Biomedical subjects

H Hasle

Publications and source records attributed to H Hasle.

At least 37 records · Page 2Linked to original sources

PubMed1999

A case of childhood acute myeloid leukemia associated with inversion (7)(p21q31).

We describe a case of acute myeloid leukemia in a 2 1/2-year-old boy presenting with a mediastinal tumor causing respiratory distress, and lymph node enlargement in the cervical and inguinal regions. Apart from myeloid markers CD13 and CD33, blast cells also expressed stem cell marker CD34 and megakaryocytic marker CD61. Cytogenetically, inv(7)(p21q31) was found in 9/25 and 15/25 analyzed metaphases from short-term cultures of lymph node and bone marrow cells, respectively. The patient is in continued complete remission 26 months post diagnosis. The case demonstrates that chromosome aberrations other than inv(16), t(8;21), and t(9;11) may be associated with extramedullary disease, and that not all chromosome 7 aberrations are prognostic adverse findings.

Child, Preschool↗

PubMed1999

RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML).

Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder of early childhood with excessive proliferation of the myeloid and monocytic lineage. Deregulation of the RAS signal transduction pathway is thought to play a key role in its pathogenesis. We examined peripheral blood or bone marrow cells of 36 children with JMML for activating point mutations in codons 12, 13 and 61 of the NRAS and KRAS proto-oncogenes by allele-specific restriction assay, single-strand conformation polymorphism and/or direct sequencing. Codons 12, 13 and 61 of HRAS were examined in 26 of these patients. We detected RAS mutations in six cases (17%) located at N12 (n = 2), N13 (n = 3) and K13 (n = 1). In addition, we performed clonality studies on different cell lineages in four of these patients applying the RAS mutation, the karyotype and X-chromosome inactivation patterns as clonal markers. Erythroid cells carried mutant RAS, indicating clonal origin. In EBV B cell lines, one of three patients studied harbored a RAS mutation, while the other two patients had polyclonal B cells with wild-type RAS. T lymphocytes were examined in one patient; they were polyclonal and had wild-type RAS. It is likely that JMML is a heterogeneous disease with respect to clonal involvement of different lineages.

Amino Acid Substitution↗

PubMed1999

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.

Acute Disease↗

PubMed1999

The breakpoints of a constitutional inversion of chromosome 9 associated with haemophagocytic lymphohistiocytosis are not linked to the disease gene.

Haemophagocytic lymphohistiocytosis (HLH) is a severe disorder of early infancy consistent with an autosomal recessive inheritance. Neither the genetic locus nor the biochemical defect is known for the disease. A constitutional pericentric inversion of chromosome 9, with breakpoints in bands 9p23 and 9q31, has been reported in a case of HLH, suggesting a possible relationship between this chromosome abnormality and the disease. We investigated such an association, performing a genetic linkage analysis in a set of five consanguineous HLH families. 27 polymorphic markers on chromosome 9 were studied, excluding most of chromosome 9 as a putative site for the HLH gene.

Chromosome Breakage↗

PubMed1999

A population-based study of childhood myelodysplastic syndrome in British Columbia, Canada.

Myelodysplastic syndrome (MDS) is considered to be very rare in children. However, the only two published population-based studies reported widely divergent incidence figures. To further explore the epidemiology of childhood MDS and to evaluate the accuracy of cancer registry and treatment trial data, we conducted a population-based study of children aged 0-14 years in British Columbia (BC), Canada, between 1982 and 1996. MDS was diagnosed in 31 cases corresponding to an annual incidence of 3.2 per million children or 6% of all leukaemias, compared with an incidence of 6.0/million for acute myeloid leukaemia (AML), and of 0.5/million for chronic myeloid leukaemia. There was a non-significant (P = 0.19) trend toward an increase in MDS incidence with time, the increase was partly explained by an increasing number of patients with Down syndrome. Associated abnormalities were found in 48% of the MDS cases with Down syndrome as the most common (seven cases). Only one third of the MDS cases were correctly registered in the Cancer Registry and less than half of the eligible MDS patients were enrolled on a cooperative group study. Data on MDS from treatment-based studies and cancer registries were inaccurate and seemed to significantly underestimate the incidence of MDS in children.

Adolescent↗

PubMed1998

Occurrence of cancer in a cohort of 183 persons with constitutional chromosome 7 abnormalities.

