Dezso Schuler

Identification of the Fanconi anemia complementation group I gene, FANCI

To identify the gene underlying Fanconi anemia (FA) complementation group I we studied informative FA-I families by a genome-wide linkage analysis, which resulted in 4 candidate regions together encompassing 351 genes. Candidates were selected via bioinformatics and data mining on the basis of their resemblance to other FA genes/proteins acting in the FA pathway, such as: degree of evolutionary conservation, presence of nuclear localization signals and pattern of tissue-dependent expression. We found a candidate, KIAA1794 on chromosome 15q25-26, to be mutated in 8 affected individuals previously assigned to complementation group I. Western blots of endogenous FANCI indicated that functionally active KIAA1794 protein is lacking in FA-I individuals. Knock-down of KIAA1794 expression by siRNA in HeLa cells caused excessive chromosomal breakage induced by mitomycin C, a hallmark of FA cells. Furthermore, phenotypic reversion of a patient-derived cell line was associated with a secondary genetic alteration at the KIAA1794 locus. These data add up to two conclusions. First, KIAA1794 is a FA gene. Second, this gene is identical to FANCI, since the patient cell lines found mutated in this study included the reference cell line for group I, EUFA592.

Guidelines for a therapeutic alliance between families and staff: A report of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology

This, the fifth official document of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology, develops another important topic: the Therapeutic Alliance between families and staff. This is addressed to the Pediatric Oncology Community as Guidelines that could be followed. Every parent, medical staff member, and psychosocial professional involved in the care of the child should be responsible for cooperating in the childs best interest. Everyone must work together toward the common goal of curing the cancer and minimizing its medical and psychosocial side-effects.

The adverse effect of prolonged prednisolone pretreatment in children with acute lymphoblastic leukemia

Between 1971 and 1981, 699 children were diagnosed to have acute lymphoblastic leukemia (ALL) in Hungary. 34 of these children had received prednisolone therapy prior to the establishment of the diagnosis. The most frequent presumptive diagnoses that prompted steroid treatment were aplastic conditions and arthritic disorders. Leukemia was diagnosed when the presenting symptoms reappeared usually several weeks after the initiation of steroid therapy and often following withdrawal of the drug. Initial leukemic burden, as judged by leukocyte count and hepatosplenomegaly, was smaller in these patients than in other children with leukemia at the time of diagnosis. Although they entered remission at the same rate as the other patients, the length of continuous complete remission was significantly shorter in the prednisolone pretreated group. It appears that prolonged prednisolone therapy given before remission induction imparts a distinct unfavorable prognosis.

Morphological diagnosis in childhood leukaemia.

Recent advances in the development of cell surface and enzyme markers have led to a better understanding of the cell populations in leukaemia. The appearance of differentiation antigens seems to be inversely related to survival: patients with Tor B-cell leukaemias have a poorer prognosis than patients who have the so-called ‘common’ acute lymphoid leukaemia (Chessels et a l , 1977). There is no doubt that the biochemical and immunological typing of leukaemias will be of great importance in the classification and treatment of the disease. At the same time, however, these tests do not make conventional morphological diagnosis unnecessary and treatment schedules are still largely based on morphological criteria. The lack of uniform classification prompted a French-American-British cooperative group to propose a new classification for the acute leukaemias (Bennett et al , 1976). The establishment of the Hungarian Study Group on Childhood Leukaemia has enabled us to review some 270 bone marrow smears from patients diagnosed in 1971-75. The May-Griinwald-Giemsa stained slides were examined by two of us independently, and a third opinion was sought in case of disagreement. Cytochemistry was also of help in some of the cases. The criteria outlined by the FAB group were adhered to in all cases. The distribution of patients in the various sub-types is given in Table I. L1 and L2 account for the great majority of cases. These two forms bear a close relationship to what we previously called ‘lymphoid’ and ‘undifferentiated’ leukaemia. The two types were always thought to belong to the same entity and their treatment was identical too. It came as a surprise therefore when we found a difference between the survival curves of the L1 and L2 groups (Fig I ) . Using the logrank test (Peto et al , 1976) the difference was found to be significant. We looked to see if the poorer survival in the L2 group was connected with a greater incidence of ‘high risk’ prognostic factors at the time of diagnosis. Patients were considered to be in the ‘high-risk’ group if their WBC count was 20 x 109/l or over, if they had a mediastinal mass, and they were under 2 or over 12 years of age. The ratio of such patients, however, was the same in both morphological sub-classes. It seems, therefore, that L2 may not only be a distinct variant within the ‘lymphoid’ group, but also one with a poorer outlook to successful treatment. We would like to point out that the survival data even in the L1 group are inferior to the results reported by some of the best centres for leukaemia therapy. Since the bone marrow slides were examined from each patient in the country we felt it important to include all cases in

