657del5 mutation in the NBS1 gene is associated with Nijmegen breakage syndrome in a Turkish family.

We report on a consanguineous Turkish family whose first son died of anal atresia and whose second son presented with severe pre- and post-natal growth retardation as well as striking microcephaly, immunodeficiency, congenital heart disease, chromosomal instability and rhabdomyosarcoma in the anal region. The proband was found to carry the homozygous 657del5 mutation in the NBS1 gene, which is responsible for Nijmegen breakage syndrome (NBS) in most of the Slav populations. Our family, the first diagnosed with NBS in the Turkish population, represents one of the most severely affected examples of the syndrome, with profound pre- and post-natal growth retardation associated with structural abnormalities, and expands the clinical spectrum of this rare disorder.

Serum levels and differential expression of CD44 in childhood leukemia and malignant lymphoma: correlation with prognostic criteria and survival.

BACKGROUND: The CD44, a cell surface proteoglycan, participates in a variety of function including tumor dissemination and metastasis. However, there are no available data on the prognostic significance of CD44 expression of tumor tissue correlated with serum sCD44 level in childhood leukemias and lymphomas. METHODS: Serum levels and leukemic cell tumor tissue expression of CD44 were detected in 54 children with acute leukemia and malignant lymphoma. Serum samples were obtained from all patients before treatment and during remission. Twelve age-matched healthy children were included as a control group. RESULTS: The serum CD44 levels were significantly higher in patients with Hodgkin's disease (HD), non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL) and acute lymphoblastic leukemia (ALL) than those in the control group. The median values were 1627.0, 1336.0, 1318.5, 1730.4, 902.7 ng/mL, respectively, and P<0.001, P<0.01, P<0.01, P<0.05 in comparisons, respectively. However, there was no significant difference between acute myeloid leukemia (AML) and the control group (median values: 900.3 and 902.7 ng/mL, respectively, P>0.05). Serum sCD44 levels significantly declined in HD, NHL and ALL patients who were in complete remission (median values: 684.0, 573.8 and 1101.1 ng/mL, respectively, P<0.05 in each comparison). Patients with HD had higher levels of serum sCD44 and correlated well with higher erythrocyte sedimentation rate (ESR), B-symptoms and advanced-stage disease (P<0.05, P<0.05 and P<0.01, respectively). Expression of CD44 was significantly high in patients with HD and NHL who were in advanced stages of disease. High serum CD44 level was also associated with high tumor tissue expression of CD44 in patients with HD and BL. In addition, patients with higher levels of serum sCD44, had a poorer outcome and survival than those with lower sCD44 levels in HD and NHL groups. CONCLUSIONS: A high serum sCD44 level and/or tumor tissue expression at diagnosis is associated with poor prognostic criteria and/or unfavorable outcome in childhood leukemias and lymphomas.

Natural killer cell numbers and cytotoxic activity in pediatric Hodgkin disease.

In this study peripheral blood natural killer (NK) cell activity was evaluated in 17 pediatric cases with Hodgkin disease (HD) (9 untreated, 8 in remission) and 20 age-matched healthy children. Peripheral blood CD16 and CD56 molecule expressions were also examined. No difference related to NK cell numbers and cytotoxic activity was detected at either stage of the disease. In cases in which long-term remission has been achieved (> or = 5 years) NK cell activity was slightly but not significantly increased in parallel with remission duration. Finally, no relation between NK cell activity and the etiology, prognosis, and severity of the disease has been established in children with HD.

Right atrial catheter-related complications in pediatric oncology patients: the situation in a developing country.

The complications of right atrial catheters (RACs) in pediatric oncology patients are unknown for centers in developing countries. This study examined the complications of RACs at Ankara University Medical School, Turkey. A total of 90 RACs were placed in 61 children for long-term chemotherapy with a total experience of 15,536 catheter days. The rate of catheter-related sepsis was 4.9 episodes per 1000 catheter days. Coagulase-negative staphylococci and Candida species were the most common organisms, accounting for 25.0 and 13.1% of all organisms, respectively. The most common reasons for the removal of the RACs were infection (42.4%) and dislodgement (32.2%). The rates of complications were significantly higher in this study than in western studies. This increase could be explained by the differences in catheter care practices in the Turkish center. In conclusion, the use of RACs in a developing country necessitates an appraisal of the benefits and risks for each patient and improvement of catheter care procedures.

Fungal colonization and infection in children with acute leukemia and lymphoma during induction therapy.

