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R Hehlmann

Publications and source records attributed to R Hehlmann.

At least 145 records · Page 8Linked to original sources
PubMed1996

Lower frequency of allele loss on chromosome 18q in human breast cancer than in colorectal tumors.

Inactivation of tumor suppressor genes is thought to be a critical step in tumorigenesis. The DCC (deleted in colorectal carcinoma) gene, located on the long arm of chromosome 18, has been shown to be frequently deleted in colorectal tumors. To investigate the involvement of allelic deletions on chromosome 18q in breast cancer tumorigenesis we analyzed 28 primary breast tumors and 28 colorectal tumors (24 carcinomas, 4 adenomas) with four different polymorphic DNA markers detecting RFLPs on chromosome 18q. In breast cancer we found loss of heterozygosity (LOH) in 4 of 27 (15%) informative cases whereas 15 of 25 (60%) colorectal tumors showed allelic deletions. In all cases of allelic loss the DCC locus or its proximal vicinity (locus SSAV1) were involved. LOH on chromosome 18q occurs both in breast and colorectal cancer, yet the frequency of these deletions in breast tumors is lower than in colorectal tumors. Moreover, in breast cancer these mutations were only detected in large and undifferentiated tumors.

Adult↗
PubMed1996

Expression of CD44 variant isoforms in peripheral blood leukocytes in malignant lymphoma and leukemia: inverse correlation between expression and tumor progression.

In a variety of human tumors, including high grade Non-Hodgkin's lymphoma (hgNHL), a linkage between expression of CD44 variant isoforms (CD44v) and tumor progression has been described. In search of an easily accessible diagnostic parameter, expression of CD44 standard (CD44s) and CD44 variant isoforms (exons v5, v6, v7 and v10) in peripheral blood lymphocytes (PBLs) of patients with hematological malignancies was evaluated by fluorescence activated cell scanning. The analysis of 30 blood samples of healthy donors and patients with non-malignant diseases and of 183 blood samples of patients with malignant hematological disorders revealed that only in patients with malignant disorders did a measurable proportion of PBLs express CD44 variant isoforms, mostly exons v5, v6, v7 and, less frequently, exon v10. Elevated levels of CD44v expression were noted in PBLs of patients with acute and chronic myeloid leukemia (AML: 16%, CML: 25%), Hodgkin's disease (HD: 17%), multiple myeloma (MM: 22%), polycythemia vera (PV: 33%), acute lymphoid leukemia (ALL: 23%) and, most frequently, in PBLs of patients with non-Hodgkin's lymphoma (NHL:54%). CD44v expression was not restricted to the malignant phenotype, but instead was also noted in T cells, B cells and monocytes, preferentially in a subpopulation of large cells. Furthermore, expression of CD44v in PBLs was not linked to the histological grading or clinical staging. There was, however, an inverse correlation with tumor progression, whereas response to therapy was frequently accompanied by upregulation of CD44v. Thus, expression of CD44v in the PBLs of patients with NHL mainly reflected immune responsiveness. Since NHL manifests itself primarily in lymphoid organs, its progression is difficult to follow. Monitoring of CD44v in PBLs could be used as an additional and convenient parameter for surveying the course of disease.

Adult↗
PubMed1996

Biological significance of human endogenous retroviral sequences.

Endogenous retroviruses (ERVs) have been known for many years to exist in numerous natural and laboratory animal species. In humans it has been demonstrated that at least 1% of the genome consists of retrovirus-related sequences. Involvement of ERVs in the development of neoplastic and autoimmune diseases in the mouse model implicated a potentially pathogenic role of ERVs for humans, too. The research in this field led to a number of results strongly suggesting that human endogenous retroviral sequences (HERVs) are biologically active, on the RNA and even on the protein level. Particle formation, regulation or dysregulation of cellular gene expression, and synthesis of potentially pathogenic viral proteins indicate the broad spectrum of mechanisms by which HERVs may obtain biological significance.