Fermented wheat germ extract reduces chemotherapy-induced febrile neutropenia in pediatric cancer patients

Purpose:An open-label, matched-pair (by diagnosis, stage of disease, age, and gender) pilot clinical trial was conducted to test whether the combined administration of the medical nutriment MSC (Avemar) with cytotoxic drugs and the continued administration of MSC on its own help to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers compared with the same treatments without MSC. Methods:Between December 1998 and May 2002, 22 patients (11 pairs) were enrolled in this study. At baseline, the staging of the tumors was the same in each pair (mostly pTNM = T2N0M0), with the exception of two cases in which patients in the MSC group had worse prognoses (metastasis at baseline). There were no significant differences in the average age of the patients, the length of treatment time (MSC) or follow-up, the number of patients with central venous catheters, the number of chemotherapy cycles, the frequency of preventive counterneutropenic interventions, or the type and dosage of antibiotic and antipyretic therapy used in the two groups. Results:During the treatment (follow-up) period, there was no progression of the malignant disease, whereas at end-point the number and frequency of febrile neutropenic events significantly differed between the two groups: 30 febrile neutropenic episodes (24.8%) in the MSC group versus 46 (43.4%) in the control group (Wilcoxon signed rank test, P < 0.05). Conclusions:The continuous supplementation of anticancer therapies with the medical nutriment MSC helps to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers.

Molecular genetics of PKU in Eastern Europe: A nonsense mutation associated with haplotype 4 of the phenylalanine hydroxylase gene

Phenylketonuria (PKU) is a genetic disorder secondary to a deficiency of hepatic phenyalanine hydroxylase (PAH). Several mutations in thePAH gene have recently been reported, and linkage disequilibrium was observed between RFLP haplotypes and specific mutations. A new molecular lesion has been identified in exon 7 of thePAH gene in a Hungarian PKU patient by direct sequencing of PCR-amplified DNA. The C-to-T transition causes the substitution of Arg243 to a termination codon, and the mutant allele is associated with haplotype 4 of thePAH gene. The mutation is present in two of nine mutant haplotype 4 alleles among Eastern Europeans and is not present among Western Europeans and Asians. The rarity of this mutant allele and its restricted geographic distribution suggest that the mutational event occurred recently on a normal haplotype 4 background in Eastern Europe.

