Treatment strategy and results in children treated on three Dutch Childhood Oncology Group acute myeloid leukemia trials.

This report describes the long-term follow-up data of three consecutive Dutch Childhood Oncology Group acute myeloid leukemia (AML) protocols. A total of 303 children were diagnosed with AML, of whom 209 were eligible for this report. The first study was the AML-82 protocol. Results were inferior (5-year probability of overall survival (pOS) 31%) to other available regimes. Study AML-87 was based on the BFM-87 protocol, with prophylactic cranial irradiation in high-risk patients only, and without maintenance therapy. This led to a higher cumulative incidence of relapse than that reported by the Berlin-Frankfurt-Münster (BFM), but survival was similar (5-year pOS 47%), suggesting successful retrieval at relapse. The subsequent study AML-92/94 consisted of a modified BFM-93 protocol, that is, without maintenance therapy and prophylactic cranial irradiation. However, all patients were to be transplanted (auto- or allogeneic), although compliance was poor. Antileukemic efficacy was offset by an increase in the cumulative incidence of nonrelapse mortality, especially in remission patients, and survival did not improve (5-year pOS 44%). Our results demonstrate that outcome in childhood AML is still unsatisfactory, and that further intensification of therapy carries the risk of enhanced toxicity. Our patients are currently included in the MRC AML studies, based on the results of their AML 10 trial.

High co-prevalence of genogroup 1 TT virus and human papillomavirus is associated with poor clinical outcome of laryngeal carcinoma.

BACKGROUND: The aetiology and factors leading to the progression of laryngeal cancer are still unclear. Although human papillomavirus (HPV) has been suggested to play a role, reports concerning the effect of HPV infection on tumour development are controversial. Recently, transfusion transmitted virus (TTV) was suggested to play a role in certain infections as a causative or coinfecting agent. AIMS: To investigate whether the development and progression of laryngeal squamous cell carcinoma is associated with coinfection with TTV and HPV. METHODS: The prevalence of TTV and HPV was investigated using the polymerase chain reaction in tissue samples from 40 healthy individuals, 10 patients with recurrent papillomatosis, five patients with papillomatosis with malignant transformation, and 25 patients with laryngeal carcinoma. The obtained prevalence data were compared and analysed statistically. RESULTS: In the 11 patients with carcinoma who had metastasis or relapse there was a high rate of coinfection with genogroup 1 TTV and HPV (eight of 11), whereas in the 14 without tumour progression no coinfection was found. Coinfection was associated with significantly lower tumour free survival in patients with carcinoma (p < 0.001). Furthermore, four of five patients who had papillomatosis with malignant transformation were coinfected with genogroup 1 TTV and HPV. CONCLUSIONS: Although the nature of cooperation between HPV and TTV needs to be investigated further, coinfection with genogroup 1 TTV and HPV appears to be associated with poor clinical outcome in laryngeal cancer.

The International Prognostic Scoring System (IPSS) for childhood myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML).

The International Prognostic Scoring System (IPSS) for myelodysplastic syndrome (MDS) is based upon weighted data on bone marrow (BM) blast percentage, cytopenia, and cytogenetics, separating patients into four prognostic groups. We analyzed the value of the IPSS in 142 children with de novo MDS and 166 children with juvenile myelomonocytic leukemia (JMML) enrolled in retro- and prospective studies of the European Working Group on childhood MDS (EWOG-MDS). Survivals in MDS and JMML were analyzed separately. Among the criteria considered by the IPSS score, only BM blasts <5% and platelets >100 x 10(9)/l were significantly associated with a superior survival in MDS. In JMML, better survival was associated with platelets >40 x 10(9)/l, but not with any other IPSS factors including cytogenetics. In conclusion, the IPSS is of limited value in both pediatric MDS and JMML. The results reflect the differences between myelodysplastic and myeloproliferative diseases in children and adults.

