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N Gattermann

Publications and source records attributed to N Gattermann.

At least 55 records · Page 3Linked to original sources
PubMed1999

Multiple basal cell carcinomas associated with hairy cell leukaemia.

We report the case of a caucasian woman who, between the ages of 49 and 51 years, developed multiple (> 20) basal cell carcinomas (BCC). There was no family history of BCC. No abnormalities in the human homologue of the Drosophila segment polarity gene patched (PTCH), glutathione S-transferases T1 and M1, or cytochrome P450 1A1 were detected by polymerase chain reaction (PCR)-based molecular analysis. There was, however, actinic damage of the skin in sun-exposed areas. The patient was diagnosed as having hairy cell leukaemia (HCL) at the age of 51 years, based upon leucocyte morphology as assessed by light and electron microscopy, tartrate-resistant acid leucocyte phosphatase (TRAP) staining, fluorescence activated cell scanning of peripheral blood leucocytes and bone marrow histology. As the leukaemia slowly progressed over a 3-month period, the patient developed four further BCCs. Given that HCL is characterized by a profound defect in T-cell function, it is conceivable that T-cell immune dysregulation can contribute to the pathogenesis of BCC, possibly enhancing the aetiological effect of ultraviolet irradiation.

Basal Cell Carcinoma↗
PubMed1998

MtDNA mutations associated with sideroblastic anaemia cause a defect of mitochondrial cytochrome c oxidase.

We have recently described heteroplasmic mutations of mitochondrial DNA in patients suffering from sideroblastic anaemia. The mutations change conserved residues 1280 and M273 in subunit I of cytochrome oxidase, the terminal enzyme of the mitochondrial respiratory chain. As a step towards elucidating the pathogenic mechanism, we studied the biochemical consequences of the mutations by transferring mtDNA from these patients' platelets into a permanent human cell line lacking a mitochondrial genome. Mutation-induced changes of the enzyme and the energy metabolism of the cells were characterised in the transmitochondrial cell lines. One of the mutations resulted in a decreased cellular concentration of the enzyme and a corresponding decrease in activity. The second mutation changed the structure around the binuclear centre and forced the cells to rely more strongly on glycolysis.

Anemia, Sideroblastic↗
PubMed1998

Increasing incidence of myelodysplastic syndromes: real or fictitious?

Over the past 10-20 years, there has been a growing interest in the myelodysplastic syndromes (MDS). Due to difficulties of diagnosis, classification and case recording, the epidemiological features of MDS are still poorly defined. Recently, a number of cancer registries have published data on the regional occurrence of MDS, suggesting that MDS are much more common than previously thought. The crude incidence of MDS in these studies was 3.5-12.6 per 100,000 population per year. In people over the age of 70 years, incidence rates varied between 15 and 50 per 100,000 per year. Contrary to the assumption of most hematologists, cancer surveys usually failed to demonstrate a rising incidence of MDS. In those studies showing a significant increase in MDS, the rising number of cases was probably due to increased physician awareness and extended use of invasive diagnostic procedures in elderly people. Differences in incidence figures between regional studies may be attributed to several causes, including regional variations in disease incidence, small and ill-defined reference populations, bias due to patient referral patterns, varying intensity of diagnostic procedures and different observation periods. Because of the paucity of clinical symptoms and insignificance of morphological bone marrow changes particularly in early stage MDS, the currently available incidence figures are likely to underestimate the true incidence of MDS. Large-scale epidemiological studies are required for obtaining truly representative statistics on the incidence and prevalence of the MDS. In industrialized countries, a dramatic increase in these disorders can be expected over the next few decades due to the 'greying' of the population.

Adult↗
PubMed1998

Problems in the classification of CMML--dysplastic versus proliferative type.

