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H Heimpel

Publications and source records attributed to H Heimpel.

At least 37 records · Page 2Linked to original sources
PubMed2000

Geographic distribution of CDA-II: did a founder effect operate in Southern Italy?

BACKGROUND AND OBJECTIVE: Congenital dyserythropoietic anemia type II (CDA-II) is an autosomal recessive condition, whose manifestations range from mild to moderate. Its exact prevalence is unknown. Based on a recently established International Registry of CDA-II (64 unrelated kindreds), a high frequency of CDA II families living in South Italy became evident. DESIGN AND METHODS: The aim of this study was to define the haplotypes of the CDA II kindreds living in Southern Italy based on markers D20S884, D20S863, RPN, D20S841 and D20S908. These markers map to 20q11.2, within the interval of the CDAN2 gene that is responsible for CDA II. Next, we looked at these markers in kindreds from other regions of Italy and from other countries, with special attention to families having ancestors in Southern Italy. RESULTS: Evaluation of the geographic distribution of the ancestry of Italian CDA-II patients clearly demonstrated the unusually high incidence of this condition in Southern Italy. Our statistical calculations and linkage disequilibrium data also clearly demonstrate a strong association of the markers of chromosome 20 with the disease locus in our sample. Almost all the regions defined by the markers here used is in disequilibrium with the disease. Combining the data from the Italian sample together with those obtained from the non-Italian ones, we can restrict the area of highest disequilibrium to that defined by markers D20S863-D20S908. INTERPRETATION AND CONCLUSIONS: Despite the presence of this linkage disequilibrium the search for a common haplotype failed. This could suggest that the mutation was very old or that it occurred more than once on different genetic backgrounds.

Adolescent↗
PubMed1999

Interferon-alpha before allogeneic bone marrow transplantation in chronic myelogenous leukemia does not affect outcome adversely, provided it is discontinued at least 90 days before the procedure.

The influence of interferon-alpha (IFN) pretreatment on the outcome after allogeneic bone marrow transplantation (BMT) in chronic myelogenous leukemia (CML) is controversial. One goal of the German randomized CML Studies I and II, which compare IFN +/- chemotherapy versus chemotherapy alone, was the analysis of whether treatment with IFN as compared to chemotherapy had an influence on the outcome after BMT. One hundred ninety-seven (23%) of 856 Ph/bcr-abl-positive CML patients were transplanted. One hundred fifty-two patients transplanted in first chronic phase were analyzed: 86 had received IFN, 46 hydroxyurea, and 20 busulfan. Forty-eight patients (32%) had received transplants from unrelated donors. Median observation time after BMT was 4.7 (0.7 to 13.5) years. IFN and chemotherapy cohorts were compared with regard to transplantation risks, duration of treatments, interval from discontinuation of pretransplant treatment to BMT, conditioning therapy, graft-versus-host disease prophylaxis and risk profiles at diagnosis and transplantation, and IFN cohorts also with regard to performance and resistance to IFN. Outcome of patients receiving related or unrelated transplants pretreated with IFN, hydroxyurea, or busulfan was not significantly different. Five-year survival after transplantation was 58% for all patients (57% for IFN, 60% for hydroxyurea and busulfan patients). The outcome within the IFN group was not different by duration of prior IFN therapy more or less than 5 months, 1 year, or 2 years. In contrast, a different impact was observed in IFN-pretreated patients depending on the time of discontinuation of IFN before transplantation. Five-year survival was 46% for the 50 patients who received IFN within the last 90 days before BMT and 71% for the 36 patients who did not (P =.0057). Total IFN dosage had no impact on survival after BMT. We conclude that outcome after BMT is not compromised by pretreatment with IFN if it is discontinued at least 3 months before transplantation. Clear candidates for early transplantation should not be pretreated with IFN.

Adolescent↗
PubMed1999

Aetiology and clinical significance of thrombocytosis: analysis of 732 patients with an elevated platelet count.