Bone mineral density and markers of bone turnover in young adult survivors of childhood lymphoblastic leukaemia.

OBJECTIVE: In order to determine if a serious disease like childhood acute lymphoblastic leukaemia (ALL) and the treatment necessary to cure the patients has long term effects on bone mass, we assessed bone mineral density (BMD) and several parameters involved in bone formation in a group of young adult survivors of ALL. DESIGN AND PATIENTS: Fourteen male and ten female survivors, treated for ALL in childhood, were cross-sectionally studied, at a mean age of 25.1 years (range 20.1-34.9). All patients, except for two, had received cranial irradiation as part of their treatment (mean radiation dose 2460 cGy). MEASUREMENTS: Height and weight were measured. Bone mineral density (BMD) was assessed using dual energy X-ray absorptiometry in the lumbar spine, femoral neck, femoral trochanter and at 1/3 distal and ultradistal in the radius. Early morning serum levels of LH, FSH, oestradiol or testosterone, IGF-1 and IGF-BP3 were determined as well as several specific markers of bone turnover. RESULTS: Mean height, expressed as standard deviation score (SDS) was -1.12, significantly reduced. BMD in the lumbar spine, femoral neck and at 1/3 distal and ultradistal in the radius, was significantly lower compared to the reference population (P < 0.05). No correlation was found between the BMD values and the cumulative dose of administered cytotoxic drugs, the age at diagnosis of ALL or the duration of follow-up. Mean IGF-1 and IGF-BP3 SDS-scores were -1.24 and -0.78 respectively, significantly reduced. GH stimulation tests performed in a subgroup of 9 patients showed an insufficient peak GH response in at least one test in all tested patients. The values of LH, FSH oestradiol or testosterone were within the normal adult range. Serum markers of bone formation and bone resorption were in the normal range, indicating that bone turnover was normal at the time of the study. CONCLUSIONS: Bone development in patients cured of acute lymphoblastic leukaemia is disturbed, resulting in a significantly reduced bone mineral density. Impaired growth hormone activity, as a long term effect of cranial irradiation, may be one of the underlying causes as well as the illness itself and the administered cytotoxic drugs. Since a reduced bone mineral density predispose patients to osteoporosis, intervention in order to improve bone mass should be considered.

Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7. European Working Group on MDS in Childhood (EWOG-MDS).

We reviewed the clinical features, treatment, and outcome of 100 children with myelodysplastic syndrome (MDS), juvenile myelomonocytic leukemia (JMML), and acute myeloid leukemia (AML) associated with complete monosomy 7 (-7) or deletion of the long arm of chromosome 7 (7q-). Patients with therapy-induced disease were excluded. The morphologic diagnoses according to modified FAB criteria were: MDS in 72 (refractory anemia (RA) in 11, RA with excess of blasts (RAEB) in eight, RAEB in transformation (RAEB-T) in 10, JMML in 43), and AML in 28. The median age at presentation was 2.8 years (range 2 months to 15 years), being lowest in JMML (1.1 year). Loss of chromosome 7 as the sole cytogenetic abnormality was observed in 75% of those with MDS compared with 32% of those with AML. Predisposing conditions (including familial MDS/AML) were found in 20%. Three-year survival was 82% in RA, 63% in RAEB, 45% in JMML, 34% in AML, and 8% in RAEB-T. Children with -7 alone had a superior survival than those with other cytogenetic abnormalities: this was solely due to a better survival in MDS (3-year survival 56 vs 24%). The reverse was found in AML (3-year survival 13% in -7 alone vs 44% in other cytogenetic groups). Stable disease for several years was documented in more than half the patients with RA or RAEB. Patients with RA, RAEB or JMML treated with bone marrow transplantation (BMT) without prior chemotherapy had a 3-year survival of 73%. The morphologic diagnosis was the strongest prognostic factor. Only patients with a diagnosis of JMML fitted what has previously been referred to as the monosomy 7 syndrome. Our data give no support to the concept of monosomy 7 as a distinct syndrome.

