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.

An intensive approach to the treatment of disseminated BCG infection in a SCID patient.

There is an appreciable mortality associated with BMT in patients with SCID and advanced BCG infection. We present a girl with T-B+ SCID complicated by spina ventosa and disseminated BCG osteitis after receiving a fully matched sibling marrow transplant. Considerable progression characterised by two clinical activations and multiple pleural and perivertebral abscess formations occurred with conventional anti-mycobacterial chemotherapy. She finally recovered with full immune reconstitution after BMT and intensive treatment comprising five conventional and alternative agents that she received for 36 months. No side-effects and/or complications have been seen other than hearing loss.

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.

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.

Evaluation of the pancreas reserve in siblings of type I diabetic children.

INTRODUCTION: The purpose of this study was to determine the pancreas reserve in siblings of diabetic patients by screening islet cell antibodies (ICA), insulin auto antibodies (IAA), reduced C-peptide levels, first-phase insulin release and the derangement of cellular immunity (reduction of natural killer cells, abnormality of the T cell subpopulations). METHODS AND RESULTS: Twelve siblings (aged 9.3 +/- 2.8 years) of diabetic children were evaluated and results were compared with the control group (12.1 +/- 3.5 years). For siblings of the diabetic children, fasting, post-prandial and glucagon response C-peptide mean values were 2.2 +/- 1.2, 7.2 +/- 7.1 and 5.3 +/- 3.6 ng/mL, respectively, while in the control group they were 1.5 +/- 0.8, 3.6 +/- 2.0 and 5.1 +/- 2.9 ng/mL, respectively. There were no differences between the two groups. In 33%, postprandial C-peptide, and in 11% of the siblings, glucagon response C-peptide values were exaggerated. In siblings the first phase insulin release (FPIR) during an intravenous glucose tolerance test was 128.5 +/- 96.6 (above the 50th percentile) and stimulated insulin release (SIR) was 103.8 +/- 92.5 (above 25th percentile). Sibling values were significantly lower than the control group (FPIR 152.4 +/- 42.5, P = 0.01; SIR 134.9 +/- 38.2, P = 0.01). Values for FPIR (in two children) and SIR (three cases) were below the 5th percentile. In one, FPIR and SIR levels were both below the 1st percentile. Islet cell antibodies and IAA were also present in this subject. Treatment with nicotinamide was started in the cases with FPIR and SIR below the 5th percentile. We did not observe overt diabetic symptoms during the follow-up period of more than 3 years. CONCLUSION: We recommend that borderline insulin secretion be tested annually in siblings who show insufficient FPIR.

Late effects of chemoradiotherapy in pediatric Hodgkin's disease.

We treated 137 Turkish children with biopsy-proven Hodgkin's disease, followed up between the years 1964 and 1989. Most patients were treated and were in advanced stage with histological subtype of mixed cellularity (67.5%). Radiotherapy (Mantle form) and/or MOPP, ABVD and OPPA combination chemotherapy regimens were used in 75.84% of patients. The follow-up period in these patients ranged from 5 to 24 years. The late effects in 28 patients who were evaluated for the late sequelae of chemoradiotherapy are presented. Seven out of 28 patients showed retarded sexual maturation. Testicular and ovarian functions were assessed in 11 patients, all of whom showed elevated serum FSH levels and 2 azoospermia. Analysis of thyroid functions was carried out in patients receiving radiotherapy to the neck. The thyroid gland was palpable in 6 patients. Further analysis showed diffuse hyperplasia in 5 and nodular in 1 patient. The nodule was excised and reported as "nodular colloidal goiter". Two patients had elevated TSH levels. "Swan-like neck" was observed in 3 patients who had received 40 to 42 Gy radiotherapy to the neck. Cirrhosis due to chronic hepatitis B infection was diagnosed in 2 patients as an unusual late complication. The secondary malignancy occurred in only 1 case in the form of "fibrosarcoma". The second neoplasm was probably radiation-induced as it occurred in the field of prior radiotherapy.

Granulocyte-macrophage colony stimulating factor (rh-GM-CSF) in the treatment of chemotherapy-induced neutropenia.