OBJECTIVE: To determine the aetiology and clinical significance of an elevated platelet count (thrombocytosis) in a large cohort of patients. DESIGN: A retrospective review of the medical records was performed on all patients, who had at least one platelet count > or = 500 x 10(9) L-1. SETTING: Departments of Medicine and Surgery, University of Ulm, Germany. SUBJECTS: A total of 732 patients with thrombocytosis. MAIN OUTCOME MEASURES: Classification of thrombocytosis and thromboembolic complications, and evaluation of laboratory parameters distinguishing between primary and secondary thrombocytosis. RESULTS: Of the total of 732 patients, 89 (12.3%) had primary and 643 (87.7%) had secondary thrombocytosis. Essential thrombocythaemia was observed in 40 of 89 patients (45%) with primary thrombocytosis. The most frequent causes of secondary thrombocytosis were tissue damage (42%), infection (24%), malignancy (13%) and chronic inflammation (10%). Primary thrombocytosis was significantly associated with a higher platelet count and an increased incidence of both arterial and venous thromboembolic complications. In secondary thrombocytosis, thromboembolic events were restricted to the venous system and occurred only in the presence of other risk factors. Mean values of leucocyte count, haematocrit, erythrocyte sedimentation rate, fibrinogen, serum potassium and lactate dehydrogenase were significantly different in primary and secondary thrombocytosis. CONCLUSIONS: The finding of an elevated platelet count on routine blood examination has diagnostic, prognostic and therapeutic implications. It is of clinical importance to distinguish between primary and secondary thrombocytosis, as thrombotic complications occur more frequently in primary thrombocytosis. Unless additional risk factors are present, secondary thrombocytosis is not associated with a significant risk for thromboembolic events.

Adolescent↗
PubMed1998

Survival with bone marrow transplantation versus hydroxyurea or interferon for chronic myelogenous leukemia. The German CML Study Group.

Hydroxyurea, interferon, and HLA-identical sibling bone marrow transplantation are common therapies for chronic myelogenous leukemia (CML) in chronic phase. Which is best is controversial. The purpose of this study was to compare survival of patients with CML receiving HLA-identical sibling transplants versus hydroxyurea or interferon. The transplant cohort included 548 recipients of HLA-identical sibling transplants, reported to the International Bone Marrow Transplant Registry. The nontransplant cohort included 196 patients receiving hydroxyurea (n = 121) or interferon (n = 75) on a randomized trial of the German CML Study Group. Survivals were compared using proportional hazards regression with fixed and time-dependent variables to adjust for patient differences and changing risks over time. For the first 18 months after diagnosis, mortality was higher in the transplant than the nontransplant cohort (relative risk [RR], 5.85; P < .0001). From 18 to 56 months, mortality was similar (RR, 0.80; P = .38). After 56 months, mortality was lower in the transplant cohort (RR, 0.16; P < .0001). Seven-year survival probabilities (95% confidence interval) were 58% (50% to 66%) with transplant and 32% (22% to 41%) with hydroxyurea or interferon. There was a significant survival advantage for hydroxyurea or interferon in the first 4 years after diagnosis and for transplants starting 5.5 years after diagnosis. For transplants done within 1 year of diagnosis, the survival advantage for transplantation began earlier. Survival advantage for transplants was greater and occurred earlier in patients with intermediate- and high-risk prognostic features than in those with low-risk features. This study confirms higher early mortality, but a long-term survival advantage for HLA-identical sibling transplants over hydroxyurea or interferon in CML.

Adolescent↗
PubMed1998

High levels of thrombopoietin in sera of patients with essential thrombocythemia: cause or consequence of abnormal platelet production?