[Chronic granulomatous disease (CGD): dysfunction of the neutrophil granulocyte NADPH-oxidase enzyme system]. / Krónikus granulomatózus betegség (CGD): a neutrofil granulocita NADPH-oxidáz enzimrendszerének múködésképtelensége.

Dysfunction of NADPH oxidase results in chronic granulomatous disease (CGD), a syndrome characterized by severe bacterial and fungal infections. Phagocytes of the patients are unable to kill ingested microorganisms which leads to the formation of granulomas and abscesses. Predominant pathogens are the catalase-positive bacteriae (Staphylococcus aureus) and some fungi (Aspergillus species). Infections of these patients should be treated by antimicrobial agents, which penetrate cells and kill pathogens inside. The aim of this study was to give a short description of the structure and function of the NADPH oxidase enzyme and to summarize the results obtained during the diagnostic of 10 patients with chronic granulomatous disease. Characterization of the disease was confirmed by mutation analyses.

[Hemophagocytic syndrome]. / Het hemofagocytair syndroom.

A lymph node biopsy sample from a boy aged with fever, pneumonia, hepatosplenomegaly, lymphadenopathy and pancytopenia, showed histiocytosis with erythrophagocytosis, compatible with the haemophagocytic syndrome. Treatment consisted of dexamethasone and etoposide, with cyclosporine added in a later phase. During the subsequent remission phase, bone marrow transplantation was carried out. Haemophagocytic syndrome is a rare condition, characterized by fever, pancytopenia, hepatosplenomegaly and characteristic laboratory findings (including a high interferon-gamma level) and morbid-anatomical findings (haemophagocytic histiocytic cells in bone marrow, lymph nodes, liver and spleen, but also in the CNS, kidneys and lungs). Recent pathophysiological discoveries indicate an enhanced T-cell response, leading to hypercytokinaemia. As a rule the patient dies from multiorgan failure and diffuse intravascular coagulation. Bone marrow transplantation is the treatment of choice.

Familial sideroblastic anemia with emergence of monosomy 5 and myelodysplastic syndrome.

The case history of two sisters with pyridoxine-refractory familial sideroblastic anemia (FSA) is presented in which one developed a myelodysplastic syndrome (MDS) with monosomy for chromosome 5. Bone marrow examination of both patients at diagnosis showed erythroid hyperplasia with more than 50% ring sideroblasts. Karyotypic analysis initially showed a normal 46, XX karyotype in both of the children. Therapeutic trials with pyridoxine, prednisone, and erythropoietin were unsuccessful. The first patient required regular transfusions and developed a significant hemosiderosis. At the age of 9 years, 7.5 years after the diagnosis of FSA, refractory anemia with excess of blasts (RAEB) was diagnosed. Bone marrow cytogenetic analysis revealed a clone with monosomy for chromosome 5. Her sister's illness was detected at the age of 12 years. She has a more benign course of disease, remains largely transfusion independent and until now shows no signs of myelodysplasia. To our knowledge this is the first observation of a transition of FSA to MDS accompanied by the appearance of a chromosomal abnormality. FSA might be another type of bone marrow failure syndrome, therefore close follow-up of these patients may be necessary.

Different cellular drug resistance profiles in childhood lymphoblastic and non-lymphoblastic leukemia: a preliminary report.