Cytogenetic abnormalities in human malignancies frequently involve chromosome 7. The existence of several tumor suppressor genes on the long arm of chromosome 7 has been suggested in both epithelial and hematologic malignancies. From the Danish Cytogenetic Register, we identified 183 persons with constitutional abnormalities involving chromosome 7, including 16 patients with Williams syndrome. By linkage to the Danish Cancer Registry, we found five persons with cancer, including one thyroid carcinoma, three carcinomas of the digestive tract, and one malignant melanoma. There were no cases of leukemia. The overall risk of developing cancer was not increased.

Adult↗

PubMed1998

Parvovirus B19-induced anemia as the presenting manifestation of X-linked hyper-IgM syndrome.

Parvovirus B19 (B19) can cause chronic anemia due to persistent infection in immunocompromised hosts who cannot produce neutralizing antibody necessary for clearing B19. Three patients with X-linked hyper-IgM syndrome (XHIM), who were all asymptomatic until they developed B19-induced chronic anemia at the ages of 8, 14, and 17 years, respectively, were found to have mutations of the CD40L gene, including a missense mutation (T254M), a nonsense mutation resulting in a new initiation codon and loss of the intracellular domain (R11X), and a splice site mutation (nt 309+2t-->a). Antibody responses to the T cell-dependent antigen, bacteriophage phiX174, were impaired, but neutralizing antibody titers were higher than in XHIM patients with classic phenotype. All 3 patients responded to intravenous immune globulin (IVIG) treatment. Certain mutations of the CD40L gene result in a mild XHIM phenotype that may become apparent following B19 infection in patients not on IVIG therapy and therefore not protected from B19 infection.

Adolescent↗

PubMed1997

Inhibition of granulocyte-macrophage colony-stimulating factor prevents dissemination and induces remission of juvenile myelomonocytic leukemia in engrafted immunodeficient mice.

Granulocyte-macrophage colony-stimulating factor (GM-CSF ) and tumor necrosis factor alpha (TNFalpha) have been implicated in the pathogenesis of the fatal childhood disease termed juvenile myelomonocytic leukemia (JMML). We used a severe combined immunodeficient/nonobese diabetic (SCID/NOD) mouse model of JMML and examined the effect of inhibiting these cytokines in vivo with the human GM-CSF antagonist and apoptotic agent E21R and the anti-TNFalpha monoclonal antibody (MoAb) cA2 on JMML cell growth and dissemination in vivo. We show here that JMML cells repopulated to high levels in the absence of exogeneous growth factors. Administration of E21R at the time of transplantation or 4 weeks after profoundly reduced JMML cell load in the mouse bone marrow. In contrast, MoAb cA2 had no effect on its own, but synergized with E21R in virtually eliminating JMML cells from the mouse bone marrow. In the spleen and peripheral blood, E21R eliminated JMML cells, while MoAb cA2 had no effect. Importantly, studies of mice engrafted simultaneously with cells from both normal donors and from JMML patients showed that E21R preferentially eliminated leukemic cells. This is the first time a specific GM-CSF inhibitor has been used in vivo, and the results suggest that GM-CSF plays a major role in the pathogenesis of JMML. E21R might offer a novel and specific approach for the treatment of this aggressive leukemia in man.

Adolescent↗

PubMed1997

Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS)

Chronic myelomonocytic leukemia (CMML) is a rare hematopoietic malignancy of childhood. To define the clinical and hematologic characteristics of the disease, we performed a retrospective analysis of 110 children given the diagnosis CMML irrespective of karyotype. Median age at diagnosis was 1.8 years. Neurofibromatosis type 1 was known in 14% and other clinical abnormalities in 7% of the children. At presentation, the medium white blood count was 35 x 10(9)/L, with a median monocyte count of 7 x 10(9)/L. Karyotypic abnormalities in bone marrow cells were noted in 36% of the patients, whereas 26% of the children had monosomy 7. Children with monosomy 7 did not differ from those with normal karyotype with respect to their clinical presentation. However, they did display some characteristic hematologic features. Of 110 children, 38 received an allogeneic bone marrow transplant (BMT). The probability of survival at 10 years was 0.39 (standard error [SE] = 0.10) for the BMT group and 0.06 (SE = 0.4) for the 72 patients of the non-BMT group. Platelet count, age, and hemoglobin F at diagnosis were the main predicting factors for the length of survival in the non-BMT group. There is a strong need for a broad agreement on nomenclature in children with myelodysplastic syndromes (MDS). We propose here to use the French-American-British classification for MDS in childhood.

Bone Marrow Transplantation↗

PubMed1997

Prolonged extreme thrombocytosis associated with neurofibromatosis type 1.

