, only a few mutations are prevalent. In contrast, beta-thalassemia in Turkey does not seem to be associated with a few predominant mutations. The six most frequent alleles, IVS-I-110 (G----A), IVS-I-6(T----C), FSC-8 (-AA), IVS-I-1(G----A), -30(T----A) and FSC-5 (-CT), account for only 69.3% of the disease genes; indeed, all 26 mutations assayed represent 85.8% of the disease genes, confirming the considerable molecular heterogeneity of beta-thalassemia among Turks, and indicating the possible presence of rare, previously undefined, mutations in the population. Two mutations observed in this study, IVS-I-116 (T----G) and Cd44(-C), have not been reported in the Turkish population to date. Since preventive medical services, such as genetic counseling and prenatal diagnosis, are greatly improved by detailed knowledge of the molecular pathology of beta-thalassemia, we strongly believe that the presented data will facilitate the intended establishment of a prenatal diagnosis center, based on DNA analysis, in Turkey.

Molecular basis of beta-thalassemia in Turkey: detection of rare mutations by direct sequencing.

Using restriction endonuclease analysis, oligonucleotide hybridization, and direct sequencing of amplified genomic DNA, we characterized 11 different mutations in the DNA of 26 patients from Turkey homozygous for beta-thalassemia. We found that mutations IVS-1 nt110, IVS-1 nt6, and the frameshift at codon 8 were the most frequent. By direct sequencing we characterized two very rare mutations not previously reported in the Turkish population: a frameshift +1 at codons 9/10 and a nonsense mutation at codon 15.