[Hepatitis G virus infection: the epidemiological aspects and clinical relevance].
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Acute Disease↗
Biomedical subjects
D Huhn
Publications and source records attributed to D Huhn.
Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection.
We report here a series of 16 highly malignant diffuse large B-cell lymphomas of the oral cavity with unique immunohistologic features. Fifteen of these developed in human immunodeficiency virus-positive patients. All cases displayed morphologic features of diffuse large-cell lymphomas but strikingly differed from them in that they showed a minimal or absent expression of the leukocyte common antigen as well as of the B-cell antigen CD20. Instead, the tumor cells showed a constant reaction with the plasma cell characteristic antibody VS38c and a frequent reaction with the CD79a antibody. This, in conjunction with a variable expression of cytoplasmic Ig and a monoclonal rearrangement of the Ig heavy chain gene in all of the three tested cases confirmed the B-cell nature, the clonal origin, and the plasmacellular differentiation of these neoplasms. The majority of these tumors were negative for the BCL-6 protein, with the remaining cases showing only a partial and weak expression of this antigen. An association with the Epstein-Barr virus (EBV) was found in 9 of 15 tested cases showing abundant EBV-encoded nuclear RNA transcripts in the absence of EBNA-2. Five of the EBV-positive cases variably expressed LMP-1. We propose to name these tumors plasmablastic lymphomas, in accordance with their morphologic and immunohistologic features. Knowledge of this lymphoma entity is important to avoid confusion with nonlymphoid malignancies due to the lack of commonly used lymphoid markers.
Adult↗
Long-term survival of patients with recurrent or refractory germ cell tumors after high dose chemotherapy.
BACKGROUND: The optimal treatment of patients with recurrent or refractory germ cell tumors is still a debated topic. High dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) might be promising for intensification of first or subsequent salvage treatment. However, the long-term results of this approach remain largely unknown. METHODS: Between August 1989 and September 1992, 74 patients with recurrent and/or refractory germ cell tumors were treated in a Phase I/II trial with HDCT consisting of carboplatin (1500-2000 mg/m2), etoposide (1200-2400 mg/m2), and ifosfamide (0-10 g/m2). In September 1995 all patients were reevaluated to determine overall response, late toxicities, and survival. RESULTS: Two patients died from treatment-related toxicity shortly after HDCT, and 47 had recurrence or progression of disease after a median of 3 months (range, 1-44 months). Of these latter patients, three were living continuously disease free at the conclusion of this study after a second HDCT regimen, salvage surgery, or chronic oral etoposide treatment. The results were an overall survival of 38% (95% confidence interval, 27-50%) and a failure free survival of 31% (95% confidence interval, 21-43%) at 5 years. There were no long-term survivors among patients whose disease progressed while they were receiving conventional doses of cisplatin before HDCT. Late toxicities consisted mainly or renal impairment (in 21% of patients), paresthesias (in 29%), and ototoxicity (in 18%). CONCLUSIONS: HDCT can be curative for patients with germ cell tumors who do not become disease free after conventional dose chemotherapy but respond to this treatment.
Adult↗
Preparation of autologous bone marrow grafts for cryopreservation using the AS104 cell separator.
We evaluated the AS104 cell separator (Fresenius AG, Bad Homburg, Germany) for ex vivo processing of bone marrow (BM) grafts of 43 patients suffering from germ cell cancer (GCC, n = 22), acute lymphocytic leukemia (ALL, n = 13) and malignant lymphoma (ML, n = 8). Recoveries of total nucleated cells (TNC), mononuclear cells (MNC) and colony-forming units granulocyte-macrophage (CFU-GM) were determined in the BM concentrates prepared for cryopreservation. Hematopoietic reconstitution was analyzed in patients who underwent autologous transplantation following high-dose radio-/chemotherapy (HDRCT). Processing of the BM suspension with a median volume of 1,013 ml (range: 422-1,574) resulted in 156 ml (80-186) within 50-120 min (median: 90). In the BM concentrates, medians of 28.6% TNC (10.6-69.6), 37.9% MNC (22.3-86.4), and 52.4% CFU-GM (20.8-96.4) were recovered. Twenty-six patients underwent HDRCT with reinfusion of autologous BM and were evaluable for engraftment. They received a median of 0.8 x 10(8) MNC/kg (0.3-1.6 x 10(8)) and 2.2 x 10(4) CFU-GM/kg (0.6-12.8 x 10(4) for hematopoietic rescue. Engraftment with neutrophils > 500/microliter occurred in a median time of 12 days (8-33) in all patients. We conclude that ex vivo processing of autologous BM with median recovery rates of 37.9% for MNC, and 52.4% for CFU-GM, results in a cell population that can rescue patients from HDRCT. The described technique is convenient, time-efficient, and provides reliable results in preparing BM autografts for cryopreservation.