The better prognosis of acute lymphoblastic leukemia (ALL) than of acute non-lymphoblastic leukemia (ANLL) in children, and the often observed better prognosis of myeloid-antigen (MyAg) negative ALL than of MyAg-positive ALL, may be related to differences in cellular drug resistance. We therefore compared the resistance to 12 drugs of 125 ALL and 28 ANLL samples with the MTT assay. ALL samples were median > 75-fold more sensitive to the glucocorticoids prednisolone and dexamethasone (p < 0.00001), and 2-fold more sensitive to vincristine (p = 0.05) than ANLL samples. Differences for the other drugs were not significant. MyAg-negative ALL samples were more sensitive to glucocorticoids than MyAg-positive ALL-samples (p < or = 0.04). Prednisolone, and dexamethasone if tested, had a stimulatory effect on leukemic cell survival in 36% of ANLL, but in only 2% of ALL samples (p < 0.0001). Vincristine, and vindesine if tested, had a similar effect in 11% of ANLL, and in 4% of ALL samples (p = 0.11). We conclude that the more favorable response of ALL against ANLL to combination chemotherapy in children may be explained by the higher antileukemic activity of glucocorticoids and of vincristine in ALL, while none of the drugs was more active in ANLL. Similarly, the better prognosis of MyAg-negative ALL than of MyAg-positive ALL may be explained by a relative sensitivity to glucocorticoids. Glucocorticoids and vinca-alkaloids induced leukemia cell proliferation in part of the samples, most frequently in ANLL. The findings may be useful in the design of new chemotherapeutic regimens for ALL and ANLL.

[Leukocyte adhesion defect--a rare form of congenital immune deficiency]. / Leukocita adhéziós defektus (LAD)--a veleszületett immundefektusok ritka formája.

Leukocyte adhesion defect (LAD) is an inherited defect of phagocytic function. This disorder is characterised by delayed separation of the umbilical cord, severe recurrent bacterial infections, impaired formation of pus, and high leukocyte counts. The granulocytes have severe defect in their chemotactic mobility and endocytosis. The disease is attributed to the absence of the leukocyte adhesion molecules. (CD11/CD18), which can be verified with monoclonal antibodies. The authors describe the disease-process of the first patient diagnosed in Hungary. Perinatally the omphalitis, periumbilical abscess and periproctal abscess leading to rectovaginal fistula, in the first months the otitis, mastoiditis, and expressed leukocytosis referred to the impaired function of phagocytic cells, which was verified by laboratory tests as well. The decreased inflammation and cicatrization were also striking. This severe form of LAD can be cured only by bone marrow transplantation with preliminary sanitation of the foci of infection. It took about six months. Unfortunately, the patient died of sepsis immediately before transplantation.

[Rare congenital forms of bone marrow deficiency]. / A csontvelöelégtelenség ritka, veleszületett formái.

Cases of rare congenital forms of aplastic anaemia are presented. Fanconi anaemia is most frequently diagnosed, while reticular dysgenesis, amegakaryocytic thrombocytopenia and dyskeratosis congenita occur exceptionally rarely. A presumably new entity of congenital aplastic anaemia called "RAC" syndrome (retinopathy--aplastic anaemia--central nervous system abnormalities) is presented too. A short summary of the pathomechanism of congenital aplastic anaemias and present therapeutic attempts, including the possible therapeutic use of the newly discovered stem cell factor are described.

Childhood acute lymphoblastic leukemia immunophenotypes and their prognostic significance: experience of the IGCI-study in 389 children. International Society for Chemo-immunotherapy (IGCI-Vienna) Cooperative Group.

The prognostic significance of immunophenotype and other features including sex, age, anaemia, WBC, FAB type, and PAS staining were analysed in a group of 389 children newly diagnosed as acute lymphoblastic leukemia (ALL) and treated according to the BFM 1981/1983 protocol. The CR rate was higher (82-94%) in immunophenotypic subgroups defined as 'non-B' compared with B-ALL (54%). The probability of being in CCR at the end of follow up was 0.68 (median. observation, 3 years). Using the stepwise Cox regression analysis the following independent factors predictive of duration of CCR were selected (relative risk in brackets): 1. WBC (> 25G/1:< 25G/1 = 2.0, P = 0.0008), 2. age (> 10y:2-10y = 1.3, P = 0.04), 3. CALLA positivity (neg.:posit. = 2.4, P = 0.04), 4. CALLA within B-cell progenitor ALL (pre;preB,Calla-:Calla+ = 1.7, P = 0.007). T-ALL appeared to have a worse prognosis than U-ALL and B-progenitor derived ALL but it did not retain independent prognostic significance in multivariate analysis.