The FAB group proposed to distinguish two subgroups of chronic myelomonocytic leukemia (CMML). Depending on the total leukocyte count, a myelodysplastic type (MDS-CMML) (< or = 13,000 microl(-1)) was separated from a myeloproliferative type (MPD-CMML) (> 13,000 microl(-1)). Based on retrospective analyses of 158 patients with CMML, we compared the presenting clinical and hematological features of both disorders and examined whether the refined classification is important in terms of prognosis. There were 81 patients with MDS-CMML and 77 patients with MPD-CMML. Median age of patients at diagnosis (70 versus 72 years) was not different. The sex ratio showed a preponderance of males in the MPD group (m:f; 2.1:1). Splenomegaly was more common in MPD-CMML (54 versus 30%; P = 0.002). With regard to laboratory findings, patients with MPD-CMML presented with significantly higher LDH values (medians 295 versus 231 U ml(-1); P = 0.008) and higher serum deoxythymidine kinase levels (medians 150 versus 41 U microl(-1); P = 0.0025). Except for white blood cell count (WBC), peripheral blood counts were not different. Median percentage of bone marrow blasts was 9% and cumulative survival rates were similar in both disorders. Two years after diagnosis, actuarial survival for patients with MPD-CMML was 33%, as compared to 50% for patients with MDS-CMML (P = 0.31). The probability of transformation to AML was higher in MDS-CMML (32 versus 17% after 5 years), but this difference also did not reach statistical significance. The survival of patients with MDS-CMML was similar to that of other MDS patients (RAEB) who had corresponding medullary blast counts. Using the Düsseldorf-score, we could define two risk groups within MDS-CMML with a median survial of 12 versus 40 months (P = 0.001). None of the known scoring systems could define risk groups within the MPD-CMML group. In summary, these data suggest that MDS-CMML and MPD-CMML are clinically distinguishing conditions, but the separation provides little prognostic information. Further studies are needed to clarify whether response to therapy is different in MDS-CMML and MPD-CMML.

Adult↗
PubMed1997

Heteroplasmic point mutations of mitochondrial DNA affecting subunit I of cytochrome c oxidase in two patients with acquired idiopathic sideroblastic anemia.

Mitochondrial iron overload in acquired idiopathic sideroblastic anemia (AISA) may be attributable to mutations of mitochondrial DNA (mtDNA), because these can cause respiratory chain dysfunction, thereby impairing reduction of ferric iron (Fe3+) to ferrous iron (Fe2+). The reduced form of iron is essential to the last step of mitochondrial heme biosynthesis. It is not yet understood to which part of the respiratory chain the reduction of ferric iron is linked. In two patients with AISA we identified point mutations of mtDNA affecting the same transmembrane helix within subunit I of cytochrome c oxidase (COX I; ie, complex IV of the respiratory chain). The mutations were detected by restriction fragment length polymorphism analysis and temperature gradient gel electrophoresis. One of the mutations involves a T --> C transition in nucleotide position 6742, causing an amino acid change from methionine to threonine. The other mutation is a T --> C transition at nt 6721, changing isoleucine to threonine. Both amino acids are highly conserved in a wide range of species. Both mutations are heteroplasmic, ie, they establish a mixture of normal and mutated mitochondrial genomes, which is typical of disorders of mtDNA. The mutations were present in bone marrow and whole blood samples, in isolated platelets, and in granulocytes, but appeared to be absent from T and B lymphocytes purified by immunomagnetic bead separation. They were not detected in buccal mucosa cells obtained by mouthwashes and in cultured skin fibroblasts examined in one of the patients. In both patients, this pattern of involvement suggests that the mtDNA mutation occurred in a self-renewing bone marrow stem cell with myeloid determination. Identification of two point mutations with very similar location suggests that cytochrome c oxidase plays an important role in the pathogenesis of AISA. COX may be the physiologic site of iron reduction and transport through the inner mitochondrial membrane.

Aged↗
PubMed1997

Fatal hyperleukocytic syndrome in a patient with chronic myelomonocytic leukemia.

A 53-year-old male patient was admitted to our hospital with painful splenomegaly. He was diagnosed as having chronic myelomonocytic leukemia (CMML) with leukocytosis, monocytosis, increased lysozyme concentrations in serum und urine, and lack of the Philadelphia chromosome. The clinical course of the disease was characterized by rapidly rising leukocyte counts, cutaneous infiltrates, respiratory insufficiency and neurological symptoms. Excessive hyperleukocytosis with a significant increase in monocytic cells led to microcirculatory obstruction, vascular endothelial damage and organ malfunction. This complication could not be prevented by low-dose chemotherapy with cytosine arabinoside. The patient finally died from pulmonary and cerebral hyperleukocytic syndrome.

Fatal Outcome↗
PubMed1997

Chronically ultraviolet-exposed human skin shows a higher mutation frequency of mitochondrial DNA as compared to unexposed skin and the hematopoietic system.

Normal ageing processes are associated with an accumulation of mutations within the mitochondrial (mt) DNA. The most frequent mutation is a 4977 base pair (bp) deletion known as common deletion. In order to test the hypothesis that chronically sun-exposed skin is characterized by an increased mutation frequency of mtDNA, the mutation frequency of the common deletion between skin and another replicating tissue (the hematopoietic system) and chronically sun-exposed versus sun-protected skin was compared in the same individuals. This was done by comparing the amount of mutated mtDNA molecules with the whole mitochondrial genome in the same specimen with a semiquantitative polymerase chain reaction method, thus allowing direct comparison of different tissues. In all skin specimens the common deletion could be observed. In contrast only 3 of 10 blood samples revealed detectable amounts of the common deletion. Comparison of sun-exposed versus sun-protected skin exhibited a higher content of the common deletion in sun-exposed skin in 7 of 10 individuals. Additionally, a hitherto undescribed mtDNA mutation was detected exclusively in human skin. These studies indicate that exposure of human skin to solar radiation leads to an accumulation of mtDNA mutations, possibly via oxidative damage, which may play an important role in photoageing.