Animals↗
PubMed1996

Interferon-alpha in the treatment of essential thrombocythemia.

Interferon alpha (IFN) inhibits the growth of megakaryocytic progenitors in normal hematopoiesis and in patients with essential thrombocythemia (ET) leading to a reduction of peripheral platelet counts. The effectiveness in the induction therapy of patients with ET is demonstrated in 11 international studies including 212 patients. With an average dose of about 3 mill IU IFN daily, the response rate was about 90%. Further studies investigated the practicability and the success of IFN maintenance therapy. The results show that IFN can effectively control platelet counts over a period of several years. During maintenance the IFN dose could be reduced in the majority of patients. However, sustained unmaintained complete remissions were obtained in only 12% of the patients. Side effects were frequently the limiting factors in treatment with IFN especially in older patients. Analyzing a total of 273 patients, IFN therapy was terminated in 25% against the primary treatment plan. Of the currently effective drugs in controlling the platelet counts in ET, IFN is the only antiproliferative agent with immuno-modulating properties. Thus far, no leukemogenic or significant gonadotoxic effects have been observed. In a subset of the patients off all therapy, the sustained remissions support a long-term tumor load reduction effect by IFN. Thus, IFN is a promising agent in cytoreductive treatment of ET especially in younger patients.

Bone Marrow↗
PubMed1996

Current aspects of drug therapy in Philadelphia-positive CML: correlation of tumor burden with survival.

One therapeutic concept in chronic myeloid leukemia (CML) assumes that a reduction of clonal genetically unstable cells also reduces the rate of secondary genetic changes and thereby postpones blast crisis. According to this concept, the degree of reduction of tumor burden should correlate with a prolongation of survival. The recent literature, in particular on controlled studies of IFN, hydroxyurea or intensive chemotherapy is reviewed and analyzed with regards to this concept. In chronic phase CML, intensity of treatment as determined by the degrees of WBC suppression, and, more recently, of cytogenetic remission, as measures of the reduction of tumor burden appear to correlate directly with survival. The superiority of a therapeutic regimen in chronic phase CML seems to primarily depend on whether its pharmacology permits a sufficiently high dosage to achieve the necessary reduction of tumor burden. The concept underlies present strategies that try to prolong survival in CML by IFN alone or in combination with intensive chemotherapy, by hydroxyurea, alone or in combination with IFN, and by high-dose chemotherapy followed by autografting.

Antineoplastic Agents, Alkylating↗
PubMed1996

[Chronic myeloid leukemia].

The chronic myelogenous leukemia [CML] is a clonal disease of hematopoietic stem cells with unknown etiology. The incidence is around 2/100,000/year, the median age at diagnosis about 47 years. The course of CML is characterized by a chronic phase with few symptoms and good therapeutic response of about 4 to 5 years duration and by transition to a prognostically unfavourable blast phase of about 3 months duration. Therapy of choice, at present, is early allogenous bone marrow transplantation [BMT], which is curative in 40 to 80% of transplanted cases. In patients below 55 years, a donor search should be started at the earliest possible time after diagnosis. Drug therapy of choice are interferon alpha [IFN] and hydroxyurea, which are both superior to busulfan with regard to duration of chronic phase and survival. Complete cytogenetic remissions are observed in 5 to 9% of IFN-treated patients in randomized studies, but virtually all remain positive for bcr/abl by PCR. Whether and in how far IFN is superior to hydroxyurea appears, at least in part, to depend on the treatment intensity with hydroxyurea and on patients characteristics. In analyzing median survival times, the risk profiles of the patients have to be considered. In the future, intensive chemotherapy with or without autografting might play an important role in the therapy of chronic-phase CML. Forthcoming trials have to consider both, conventional and new experimental treatment modalities. An example is the treatment strategy of the ongoing randomized study of the German CML Study Group which compares allogenous BMT with the best available drug therapy and, in addition, analyses the influence of intensified drug therapy on survival.