Ki-1 positive (anaplastic, large cell) lymphoma (case reports and review).

Ki-1 positive (anaplastic, large cell) lymphoma is a subgroup of non-Hodgkin lymphomas identified recently by Ki-1 (or BER-H2) (CD 30) monoclonal antibody. The clinicopathological features of two such pediatric cases of lymph node origin described here, and also the available literature emphasize the heterogenous nature of Ki-1 positive lymphomas, in almost every respect. Nevertheless, the Ki-1 antibody serves as an important diagnostic tool to differentiate lymphomas from other anaplastic, large malignancies.

Immunoglobulin prophylaxis during intensive treatment of acute lymphoblastic leukemia in children.

60 children with acute lymphoblastic leukemia were sequentially randomized at the time of diagnosis: Immunoglobulin (Endobulin, Immuno) was administered intravenously to 30 patients at a dose 100 mg/kg/week during the first 3 months, followed by 2 x 200 mg/kg/month immunoglobulin during the 4., 5., 6. months. No immunoglobulin was administered to the control patients. We studied the effect of immunoglobulin prophylaxis on the number of days with fever, number of cases with bacteriologically proved infections, length and frequency of antibiotic therapy. Our data confirm the efficacy of immunoglobulin prophylaxis during the intensive phase of leukemia therapy in children.

Susceptibility of multidrug-resistant human leukemia cell lines to human interleukin 2-activated killer cells.

Considering the possibility to overcome drug resistance by other treatment strategies than chemotherapy we investigated the susceptibility of three independently selected multidrug-resistant sublines of the T-lymphoblastoid leukemic cell line CCRF-CEM to lymphokine-activated killer (LAK) cells. We found that two of the multidrug-resistant sublines were significantly less susceptible targets to LAK cells. A third one, however, was as susceptible as the parental CCRF-CEM cell line. Moreover, a multidrug-resistant subline that reverted to an almost drug-sensitive phenotype was observed to be also revertant for resistance against LAK cells. We found an inverse relationship between the expression of the mdr1 gene (P-glycoprotein) and the susceptibility to LAK cells. Verapamil, a calcium channel blocker, while increasing the drug sensitivity of a multidrug-resistant subline, did not induce a reversal of the suppression of LAK susceptibility. The possibility of enhanced resistance to LAK cells of multidrug-resistant cells should be taken into account when one is looking for therapy strategies to overcome multidrug resistance.

[Gene rearrangement in leukemia]. / Génátrendezödés leukaemiákban.

In this report we summarize our experiences based on the gene rearrangement study of 111 leukaemic patients of different kind. The lymphocyte DNA of the patients was studied for rearrangement of the immunoglobulin light chain constant-, the heavy chain joining- and the T cell receptor beta chain constant region. Our data have well supplemented the results of the monoclonal antibody experiments. In 33 cases the DNA study was in good agreement with the immunological data. In 42 our data helped in gave different results, immunological results. In 11 cases evaluating the DNA and immunological data indicating the necessity of further investigation. The results were inconclusive in 25 cases. As a conclusion we consider the gene rearrangement study to be useful for diagnostic purposes.

Neuropsychologic and CT examinations in leukemic patients surviving 10 or more years.

Long-term survivors of childhood leukemia were studied to determine their neuropsychologic status. All had had cranial irradiation 10 or more years before. The results were 1. The IQ and academic performance of 56 cured leukemic patients show no significant difference from the normal population. 2. More exact neuropsychological tests (attention, reaction time, visual-motor coordination, memory) reveal important deficits. 3. The frequency of CT aberrations in 33 study patients was 45% and showed no correlation with either the IQ or other neuropsychological results.