Adult↗
PubMed1996

[The prognostic significance of serum thymidine kinase in the myelodysplastic syndrome].

OBJECTIVE: To assess the prognostic value of serum thymidine kinase (sTK) activity in patients with the myelodysplastic syndrome (MDS). PATIENTS AND METHODS: The study included 255 patients (144 men, 111 women, median age 67 [14-97] years) in whom primary MDS had been diagnosed between 1986 and 1995 (refractory anaemia [RA]: n = 40; RA with ring sideroblasts: n = 38; RA with increased blasts: n = 76; RA with increased blasts in transformation: n = 45; chronic myelomonocytic leukaemia: n = 56). 69 healthy persons (28 men, 41 women, median age 33 [24-62] years) served as controls. The normal laboratory range for sTK was between 0.9 and 4.9 U/microliter. RESULTS: At time of diagnosis 83% of patients had sTK levels higher than 5 U/microliter. There was no relationship between sTK levels and the proportion of medullary blasts. But serum sTK levels correlated with LDH activity (P < 0.0005) and with peripheral leukocyte count (P = 0.003). At all times patients with sTK levels < 10 U/microliter had a higher survival rate than those > or = 10 U/microliter. Cumulative survival rates in both groups was 69 +/- 10% (< 10 U/microliter) and 43 +/- 11% (> or = 10 U/microliter), respectively, after 2 years and 37 +/- 9% (< 10 U/microliter) and 20 +/- 7% (> or = 10 U/microliter) after 5 years (P = 0.0002). Multivariate analysis showed that sTK, haemoglobin concentration and proportion of medullary blasts were independent prognostic survival factors. CONCLUSIONS: Most patients with MDS have an increased sTK level when the diagnosis is made. This reflects the impaired proliferation and differentiation of haematopoiesis. sTK is a simply and rapidly measured prognostic indicator for estimating survival probability of patients with MDS.

Adolescent↗
PubMed1996

[Diagnosis and therapy strategy in myelodysplastic syndromes].

Myelodysplastic syndromes (MDS) are diagnosed with increasing frequency in recent years. Their crude annual incidence (ca. 4/100,000), is now about twice that of acute myeloid leukemias (AML). In over 70-year-old patients (age-related incidence more than 20/100,000), MDS rival CLL as the most common hematological neoplasias. Diagnosis of MDS is based on cytological and histological examination of bone marrow specimens, which may show various dysplastic features of hematopoietic precursors and an increased percentage of blast cells. In difficult cases the diagnosis of MDS is supported if cytogenetic investigation reveals an abnormal karyotype. Most patients with MDS (60 bis 80%) die from their bone marrow disorder, with infections, hemorrhages and leukemic transformation being the most frequent causes of death. Treatment must take into account the age and general condition of the individual patient as well as the natural course of his MDS. The comparatively favourable prognosis of patients with early-stage MDS should not be jeopardized by therapies carrying a high risk of treatment-related death. Therefore, treatment is often confined to supportive measures (blood transfusions, antibiotics). Patients with increased percentage of blasts, however, have such a poor prognosis that more aggressive approaches including intensive chemotherapy appear justified. Only very few patients can be treated with allogeneic bone marrow transplantation, which offers a chance for cure.

Age Factors↗
PubMed1996

A heteroplasmic point mutation of mitochondrial tRNALeu(CUN) in non-lymphoid haemopoietic cell lineages from a patient with acquired idiopathic sideroblastic anaemia.