A girl with neurofibromatosis type 1 showed in infancy extreme thrombocytosis with platelet counts exceeding 2000 x 10(9)/L. Platelet counts remained elevated the first 4 years of life. A large deletion located at chromosome 17q11 was observed. The transient thrombocythemia may relate to a regulator of megakaryocytopoiesis located in the vicinity of the NF1 gene or to the excessive risk of chronic myelomonocytic leukemia in neurofibromatosis.

Adolescent↗

PubMed1997

Cancer in relatives of children with myelodysplastic syndrome, acute and chronic myeloid leukaemia.

Familial myelodysplastic syndrome (MDS) has been claimed to account for as many as one third of children with MDS, especially among those showing monosomy 7. The present study is the first to provide population-based estimates of the risk of haematological and other malignancies in relatives of children with MDS. The study was extended to include children with acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML). The index group consisted of 46 children with MDS, 62 with AML, and eight with CML, which is thought to represent all myeloid leukaemias in Danish children, 1980-91. By linkage to the Central Population Register we identified parents (230), siblings (231), grandparents (151), aunts and uncles (132) and cousins (140). Information on the cancer incidence was obtained from the Danish Cancer Registry. 27 cancers were observed versus 26.7 expected (relative risk 1.0). Leukaemia in relatives was observed in only one family. None of 11 children with MDS and monosomy 7 had family members affected by leukaemia. We found no evidence of an increased overall risk of cancer in the relatives. The risk of familial MDS may be considerably lower than previously estimated.

Adolescent↗

PubMed1997

Allogeneic bone marrow transplantation for chronic myelomonocytic leukemia in childhood: a report from the European Working Group on Myelodysplastic Syndrome in Childhood.

PURPOSE: To evaluate the role of allogeneic bone marrow transplantation (BMT) in children with chronic myelomonocytic leukemia (CMML). PATIENTS AND METHODS: Forty-three children with CMML given BMT and reported to the European Working Group on Myelodysplastic Syndrome in Childhood (EWOG-MDS) data base were evaluated. In 25 cases, the donor was a human leukocyte antigen (HLA)-identical or a one-antigen-disparate relative, in four cases a mismatched family donor, and in 14 a matched unrelated donor (MUD). Conditioning regimens consisted of total-body irradiation (TBI) and chemotherapy in 22 patients, whereas busulfan (Bu) with other cytotoxic drugs was used in the remaining patients. RESULTS: Six of 43 patients (14%), five of whom received transplants from alternative donors, failed to engraft. There was a significant difference in the incidences of chronic graft-versus-host disease (GVHD) between children transplanted from compatible/one-antigen-mismatched relatives and from alternative donors (23% and 87%, respectively; P < .005). Probabilities of transplant-related mortality for children given BMT from HLA-identical/one-antigen-disparate relatives or from MUD/ mismatched relatives were 9% and 46%, respectively. The probability of relapse for the entire group was 58%, whereas the 5-year event-free survival (EFS) rate was 31%. The EFS rate for children given BMT from an HLA-identical sibling or one-antigen-disparate relative was 38%. In this latter group, patients who received Bu had a better EFS compared with those given TBI (62% v 11%, P < .01). CONCLUSION: Children with CMML and an HLA-compatible relative should be transplanted as early as possible. Improvement of donor selection, GVHD prophylaxis, and supportive care are needed to ameliorate results of BMT from alternative donors.

Bone Marrow Transplantation↗

PubMed1996

Parvovirus B19 infection infrequently involved in children and adults with myelodysplastic syndrome.

Parvovirus B19 infection has occasionally been reported to mimic myelodysplastic syndrome (MDS) or to cause worsening of anemia in MDS. We examined the presence of parvovirus DNA in a series of children (n=19) and adults (n=39) with a diagnosis of MDS. The series of adults included only refractory anemia (RA) and RA with ring sideroblasts (RARS). Investigation for parvovirus B19 DNA in bone marrow cells was performed employing the nested form of the polymerase chain reaction (PCR). Only a 51-year-old male with RA tested positive for parvovirus DNA. Serial examinations demonstrated the disappearance of parvovirus DNA from the bone marrow. We conclude that parvovirus infection may only rarely mimic MDS or be a superimposed infection in childhood MDS or in RA and RARS in adults.

Adolescent↗

PubMed1996

Occurrence of cancer in women with Turner syndrome.