Hungarian experience with Langerhans Cell Histiocytosis in childhood

The Langerhans cell histiocytosis (LCH) in children is relatively rare and the long-term analysis of therapy results has not been done yet in Hungary. The aim of this study was to investigate the incidence, clinical features, prognostic risk factors, and treatment results of childrens LCH in Hungary in a 20-year period. Children less than 18 years of age with newly diagnosed LCH in Hungary were entered in this study. Clinical data of all children with LCH were reported to the National Childhood Cancer Registry in Hungary from 1981 to 2000. The clinical files were collected and abstracted for information regarding age at diagnosis, gender, disease characteristics, treatment, and outcome of treatment. Median follow-up duration of surviving patients is 10.98 years. Between January 1981 and December 2000, 111 children under 18 years of age were newly diagnosed with LCH in Hungary. The annual incidence of LCH in children younger than 18 years of age was 2.24/million children. The male–female ratio was 1.36:1; the mean age was 4 years 11 months. Thirty-eight children had localized disease and in 73 cases systemic dissemination was found already at the time of diagnosis. Twenty-two patients were treated only by local surgery, 7 by surgery with local irradiation, and 5 children got only local irradiation. In 2 cases remission was achieved with local steroid administration. Seventy-five patients received chemotherapy. In the 20 years of the study 14 children died, 9 due to the progression of the disease. Sixteen patients had relapse with a mean of 2.16 ± 1.29 years after the first diagnosis. Three patients with relapse got chemotherapy generally used in lymphoma and remission was achieved. The overall survival of all patients (n = 111) was 88.3 ± 3.1% at 5 years and 87.3 ± 3.2% at 10 and 20 years. Childhood LCH is a well-treatable disease and the survival rate is high. Even disseminated diseases have a quite good prognosis in childhood.

Prognostic importance of systemic clearance of methotrexate in childhood acute lymphoblastic leukemia

SummaryPharmacokinetic studies of methotrexate have been carried out in 21 children with acute lymphoblastic leukemia diagnosed in 1981. Children were treated with intermediate dose (500 mg/m2) methotrexate in keeping with the 1981 ALL treatment Protocol of the Hungarian Childhood Leukemia Working Group. Of the 21 children, 8 relapsed, and 13 are in continuous complete remission. In the relapsed patients significantly increased systemic clearance of methotrexate was observed at the time of the second methotrexate treatment cycle compared with the calculated value after the first administration of the drug. No such change in the clearance was found in patients who are still in remission. There was no difference between children who relapsed or who are in remission in the elimination half-time of the drug. Age, sex, WBC at diagnosis, and systemic clearance of methotrexate were found to be connected with the probability of relapse in the patients studied. The possible reasons for the prognostic role of systemic methotrexate clearance are discussed.

NALOXONE ANTAGONISES EFFECT OF α-GLIADIN ON LEUCOCYTE MIGRATION IN PATIENTS WITH COELIAC DISEASE

The effect of naloxone on inhibition of leucocyte migration by alpha-gliadin was examined in 24 patients with coeliac disease. In all cases in which alpha-gliadin inhibited leucocyte migration, naloxone blocked this inhibitory effect, which suggests that the effect of gliadin on lymphocytes from patients with coeliac disease may be mediated through opioid-like receptors.

Methotrexate administered by 6-h and 24-h infusion: a pharmacokinetic comparison.

SummaryThe pharmacokinetics of 8 g/m2 methotrexate (MTX) was compared following short (6 h) and long (24 h) infusions of the drug to 11 children with osteogenic sarcoma (OS; 42 infusion) and 28 children with acute lymphoblastic leukemia (ALL: 118 infusions), respectively. No difference was observed in the first-phase half-life, in systemic clearance or in the volume of distribution of the drug (P>0.05). The concentration of MTX at the end of the infusion was ∼4-fold higher when the drug was given over only 6 h. However, patients receiving 24-h infusions had ∼9-fold higher levels by 24 h after the beginning of the infusion. The area under the data curve from start of the MTX infusion until the beginning of folinic acid rescue administration was significantly higher in patients with osteogenic sarcoma (6-h infusions), while the area under the log-data curve was significantly longer in the ALL group (24-h infusions) for the same period. The latter parameter is considered to be characteristic for the concentration-time-effect relationship. The longer duration of MTX administration (with delayed rescue) is thought to be more beneficial from the pharmacokinetic aspect. Patients with osteogenic sarcoma had significantly lower concentrations of MTX at the end of their last treatment with MTX than at the end of the first infusion. Patients developing MTX toxicity had shorter half-lives of MTX in the beta phase. It is suggested that cisplatin induced tubular loss of MTX and folinic acid is responsible for these observations. A wider application of clinical pharmacologic findings in the practice of the administration of cytostatics is indicated.