BACKGROUND: Fungal infection represents a growing problem in children with hematologic malignancies. During chemotherapy induced neutropenia, colonization with fungi is considered a major risk factor for subsequent fungal infection. The rates and risk factors for mycotic infections in pediatric oncology patients is undetermined, particularly for centers in developing countries. The aim of this study was to evaluate the rates and risk factors of fungal colonization in children with acute leukemia and lymphoma at one of the major pediatric hematology/oncology centers in Turkey. PROCEDURE: Fifty-two consecutive children newly diagnosed with acute leukemia and lymphoma during intensive remission induction therapy were evaluated for the occurrence of fungal colonization (defined as at least one positive surveillance culture) and infection. RESULTS: Thirty-six of the 52 patients (69.2%) were colonized by Candida albicans which was the only fungus isolated from surveillance cultures. There were three (5.8%) proven systemic fungal infections: two cases of candidemia and one case of brain abscess with Aspergillus spp. isolated from tissue. All patients with fungal colonization were receiving prophylactic or curative antibiotics. No significant association was found between type of disease and fungal colonization, but there was a significant association with neutropenia. CONCLUSIONS: Our findings suggest that there is a high rate of fungal colonization in children receiving remission induction therapy for acute leukemia and lymphoma. Limiting the use of antibiotics and instituting antifungal chemoprophylaxis may decrease the rate, while the early initiation of empiric antifungal therapy in patients with fever and suspected mycotic colonization may increase survival in these patients.

Serum levels and differential expression of intercellular adhesion molecule-1 in childhood leukemia and malignant lymphoma: prognostic importance and relationship with survival.

Serum levels and leukemic cell-tumor tissue expression of intracellular adhesion molecule-1 (ICAM-1/CD 54) were detected in 54 children with acute leukemia and malignant lymphoma. Serum samples were obtained from all patients before treatment and after cessation of the therapy from malignant lymphoma cases and during remission from leukemic patients. Twelve age-matched healthy children were included as a control group. The serum ICAM-1 levels were significantly higher in patients with acute lymphoblastic leukemia (ALL) or Hodgkin's disease (HD) than those in the control group (median values: 350.9, 286.4, and 138.4 ng/mL, respectively; P < .01 in each comparison). However, there were no significant differences concerning serum ICAM-1 levels between the control group and each of the acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL), and Burkitt's lymphoma (BL) case groups (median values: 235.7, 222.7, 195.9, and 138.4 ng/mL, respectively; P > .05 in each comparison). Moreover, serum soluble ICAM-1 levels significantly declined in ALL or HD patients who were in complete remission (median values: 185.0 and 145.4 ng/mL, respectively; P < .05 in each comparison). In HD patients high levels of serum ICAM-1 could be correlated with high ESR (P < .01), whereas no statistically significant difference could be found when serum ICAM-1 titers were compared with stages, B symptoms, and histological subgroups, probably because of the inadequate number of patients in each group. Expression of ICAM-1 was mainly attributed to lymphocytes, vessels, and weakly to Hodgkin's cells, and this was significantly high in patients who were in advanced stages of disease. High serum sICAM-1 level was also associated with poor outcome and survival. Determination of serum level and/or tumor tissue expression of ICAM-1 in HD and ALL might represent an additional, but probably not independent, disease-associated marker to be used in the evaluation and/or monitoring of treatment response in patients with HD and ALL.

Unusually high frequency of a 69-bp deletion within the carboxy terminus of the LMP-1 oncogene of Epstein-Barr virus detected in Burkitt's lymphoma of Turkish children.

Burkitt's lymphoma (BL) in Turkish children is commonly associated with Epstein-Barr virus (EBV) infection. The C-terminus of the latent membrane protein 1 (LMP-1) of EBV is essential for transformation and the 30-bp deletion detected in this region has been implicated to be associated with a more aggressive malignant phenotype. To understand the molecular mechanisms underlying EBV pathogenesis in BL of Turkish children, we analyzed 30-bp deletion and 33-bp variable repeat regions of the LMP-1 gene from paraffin-embedded tumor tissues of 30 BL patients (mean age 5.9 years). Primer pairs spanning the 30-bp deletion and 33-bp repeat regions were designed for amplification by polymerase chain reaction (PCR). The PCR-amplified products were analyzed by gel electrophoresis, Southern blot hybridization, and DNA sequencing. Twenty-eight (93%) of 30 BL biopsy samples were EBV positive as determined by PCR. Variable copy numbers (ranging from 4.5 to 7) of the 33-bp repeat of LMP-1 gene were detected in these EBV-containing tumor samples. To determine the frequency of the 30-bp deletion of the LMP-1 gene, we sequenced the amplimers encompassing this region. Analyses of DNA sequence of 28 Turkish BLs have disclosed four patterns: the first (32% (9/28)) is identical to B95-8 with no deletion, the second (11% (3/28)) is identical to Asian NPC CAO strain with 30-bp deletion, the third (46% (13/28)) is prevalent in Turkish BLs with a longer deletion (69 bp), and the fourth (11% (3/28)) consists of a mixture of 30-bp and 69-bp deletion. The occurrence of high frequency of the 69-bp deletion appears to have no correlation with the disease site. Mutations found in the CAO strain were also detected in the Turkish BL clustering at the amino acids 322, 334, 338 and 342; whereas mutations specific for Turkish BL were clustered at amino acids 326, 352 and 361. To assess the EBV genotype with the changes in C-terminus of LMP-1 gene, we performed genotyping by PCR to differentiate type A and B strain. All 28 patients were infected by type A EBV. Such a high frequency of the larger size (69 bp) deletion has never been reported. Ascertaining the role of this deletion in BL pathogenesis will require further study.