A study of cancer incidence in a cohort of 597 women with Turner syndrome (TS) and a virtually complete follow-up is presented. The cohort was established from the Danish Cytogenetic Register. Information on cancer incidence was obtained from the Danish Cancer Registry and compared with the expected number calculated from the age-, period- and site-specific cancer rates for Danish women. A total of 21 neoplasms was observed, of which 13 occurred more than 1 year after diagnosis of TS, corresponding to a relative risk of cancer of 1.1. Wilms' tumour was the only identified childhood cancer. No case of gonadoblastoma or dysgerminoma was identified in the 29 women with a Y chromosome or in the women in whom no Y chromosome material was detected by standard cytogenetic methods, suggesting that the risk of ovarian germ cell tumours may be lower than previously estimated. Colon cancer was observed in five patients (relative risk 6.9, 95% confidence interval 2.2-16.2). Further studies are needed to assess whether colon cancer in TS is related to Turner-associated genes on the sex chromosome(s).

Adolescent↗

PubMed1996

Chronic neutrophil leukaemia in adolescence and young adulthood.

Chronic neutrophil leukaemia (CNL) is a rare myeloproliferative disorder predominantly reported in elderly patients. We present a 15-year-old girl and a 25-year-old male with CNL. Clonal cytogenetic abnormalities were detected in both patients. One showed trisomy 21 evolving into tetrasomy 21. The second patient showed a unique chromosome aberration during blast crisis: t(2;2)(q32;p24). Both patients were successfully treated with allogeneic bone marrow transplantation (BMT). CNL should also be considered as a differential diagnosis in adolescence and young adulthood. BMT represents a potentially curative treatment option in such patients.

Adolescent↗

PubMed1996

Haemophagocytic lymphohistiocytosis associated with constitutional inversion of chromosome 9.

Familial haemophagocytic lymphohistiocytosis (HLH) is considered an autosomal recessive disease, although the putative gene responsible for the disease has not yet been localized. Identification of the involved gene may elucidate the pathogenesis of the disease and is essential for prenatal testing in affected families. We present an infant with HLH and constitutional inversion 9 (p23q31) in cells from bone marrow, lymphocytes and fibroblasts. The parents had normal karyotypes. It may be speculated that one of the parents was a carrier of HLH and a de novo inversion occurred in chromosome 9 from the non-carrier parent. This would imply that the putative HLH-related gene is located at one of the two breakpoints on chromosome 9.

Chromosome Inversion↗

PubMed1996

Parvovirus B19 infection and Diamond-Blackfan anaemia.

It is the purpose of the study to report the frequency of parvovirus in children with a diagnosis of Diamond-Blackfan anaemia and to discuss the possible aetiological role of parvovirus in Diamond-Blackfan anaemia. We found parvovirus DNA in 3 of 11 bone marrow smears. Giant pronormoblasts showed low sensitivity (33%) and poor specificity (75%). The presence of giant pronormoblasts was associated with a very high myeloid:erythroid ratio, and may not be specific for parvovirus infection, but a feature of severely suppressed erythropoiesis. The three parvovirus-positive patients were the only children who experienced a remission, and who are free of medication. The seven surviving parvovirus-negative patients are all currently on steroid treatment.

Bone Marrow↗

PubMed1996

Intensive chemotherapy in childhood myelodysplastic syndrome. A comparison with results in acute myeloid leukemia.

Myelodysplastic syndrome (MDS) in children is often considered as a variant of acute myeloid leukemia (AML) and frequently treated as such. However, there are very few reported data on the outcome following AML treatment. We analyzed 20 consecutive cases of de novo MDS treated in Denmark according to the NOPHO AML protocols. The results were compared with those obtained in 31 children with de novo AML treated with the same protocols, and with the outcome in 10 children with MDS who received allogeneic bone marrow transplantation (BMT) without prior AML therapy. Distinction between MDS and AML was made morphologically according to the FAB criteria. All children were followed for at least 37 months. The proportion of complete remission in MDS and AML was 35 percent vs 74 percent. (P = 0.005), resistant disease 25 percent vs 10 percent (P = 0.14), death in cytopenia 40 percent vs 16 percent (P= 0.06), and 3-year survival 15 percent vs 35 percent. (P = 0.11), respectively. Duration of treatment-related cytopenia was similar in MDS and AML, except for a longer period of leukopenia in MDS following the second course of induction. Seven of 10 MDS children receiving BMT without prior chemotherapy are long-term survivors. Our data suggest that conventional AML regimens are associated with a low rate of complete remission, a high risk of death in cytopenia, and a limited curative potential in childhood MDS. Allogeneic BMT was in contrast associated with a high survival rate. BMT may, at least in some patients, be performed successfully without prior induction chemotherapy. The different response to therapy in MDS and AML may reflect fundamental biological differences between the two conditions.

Acute Disease↗