Thrombopoietin (TPO) is the most important regulator of megakaryocyte development and platelet production. Platelet production is thought to be regulated by a negative regulatory feed back loop. In an attempt to evaluate the role of TPO in the pathobiology of essential thrombocythemia (ET), we have examined levels of TPO and other cytokines with thrombopoietic activity (interleukin-6 and interleukin-11) in sera obtained from 25 patients with ET (ten treated, 15 untreated) and 117 healthy control subjects. TPO serum levels were assessed using a sandwich-antibody ELISA that utilizes a polyclonal rabbit antiserum for both capture and signal. The mean serum TPO level in 25 ET patients was significantly elevated (545+/-853 pg/ml) as compared with that in healthy controls (95.3+/-54.0 pg/ml,p<0.001). The difference in TPO serum levels between ten treated (781+/-1229 pg/ ml) and 15 untreated ET patients (388+/-458 pg/ml) did not reach statistical significance (p = 0.09). We conclude that either consumption or production of TPO is altered in ET. Failure of appropriate feedback regulation and continued megakaryocyte stimulation by an elevated TPO may play an important role in the pathobiology of ET.

Blood Platelets↗
PubMed1998

Thrombopoietin serum levels in patients with aplastic anaemia: correlation with platelet count and persistent elevation in remission.

In an attempt to evaluate the role of thrombopoietin (TPO) in the pathobiology of aplastic anaemia (AA), we have examined TPO levels in sera from 54 AA patients and 119 healthy controls. A total of 92 samples were collected from AA patients: 43 samples were harvested at diagnosis, 23 samples in the cytopenic period after treatment, and 26 samples when patients were in partial (n=10) or complete remission (n=16) following immunosuppressive treatment. TPO serum levels were assessed by a sandwich-antibody ELISA that utilized a polyclonal rabbit antiserum for both capture and signal. Serum samples from normal donors revealed a mean TPO level of 95.3 +/- 54.0 pg/ml (standard deviation). Mean TPO levels in AA sera collected at diagnosis and before onset of treatment were 2728 +/- 1074 pg/ml (P<0.001 compared to normal controls: mean platelet count at that time: 27x10(9)/l). TPO serum levels of AA patients in partial or complete remission after immunosuppressive treatment were significantly lower than TPO levels at diagnosis (P<0.001). However, despite normal platelet counts (mean 167x10(9)/l), TPO levels remained significantly elevated in complete remission (mean TPO 1009 +/- 590 pg/ml, P<0.001 compared to normal controls). There was a significant inverse correlation between serum TPO levels and platelet counts in AA patients who were not transfused for at least 2 weeks prior to sample collection (coefficient of correlation (r) = -0.70, P<0.0001). In summary, TPO levels were highly elevated in sera of patients with AA. Thus there is no evidence to suggest an impaired TPO response contributing to thrombocytopenia in AA. Thrombopoietin did not return to normal levels in remission, indicating a persisting haemopoietic defect in remission of AA. We hypothesize that elevated levels of TPO may be required to maintain normal or near normal platelet counts in remission of AA.

Adolescent↗
PubMed1998

Chronic myeloid leukemia in accelerated phase: treatment results with conventional chemotherapy and allogeneic bone marrow transplantation in 96 patients.

The treatment results of 96 patients with Philadelphia-positive chronic myeloid leukemia (CML) in accelerated phase (AP) were reviewed retrospectively. Treatment of AP consisted of allogeneic bone marrow transplantation in 20 (14 related and 6 unrelated donors) or conventional chemotherapy (CC) in 76 patients. Three main treatment strategies were followed in the CC group: continuation (group A) or dose escalation (group B) of chronic phase therapy or change of chronic phase therapy to hydroxyurea (group C). Median survival was 7.0 months in group A (range 1.8-110), in group B 8.3 months (range 0.9-40) and in group C 9.6 months (range 1.5-47.6), p=0.89. Survival in CC was dependent on response to therapy as the achievement of a second chronic phase was significantly associated (p<0.001) with a longer median survival (21 months) compared with stable accelerated phase disease (11 months) or treatment failure (5 months). Median survival in the BMT group was 16.7 months (range 5-77), the 5-yr probability of relapse was 25% and the 5-yr disease-free survival was 36%. For patients <55 yr median survival after BMT was significantly prolonged compared with median survival after CC (n=45, 8.3 months, p=0.008). After developing criteria of AP, median survival in our analysis has been less than 1 yr. The results of conventional chemotherapy in the treatment of accelerated phase CML are disappointing. If a suitable donor is available allogeneic BMT should be performed without delay in patients with AP.