Hodgkin's disease in 82 Turkish children diagnosed over a 10-year period: epidemiological, clinical, and histopathologic features and prognosis with prolonged chemotherapy.

In this study, 82 Turkish children with Hodgkin's disease (HD) between 1 and 14 years of age and diagnosed over a 10-year period were evaluated retrospectively. More than half of the patients (54%) presented with advanced stages of HD. Mixed cellularity (MC) was the most frequent (56.1%) histopathologic type, which was followed by nodular sclerosing (NS, 18.3%) in frequency. None of the patients received radiotherapy as initial treatment. In 67 children the COPP regimen alone and in 15 the ABVD regimen alternating with COPP were started, to be given as a total of 12 courses. In the patients who presented with stage I-II HD the overall survival (OAS) rate and 5-year event free survival (EFS) rate were 92.3% and 77.8%, respectively. In the patients with advanced disease (stage III-IV) OAS and 5-year EFS were estimated to be 89.5% and 67.4%, respectively. No serious toxicity of chemotherapy was detected during the follow-up. In this group, clinical, epidemiological and histopathologic features of the disease showed a special pattern close to the type I pattern of HD. Regarding the survival rules and occurrence of low toxicity in our patients, results of prolonged chemotherapy alone seem to be encouraging in most of the children with HD. However, the follow-up duration is not yet sufficient to declare a clear conclusion related to the late complications.

Burkitt's lymphoma in 63 Turkish children diagnosed over a 10 year period.

Sixty-three Turkish children with Burkitt's lymphoma (BL) diagnosed over a 10-year period in a single institution were retrospectively analyzed. Burkitt's lymphoma included 41.7% of non-Hodgkin's lymphomas and 17.2% of all childhood malignant solid tumors diagnosed in our department in this duration. The patients studied with BL were aged between 3 and 14 years (mean 5.9 years), with a male of female ratio of 2:1. While the age distribution in our patients was similar to that in African BL (endemic), the predominance of abdominal involvement and the frequency of bone marrow infiltration and pleural effusion were reminiscent of American BL (sporadic). The incidence of jaw involvement (15.9%) in our group was higher than in American BL, however, and was not a high as in African BL. Most of the patients were of a lower socioeconomic status. Significant growth retardation was found in the children with BL compared with 40 age-matched children without malignancy, nor chronic or endocrinologic disorders, who were of a similar socioeconomic status. A serological study for Epstein-Barr virus (EBV) was performed in 18 children, and the IgG-type antibody to the viral capsid antigen of EBV was found to be positive in all of them. As a result, BL seems to include a considerable proportion of all childhood malignant solid tumors in Turkey. The epidemiological and clinical presentation and course indicate that BL appears in Turkish children in a form that is between the African and American types of the disease. Further molecular and chromosomal studies in Turkish children with BL are needed.

Production of granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, and tumor necrosis factor alpha during remission and infections in patients with acute leukemia.

We measured circulating serum levels of granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating comparable to the levels of these factors in 12 children with acute febrile infections without malignancy or hematological disorders and 15 age matched healthy controls. There were significantly elevated levels of G-CSF, GM-CSF and TNF alpha, in 12 children with infections without leukemia, as compared with controls. Also in 18 leukemic children with infections serum G-CSF and TNF alpha levels were significantly higher than those in the leukemic children without infection and healthy controls, whereas no significant difference was noted in the GM-CSF levels in these groups. Although elevation in TNF alpha levels in response to infections were similar in the children with and without leukemia, in the G-CSF levels lower elevation was noted in the leukemic children with infections as compared to the children with infections without leukemia. Despite leukopenia enhanced the production of G-CSF, even in leukopenic children with leukemia and infections, serum G-CSF levels were still lower than those for the children with infections without leukemia. We concluded that, the production of G-CSF and GM-CSF as a response to infection was deficient in the patients with acute leukemia in remission, probably due to the maintenance and reinforcement chemotherapy. Therefore, the use of recombinant G-CSF may be recommended in the infections of these patients.