Neutropenic pediatric patients with solid tumors and malignant lymphomas were treated with recombinant granulocyte-macrophage colony stimulating factor (rh-GM-CSF). Eleven patients, including seven lympho-reticular malignancies, two Ewing's sarcoma and one patient in each group with the diagnosis of nasopharyngeal rhabdomyosarcoma, malignant mesenchymal tumor, entered the study. Six were females and five were males, the mean age was 10.4 yr, the range was 4 to 21 years. rh-GM-CSF was given at the dose of 5 micrograms/kg s.c. daily, starting either on the day following the last day of cytotoxic chemotherapy or when ANC < 1000/ml was determined. All patients received rh-GM-CSF for a total of seven days. Hematopoietic recovery occurred in all children except one. The response to rh-GM-CSF was achieved in a mean time of 7.4 days. Tolerance to rh-GM-CSF treatment was good. Adverse events were documented as fever, nausea, vomiting, fatigue, chills and itching. Sagittal sinus thrombosis developed in one patient 5 days following the completion of chemotherapy and rh-GM-CSF cycle. In conclusion, rh-GM-CSF can be applied during the intensive chemotherapy schedules of pediatric cancer patients.

Burkitt's lymphoma in Turkish children: clinical, viral [EBV] and molecular studies.

Eighty-one Turkish children with Burkitt's lymphoma (BL) were observed during a period of 24 years (1968-1992). The diagnosis was established histologically according to WHO criteria. BL represented 48.5% of NHL in this series. The median age of patients was 5 years with a sex (M/F) ratio of 2.3/1. The most common primary site of tumor involvement at initial presentation was the abdomen (70.4%), which was followed by facial tumors, in particular the jaw and orbit (45.7%). The majority of the patients (84.0%) were in advanced stages (C and D) at initial diagnosis. Facial tumors observed in Turkish children with BL were more similar to African Burkitt's lymphoma than American or European cases. High titers of antibodies against VCA and EA of EBV were also observed in 32 recent cases of BL. Preliminary molecular and immunologic studies revealed EBV-DNA (type I) and T cell deficiency. The clinical presentation, median age, and association with EBV revealed that BL appears to be inbetween African and non-African types in Turkish children. This will be further elucidated in the future by direct examination of tumor cells for EBV and investigation of the molecular characteristics in these cases.

Orbito-ocular granulocytic sarcoma (OOGS) and acute myeloblastic leukemia (AML) with duplication of Philadelphia chromosome.

A 6-year-old Turkish boy with bilateral orbito-ocular granulocytic sarcoma and AML is described. Cytogenetic studies on peripheral blood disclosed an abnormal hyperdiploid population with a double Ph chromosome. Despite intensive chemotherapy, he achieved only partial remission. Repeated cytogenetic studies on bone marrow during relapse revealed the persistence of double Ph chromosome. The aggressive course and the short survival time of this patient, despite adequate chemo-radiotherapy, may be explained by the presence of the double Ph chromosome.

Burkitt's lymphoma between African and American types in Turkish children: clinical, viral (EBV), and molecular studies.

Seventy-two Turkish children with Burkitt's lymphoma (BL) observed during a period of 22 years (1968-1990) have been analysed retrospectively. The diagnosis was established histologically according to WHO criteria. BL represented 50% of NHL in this series. The patients were staged according to Ziegler's system. The median age of patients was 5.5 years with a sex (M/F) ratio of 2.1/1. The most common primary site of tumor involvement was the abdomen (69.4%), which was followed by facial tumors, in particular the jaw and orbit (49.9%). There were 21 cases with jaw (29.1%) and 15 cases with orbital involvement (20.8%) at initial presentation. The majority of the patients (84.4%) were in advanced stages (C and D) at initial diagnosis. Facial tumors observed in Turkish children with BL were more similar to African Burkitt's lymphoma than American or European cases. High titers of antibodies against VCA and EA of EBV were also seen in our recent cases of BL. Two main treatment regimens, namely, single agent chemotherapy with cyclophosphamide (CYX) (1968-1974) and three drug (COM) combination chemotherapy, were used consecutively (1974-1988). COM has been shown to produce better results than single agent therapy. The clinical presentation, mean age, and high antibodies (IgG) to EBV and preliminary molecular studies revealed that BL appears to be in between African and non-African types in Turkish children. This will be further elucidated by direct examination of tumor cells for EBV and investigation of the molecular characteristics of Turkish tumors. Such studies are presently under way.