Adolescent↗
PubMed1996

Laboratory tests of iron status: correlation or common sense?

We demonstrate that simple correlation between the various tests of iron status is not sufficient for examining their value in diagnosing iron deficiency (ID). Three degrees of ID are recognized: Iron depletion (ID grade I) is defined by decreased total body iron and normal iron support to erythropoiesis, as diagnosed by decreased storage iron, decreased ferritin, normal sideroblast count, normal zinc protoporphyrin (ZPP), and transferrin saturation >15%. When the iron supply to erythropoiesis becomes insufficient, as diagnosed by transferrin saturation < or = 15%, increased ZPP, and decreased sideroblast count, iron-deficient erythropoiesis (ID grade II) occurs. When finally hemoglobin is below its normal range, iron-deficiency anemia (ID grade III) results. The various tests for ID cannot be compared without taking into account the severity of the deficiency. Depending on the grade of ID examined, the correlation of markers seen in our patients' data varied considerably. We conclude that a "best" marker of ID does not exist. However, the different tests efficiently complement each other by detecting different stages and individually show the clinical extent of ID. Ferritin reflects the iron stores. ZPP indicates whether the ID in a given patient is clinically relevant or not. Finally, the extent of a clinically relevant ID can be assessed by the measured ZPP, hemoglobin concentration, and red cell indices.

Anemia, Iron-Deficiency↗
PubMed1996

Randomized study of the combination of hydroxyurea and interferon alpha versus hydroxyurea monotherapy during the chronic phase of chronic myelogenous leukemia (CML Study II). The German CML Study Group.

It is the long-term goal of the German CML Study Group and of the Süddeutsche Hämoblastosegruppe (SHG) to improve survival of patients with chronic myelogenous leukemia (CML). In a first randomized study (CML Study I) monotherapies with hydroxyurea or interferon alpha (IFN-alpha) were compared with a standard busulfan regimen with regard to duration of the chronic phase and survival. The main results of this study were published, 1-3 and a long-term follow up is planned. In a second randomized study the effect of the combination of IFN-alpha and hydroxyurea versus hydroxyurea monotherapy on survival is being investigated. This paper provides a first preliminary report on the study concept, patient recruitment, state of documentation and initial patients' characteristics 9 months after closure of the study.

Adult↗
PubMed1996

Quantitative molecular methods to monitor the response of CML patients to interferon-alpha.

Interferon-alpha (IFN-alpha) induces cytogenetic responses of variable degree in patients with CML. We sought to establish the relationship between BCR-ABL transcript numbers measured by competitive two-step reverse transcription polymerase chain reaction (RT-PCR) and cytogenetic status in CML patients treated with IFN-alpha. All 305 samples from 133 patients investigated by RT-PCR were positive for BCR-ABL transcripts. In order to standardize results for variability in RNA and cDNA quality, we quantified total ABL transcripts in each sample as an internal control. The BCR-ABL : ABL ratios correlated well with the cytogenetic results. Quantitative nested PCR allowed the detection of residual BCR-ABL transcripts in all complete cytogenetic responders on IFN-alpha. We conclude that competitive PCR with internal controls is a reliable method for monitoring patients on IFN-alpha and reduces the need for repeated marrow investigations.

Antineoplastic Agents↗
PubMed1996

Analysis and validation of prognostic factors for CML. German CML Study Group.