Acquired idiopathic sideroblastic anaemia (AISA) has been proposed to be a disorder of mitochondrial DNA (mtDNA). The hallmark of mitochondrial iron overload may be attributable to a respiratory chain defeat leading to impaired reduction of ferric iron (Fe3+) to ferrous iron (Fe2+), which is essential to the last step of mitochondrial haem biosynthesis. In a 71-year-old patient we identified a point mutation in one of the two mitochondrial transfer-RNAs coding for leucine (tRNA(leu)(CUN)). The mutation involves a G --> A transition in the anticodon loop, immediately adjacent to the anticodon triplet (mtDNA position 12301). The mutated guanine is highly conserved in a wide range of species. The mutation is heteroplasmic, i.e. there is a mixture of normal and mutated mitochondrial genomes (ratio c. 50:50). Heteroplasmy of mtDNA is not found in normal individuals, but is a typical feature of mitochondrial cytopathies. The point mutation was present in the patient's bone marrow and whole blood samples, in purified platelets, and in the granulocyte/erythrocyte pellet after mononuclear cell separation by density gradient centrifugation. The mutation was not found in T- and B-lymphocytes isolated by immunomagnetic bead separation. It was also absent from buccal mucosa cells and cultured skin fibroblasts. This pattern of involvement suggests that the mutation occurred in a self-renewing myeloid stem cell of the CFU-GEMM type.

Aged↗
PubMed1995

Epidemiological and etiological aspects of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are increasingly recognized as a cause of bone marrow failure, and are at least as frequent as acute myeloid leukemias. While the overall incidence is about 2-4/100,000/year, incidence figures rise steeply with age. Incidence rates of 20-30/100,000/year in persons over 70 demonstrate that MDS are among the most common hematological neoplasias in this age group. However, due to difficulties of diagnosis and classification, patient registration in population-based registers is far from complete. As a prerequisite for truly representative statistics, future revisions of disease classification systems must incorporate MDS as a separate group of disorders. The difficulties in conducting epidemiological studies also impede the identification of risk factors for the development of MDS. Current knowledge of occupational risk factors is also reviewed here. More rapid progress in our understanding of MDS may come from recent advances in methodology that have begun to shed some light on the cytogenetic and molecular aspects of leukemogenesis in general, and MDS in particular. Non-random chromosomal changes can be found in about 50% of cases at diagnosis, but they are probably late events in the evolution of MDS, reflecting the progressive genomic instability of the premalignant clone. Proto-oncogene mutations have also been suggested to be relevant to the pathogenesis of MDS, but longitudinal studies of point mutations of the N-ras proto-oncogene revealed that such events, although often associated with rapid deterioration and transformation to AML, also appear to be late events during the course of disease. Therefore, it remains a major challenge to identify those lesions that initiate the multistep development of preleukemia. As the incidence of MDS correlates strongly with age, it is reasonable to presume that age-dependent changes of the hematopoietic system may play a role in the initiation of MDS. Aging is probably associated with a compromised marrow reserve through reduction in the size of the stem cell pool. Through increased proliferative activity, the remaining stem cells may be particularly vulnerable to mutagenic insults. Immunological attack on stem cells, mitochondrial DNA mutations, and the regulatory influence of the hematopoietic microenvironment must also be considered as possibly contributing to the early stages of MDS.

Female↗
PubMed1995

Detection of the ageing-associated 5-Kb common deletion of mitochondrial DNA in blood and bone marrow of hematologically normal adults. Absence of the deletion in clonal bone marrow disorders.

In recent years, a variety of chronic degenerative diseases that mainly involve brain, heart and muscle have been shown to result from mutations in mitochondrial DNA (mtDNA). A 4977-bp deletion (mtDNA-4977, also known as the common deletion) is the most frequent abnormality in patients with mitochondrial myopathies. A low percentage of mtDNA-4977 is also found in various tissues of normal ageing individuals. Accumulation of this deletion as well as other mtDNA deletions and point mutations is thought to contribute to normal cell ageing. We examined blood and bone marrow samples of 63 hematologically normal patients undergoing sternotomy for cardiac surgery. Using short-cycle PCR, which favors the amplification of molecules carrying large deletions, we detected the common deletion in 22 (35%) of the patients. In one of the probands, a hitherto unknown 4867-bp deletion was identified (nt 8561-13429). In each sample the percentage of mtDNA-4977 was very low, since detection always required primer-shift reamplification of a primary PCR product. Because mtDNA molecules with large deletions are known to be progressively enriched through their tendency to replicate more rapidly than full-size mtDNA, the small amount of mtDNA-4977 detected is likely to be concentrated in a small fraction of cells. The common deletion was not detectable in 20 patients with myelodysplastic syndromes (MDS), 20 patients with acute myeloid leukemia (AML), and 10 patients with chronic myeloid leukemia (CML). The seeming paradox of detectability of mtDNA-4977 in hematologically normal individuals and its absence in clonal myeloid disorders is explained by varying selection against self-renewing stem cells harboring the common deletion. Selection appears to be effective under circumstances of proliferative stress (eg among continuously proliferating stem cells in clonal hematopoiesis), whereas in normal steady-state hematopoiesis, affected stem cells persist because they are rarely recruited into cell cycle and can thus tolerate mitochondrial dysfunction.

Adolescent↗