Adolescent↗
PubMed1997

Rearranged Ig heavy chain DNA is detectable in cell-free blood samples of patients with B-cell neoplasia.

Tumor-derived DNA has been shown in various cell-free body fluids. In this study, soluble tumor-derived DNA was analyzed in serum and plasma samples of patients with B-cell malignancies. DNA was extracted from tumor cell specimens as well as serum and plasma samples collected from 110 patients with non-Hodgkin's lymphoma and acute B-precursor lymphoblastic leukemia and was subjected to polymerase chain reaction (PCR) analysis for rearranged immunoglobulin heavy chain DNA. In 54% of serum or plasma samples analyzed at different times before and during treatment, clonal DNA from a rearranged immunoglobulin heavy chain locus was detectable. When examined at diagnosis and before any treatment, clonotypic DNA was found in serum or plasma of 86% of the patients. Serum or plasma from patients with systemic or bulky disease was uniformly PCR positive, whereas clonotypic DNA was also recovered from the serum or plasma from the majority of patients with limited disease stages. Degradation of clonal DNA by nucleases in vitro was shown to be one cause of false-negative PCR results. This technical drawback can be relieved by adding a nuclease inhibitor like EDTA, ie, by using plasma instead of serum for PCR analysis. Treatment of patients with cytotoxic drugs was followed by rapid clearance of DNA from the peripheral blood, suggesting that soluble tumor-derived DNA might be associated with viable and proliferating tumor cells. Follow-up studies showed a close correlation of persisting soluble tumor-derived DNA with resistant disease or early relapse. In summary, these data suggest that tumor-derived DNA can be detected in serum or plasma of the majority of patients with B-cell malignancies and that testing of serum or plasma for tumor-associated DNA may be a novel parameter for monitoring response to treatment.

Base Sequence↗
PubMed1997

The abundant presence of Söderström bodies in cytology smears of fine-needle aspirates contributes to distinguishing high-grade non-Hodgkin's lymphoma from carcinoma and sarcoma.

Söderström bodies, also termed lymphoglandular bodies (LGB) and detectable in fine-needle aspiration cytology smears, have long been accepted as indicative of lymphoid tissues. To investigate the validity of this association, we examined 588 cytologic smears from high-grade non-Hodgkin's lymphoma (NHL), carcinoma, and sarcoma. Slides with lymphocytes in the vicinity of carcinoma and sarcoma cells had been excluded. Two independent observers scored smears to number, size, color, form, and smear background of the LGB. In 68 of 359 (19%) nonlymphoid malignancies rare (defined as < 1 LGB per high-power field) or occasional LGB (defined as 1-20 LGB per high-power field) were detectable. Half of these tumors consisted of melanomas, small cell lung carcinomas, and teratomas; the other half encompassed undifferentiated sarcomas. However, none of the smears obtained from carcinoma or sarcoma tissue had abundant LGB (defined as > 20 LGB per high-power field). When number of LGB was estimated to be abundant, the sensitivity for diagnosing a lymphoma was 54%; however, specificity was 100%. The difference in showing LGB between high-grade NHL and carcinoma/sarcoma was highly significant (p = 0.0001). The presence of abundant LGB in cytologic smears strongly suggests the diagnosis of lymphoma, while the absence of LGB nearly excludes this diagnosis. No trends were observed with the other criteria which were tested. LGB in aspiration cytology smears from malignant tumors thus represent a useful tool to distinguish high-grade NHL from carcinoma and sarcoma.

Biopsy, Needle↗
PubMed1997

Usefulness of FDG-PET in diagnosing primary lymphoma of the liver.

This case report shows for the first time the usefulness of positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) in the diagnosis of primary non Hodgkin's lymphoma of the liver. Results of FDG-PET, which in contrast to other imaging techniques offers the advantage of screening the whole body, demonstrated a high glycolytic activity of a solitary mass in the liver with central necrosis (loss of glycolytic activity), but no spread of lymphoma to the body. These results were confirmed by ultrasound, computed tomography, magnetic resonance imaging and were biopsy proven. From our findings we conclude that in patients with liver masses with high uptake of FDG, lack of liver dysfunction and absence of signs indicating other malignancies, a primary lymphoma of the liver should be considered as a possible diagnosis.