The analysis and validation of prognostic factors is a decisive prerequisite with regard to the development and application of risk-adjusted therapies. Among others, the Sokal index 1 and Kantarjian's new staging system 2 were scores set up to assess the survival of every patient individually. By means of 504 Ph- and/or bcr-abl-positive patients of the German CML study I, we tried to validate both scores mentioned above. Whereas Kantarjian's staging system provided rather unsatisfactory results, the discrimination of different risk groups was more promising with respect to the Sokal index. Still, concerning the differentiation between risk groups for the interferon-alpha (IFN-alpha) treated patients of the German study I, the Sokal index also failed. Hence, we applied Cox stepwise regression technique and identified three prognostic factors for the IFN-alpha treated patients, i.e. eosinophils, erythroblasts (both in peripheral blood), and extramedullary manifestations. We developed our own score and found an encouraging 5-y survival rate of 90% (95% confidence interval (CI) 76-100%) for a certain low-risk group of 41 out of 120 IFN-alpha treated patients. With the need to validate our score and, if possible, not only to confirm the above result but also to identify other particular patient groups, we launched the European Prognostic Factors Project (E.P.F.P.). Within this project, our special interest will be dedicated to patient groups who might also benefit from a bone marrow transplantation.

Adolescent↗
PubMed1996

Intensive combination chemotherapy in treatment of CML.

Tumor load reduction has an influence on survival of patients in the chronic phase of chronic myelogenous leukemia (CML). This comprises both reduction of white blood cell (WBC) mass and reduction of the Philadelphia (Ph)-positive clone. Besides drug monotherapy, intensive combination chemotherapy is also very effective in reducing tumor burden in the chronic phase of CML. Therapeutic concepts consisting of combination chemotherapy include intensive chemotherapy alone or in combination with interferon-alpha (IFN-alpha) and preparative regimens before autografting or allografting. All these concepts demonstrate the effectiveness of this treatment form. The high toxicity of combination chemotherapy does not justify its application in unselected patients. However, in suitable patients, possibly in poor interferon-alpha responders (as carried out in the current German CML study) it might be superior with regard to survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Identification of S71-related human endogenous retroviral sequences with full-length pol genes.

The human genome contains sequences related to the simian sarcoma-associated virus SSAV. One of these endogenous retroviral elements, S71, is truncated in the pol gene and carries an insertion of a solitary HERV-K LTR. Using a PCR approach we have now identified further S71-related retroviral elements that lack the HERV-K LTR insertion and contain a full-length retroviral reverse transcriptase. Two of these sequences, pCRTK1 and pCRTK6, were cloned and further characterized. Clones pCRTK1 and pCRTK6 showed between 85 and 90% nucleotide homology to each other and to S71 within the "tether" region of the pol gene, indicating that pCRTK1 and pCRTK6 clearly belong to the S71 subgroup of C-type-related human endogenous retroviral elements. Some point mutations inactivating the reverse transcriptase are located at the same positions in pCRTK1 and pCRTK6. Therefore, we assume that these S71-related elements were dispersed in the human genome by reintegration as defective proviruses, probably using enzymes for retrotransposition provided in trans by other retrotransposons or by cellular genes. Examination of the presence of S71-related elements in apes and Old World monkeys revealed that the deletion of reverse transcriptase sequences in S71 has occurred in the lineage of primates prior to the insertion of the HERV-K LTR.

Amino Acid Sequence↗
PubMed1995

Variable numbers of BCR-ABL transcripts persist in CML patients who achieve complete cytogenetic remission with interferon-alpha.

A substantial minority of patients with chronic myeloid leukaemia (CML) achieve a complete response to treatment with interferon-alpha (IFN-alpha), defined as the disappearance of Philadelphia chromosome positive metaphases or, for patients who are Philadelphia chromosome negative but BCR-ABL positive, the disappearance of the leukaemic clone as assayed by Southern blot. We have measured the levels of BCR-ABL transcripts in 20 such patients by quantitative PCR. Results were standardized for both quality and quantity of cDNA by quantification of ABL as an internal control. All 20 patients had evidence of residual disease; the median number of transcripts was 750/micrograms RNA (range 10-22,000) and the median BCR-ABL/ABL ratio was 0.17% (range 0.0008-3.6%). Our findings show that CML has not been eradicated in any patient and that the quantity of residual disease in complete responders may vary by as much as four orders of magnitude.

Adult↗