T-lymphocyte sub-populations in orbito-ocular granulocytic sarcoma (OOGS) and acute myelocytic leukemia (AML): a preliminary study.

The aetiology of GS remains obscure and a little is known about the immune competence of these patients. Interestingly, all children with OOGS were from low 'socio-economic status' and showed diminished delayed hypersensitivity reactions and reduced T cell counts (E-R) in our previous observation. We present herewith a preliminary data on evaluation of T cell sub-populations determined by monoclonal antibodies (CD3, CD4, CD8 and CD16 cells) in 10 patients with OOGS and AML prior to treatment. Quantitative immunoglobulin determinations of IgA, IgM, IgG were also made. The percentage of Pan T (CD3), CD4, CD8 cells were significantly lower than those in the controls (p < 0.01). The immunoglobulin levels were slightly elevated suggesting normal B cell functions. In conclusion, these preliminary findings suggest that cellular immune deficiency may be an underlying cause.

High risk subgroup of acute myelomonocytic leukemia (AMML) with orbito-ocular granulocytic sarcoma (OOGS) in Turkish children. Retrospective analysis of clinical, hematological, ultrastructural and therapeutical findings of thirty-three OOGS.

Thirty-three patients presenting with orbito-ocular granulocytic sarcoma (OOGS) and acute myelomonocytic leukemia (AMML) were diagnosed in Turkish children from 1963 to 1983. OOGS, characterized by exophthalmos, chemosis and orbital masses, was observed in 33 (27.2%) of 121 AML patients compared with 41 children of AMML without ophthalmic tumors during the same period. Eye tumor and bone marrow aspirates were also studied under light and electron microscopies. The comparison of the hematological parameters did not indicate any statistical difference between the groups. Despite similar chemotherapy regimens administered to all patients, the mean survival time was 8.7 months in the OOGS group, which is significantly shorter compared to those without OOGS (28.6 months) (p less than 0.01). These cases may be classified as a "high risk" subgroup of childhood AMML.

Zinc status in pregnancy and the occurrence of anencephaly in Turkey.

Serum and hair zinc concentrations were measured in samples taken from 29 mothers with neural tube defects (NTD) (mainly anencephaly) at delivery. The control group consisted of 20 healthy mothers with normal offspring and 40 nonpregnant women 18 to 34 years of age, from middle income backgrounds. The mean maternal serum and hair zinc concentrations in the NTD group were lower than those of control mothers and the nonpregnant women. The zinc levels in the blood (plasma, red blood cells) and hair of 8 newborn infants with NTD (4 being anencephalic) were compared with those of normal newborn infants. The mean zinc concentration in the hair of malformed babies (250.4 +/- 85.2 micrograms/g) was significantly higher than that of normal infants (193.4 +/- 39.2 micrograms/g) (p less than 0.05) while the mean plasma zinc concentration was significantly lower (59.48 +/- 9.18 micrograms/dl compared with 68.75 +/- 10.89 micrograms/dl) (p less than 0.01). No difference was found between the mean values of red blood cell zinc levels for the two groups of infants. Maternal zinc deficiency was thought to be one of the factors responsible for NTD in Turkey.

Effects of zinc supplementation on linear growth in beta-thalassemia (a new approach).

Linear growth was evaluated in 32 patients with beta-thalassemia major. At the beginning of the study of 40.6% of the patients were below the 10th percentile with biochemical evidence of zinc deficiency. Effects of zinc supplementation on growth velocity (height) were assessed in a controlled manner. Twenty-one children received oral zinc sulphate for a period of 1 to 7 years (15 early- and 6 late-supplemented cases), while the remaining 11 thalassemics were maintained only on conventional transfusion therapy. The mean height velocity of early-zinc supplemented children was significantly greater than that of normal children (P less than 0.01). An increase in height was also observed in the patients who received delayed zinc retardation. The present study demonstrated that zinc deficiency is one of the factors responsible for retarded linear growth in beta-thalassemia major. Only the patients who received zinc supplementation showed an acceleration of growth in height. Administration of zinc could, therefore, be considered as an effective adjuvant therapy in homozygous beta-thalassemia.