Female↗
PubMed1997

Comparative analysis of the impact of risk profile and of drug therapy on survival in CML using Sokal's index and a new score. German chronic myeloid leukaemia (CML)-Study Group.

Survival times in chronic myeloid leukaemia (CML) may vary widely depending on the risk profiles of patients. This fact is frequently not, or not sufficiently, considered in evaluating survival in CML, and some studies do not report risk profiles. Therefore we analysed the relative impact of risk profile and therapy on survival using the median survival times of therapy groups and of risk groups of the three-arm randomized German CML Study I (interferon alpha v hydroxyurea v busulphan; median survival times 65 v 56 v 45 months, n = 490, median observation time 70.4 months). The impact of risk profile (Sokal) on survival as determined by the survival difference between high and low risk patients (40 months) was twice the maximum survival difference between treatment groups (20 months). A similar ratio was obtained after stratification for therapy and for risk profile. Since Sokal's index has been reported to prognostically discriminate IFN-treated patients less well than chemotherapy-treated patients, a new score with better discrimination of IFN-treated patients was also used. The results were similar for both scores. We conclude that the risk profile at diagnosis is still more important for survival of CML patients than therapy. Therefore patients should be stratified according to risk profile for comparisons of survival times between studies and treatment arms.

Adolescent↗
PubMed1997

Molecular response of CML patients treated with interferon-alpha monitored by quantitative Southern blot analysis. German chronic myeloid leukaemia (CML) Study Group.

We analysed 459 samples from 206 chronic myeloid leukaemia (CML) patients at diagnosis and during or after treatment with interferon-alpha (IFN-alpha) by quantitative Southern blot analysis for BCR rearrangement. In a minority (2%) of Ph-positive patients, no BCR rearrangement was detectable due to breakpoints outside the major breakpoint cluster region (M-bcr) or possibly due to M-bcr deletions. Results from 235 samples were compared with the proportion of Ph-positive metaphases found in contemporaneous bone marrow specimens analysed by conventional cytogenetics. The rank correlation between both methods was 0.82 (P < 0.001). The proportion of CML cells in samples determined by Southern blot analysis (BCR ratio) was significantly different between cytogenetically-defined minor, partial, and complete response groups (P < 0.001). Empirically-derived cut-off points in the BCR ratio were introduced in order to define molecular response groups for comparison to standard cytogenetic response groups: a BCR ratio of 0% was defined as complete molecular response and ratios of 1-24%, 25-50%, and > 50% were defined as partial, minor, and no molecular response, respectively. Using these cut-off points the concordance between both methods was 67% (P < 0.0001), a major cytogenetic response could be predicted or excluded in more than 90% of cases (P < 0.0001). Our findings demonstrated that quantitative Southern blot was as sensitive as cytogenetics and as peripheral blood samples are suitable for this technique it should be considered as the method of choice for routine monitoring IFN-alpha therapy in CML patients.

Adolescent↗
PubMed1997

Randomized studies with interferon in chronic myelogenous leukemia (CML) and comparative molecular aspects. German CML Study Group.

Four randomized prospective studies on interferon alpha (IFN) in CML report varying degrees of prolongation of the chronic phase of CML and of survival as compared to conventional therapies. There is agreement that IFN prolongs survival as compared to standard busulfan. There is disagreement, however, as to which degree IFN is superior to hydroxyurea. Whereas the randomized studies of the Italian cooperative group and of the British MRC find a statistically significant survival advantage of IFN over hydroxyurea of about 20 months, this difference is only 10 months in the German randomized study and not significant. One reason for this difference might be the more intensive treatment schedule for the hydroxyurea control group in the German study. Other reasons might be differences in risk profiles between the patient groups studied and in strategies of IFN therapy. About 1% of the human genome consists of retroviral or retroviral-like sequences. By analogy to animal models, endogenous retroviruses might also have pathogenic potential in human disease. The transposon-like structure of retroviruses that enables them to integrate at almost any position in the host genome and the capability of retroviruses to serve as efficient vehicles of cellular genes are in support of a pathogenic potential. Furthermore, particles resembling retroviruses have been observed long ago in human embryonic and malignant tissues and cell lines. Sequence information and the transcriptional activity of the endogenous sequences argue against the possibility that these sequences are only fossil relics of early evolutionary periods. Most of the sequences appear to be inactivated by stop codons or frameshifts, making the genomic localization of open reading frames with biological activity difficult. Up to now, mutagenesis by insertion of retroviral-like sequences in sporadic cases of human disease appears to be the only example of pathogenic relevance of retroviruses in man.

Antineoplastic Agents↗
PubMed1996

Quantitative analysis of cobblestone area-forming cells in bone marrow of patients with aplastic anemia by limiting dilution assay.

In the past, the analysis of primitive human hematopoietic progenitor cells with repopulating activity was limited by lack of appropriate in vitro assay systems. It was recently shown that cobblestone area-forming cells (CAFC) giving rise to cobblestone areas after 5 weeks in long-term marrow cultures (LTMC) represent a population of pluripotent progenitor cells with long-term marrow-repopulating activity. We have used a microtiter limiting dilution-type human LTMC system to quantitate the frequency of CAFC (week 5) in aplastic anemia (AA). In bone marrow mononuclear cells (BM-MNC) of healthy donors (n = 36) we observed a mean frequency of 84.4 CAFC per 10(5) BM-MNC (95% confidence interval limits, 66.4 to 102.4). The mean frequency of CAFC in BM of 31 AA patients was 6.6 per 10(5) BM-MNC (95% confidence interval limits, 5.3 to 7.9; n = 47). This frequency is significantly lower as compared with controls (P < .0001). The frequency of CAFC was reduced not only in pancytopenic AA patients (6.2 per 10(5) BM-MNC; P < .0001 v control), but also in patients in remission after immunosuppression (7.6; P < .0001 v control; P = .1 v pancytopenic AA patients). The CAFC frequency did not correlate with the severity or duration of the disease and did not predict response to immunosuppressive treatment. In summary, the frequency of primitive hematopoietic progenitor cells, as measured by the CAFC assay, is significantly reduced in AA. CAFC remain severely reduced even after hematologic recovery after immunosuppressive treatment. The low frequency of CAFC in remission patients is in keeping with other data pointing to a persisting defect of hematopoiesis in patients in remission after immunosuppressive treatment.

Adolescent↗
PubMed1996

[A case-based and multi-media computer learning program on the topic of myocardial infarct, angina pectoris and mitral valve stenosis].

BACKGROUND: Principles in the field of cognitive psychology and problem-based learning together with recent progress in multimedia technologies are providing the basis for the development of case-based and computer-assisted learning systems. With reference to the information-overload of theoretical and factual knowledge in medical education these programs can be an efficient tool to satisfy the current need for new, practical, skill-related forms of knowledge transfer. METHODS: Apple-Macintosh Computers were selected to develop interactive, multimedia patient-simulations on mitral stenosis, angina pectoris and myocardial infarction. INSTRUCTIONAL AIM AND CONTENTS: The user acquires knowledge and skills about the leading symptoms, differential diagnoses, the use and analysis of laboratory examinations and the process of diagnostic reasoning while working through the computer-simulated cases. PEDAGOGICAL DESIGN AND CONCLUSION: Important pedagogical principles associated with computer-assisted learning were employed in the program. Clinical situations can be simulated repeatedly and for every student in an authentic manner. Therefore the program can serve as a preparation for and a supplement to practical clinical education. Compared to conventional teaching media the development of instructional multimedia software requires a tremendous amount of time and resources. Thus, controlled studies are important to objectify the overall advantages such programs can have.

Angina Pectoris↗