Adolescent↗
The status of p53 in the metastatic progression of colorectal cancer.
In order to investigate the role of TP53 in tumour progression and metastasis, we analysed 33 liver metastases of colorectal carcinomas and 19 primary colon carcinomas from the same hospital with respect to mutational changes, loss of heterozygosity and expression of the TP53 tumour suppressor gene. Direct sequencing of PCR products corresponding to the coding region of TP53 revealed that 13 of 19 primary tumours (68%) and 23 of 33 liver metastases (70%) had mutations in the TP53 gene. The distribution of mutations along the coding region of TP53 was similar in liver metastases compared to primary tumours. Thus, codon specificity did not seem to be a relevant factor and cells carrying specific TP53 mutations seem to have no selective advantage in the metastasising process. Comparing our data with the mutational spectra found in other countries did not reveal differences in the distribution of mutations along the coding region. Most of the metastases analysed showed loss of heterozygosity (LOH, 9 of 12 cases, 75%) and strong nuclear staining in immunohistochemistry (10 of 17 cases, 59%). Furthermore, with respect to mRNA expression levels, tumours carrying TP53 mutations showed significantly higher p53 mRNA levels compared to those without TP53 mutations. Thus, regulation of p53 mRNA levels seems to be subject to selection processes in tumourigenesis.
Chromosome Deletion↗
Imprecision of counting CFU-GM colonies and CD34-expressing cells.
Determinations of committed haemopoietic progenitor cells, namely CFU-GM (colony-forming unit-granulocyte/macrophage) and of CD34-expression haemopoietic cells as assessed by multiparameter flow cytometry are routine diagnostic tools in haemopoietic cell therapy. Generally, the tests are used to optimise the timing and management of cytapheresis and to assess the engraftment potential of the harvested cells. Both measurements, however, are at best surrogate markers, as an adequate routine test which effectively assesses the short- and long-term repopulating haemopoietic cell is not available. Nonetheless, cell threshold doses have been established. Above these thresholds rapid engraftment is almost invariable but below these thresholds the outcome is variable. In this study we have focussed on the imprecision in counting haemopoietic cells, as assessed as CFU-GM and as CD34-expressing cells. The data on both tests have been analysed from six European institutions. The coefficient of variation in CFU-GM colony counting was about 30%, whereas the coefficient of variation in flow cytometric counting of CD34-expressing cells was about 10%. These data suggest that the technical imprecision in enumerating progenitor cells, particularly CFU-GM, at low levels, might make a major contribution to the clinical variability observed after transplantation of sub-threshold progenitor cell dose.
Antigens, CD34↗
High-dose chemotherapy with carboplatin, etoposide and ifosfamide followed by autologous stem cell rescue in patients with relapsed or refractory malignant lymphomas: a phase I/II study.
Patients with relapsed or refractory non-Hodgkin's lymphomas (NHL) and Hodgkin's disease (HD) with recurrences after an anthracyclin-containing regimen only have a chance of cure of below 10% with conventional chemotherapy. In order to improve their prognosis, we started a phase I/II trial using high-dose therapy comprising carboplatin, together with etoposide and ifosfamide (CEI), followed by autologous stem cell rescue (ASCR) as consolidation after salvage treatment. Since September 1990, 40 patients with intensively pretreated advanced NHL (n = 24) or HD (n = 16) received one cycle of high-dose therapy (HDT) consisting of carboplatin 1500 mg/m2, ifosfamide 10 g/m2 and etoposide in escalating doses from 1200 mg/m2 to 2400 mg/m2 followed by ASCR. Thirty-nine patients were assessable for toxicity and response. The following doses appeared to be safe: carboplatin 1500 mg/m2, etoposide 2400 mg/m2 and ifosfamide 10 g/m2. All patients developed grade 3 nausea and grade 3 or 4 mucositis. Granulocytopenic fever occurred in 100% with grade 4 infections in 15%. Mild transient kidney toxicity was noted in 36% and liver toxicity in 20% of patients. One toxic death occurred (2.5%). Objective responses were obtained in 36 of 39 patients (92%) with complete remissions (CR) in 24 patients (61.5%) and partial remissions (PR) in 12 (30.7%). Median observation time for surviving patients was 23.3 months (range 3.4-52.3). The probabilities of overall, event-free and relapse-free survival at 2 years are 62, 39 and 55%, respectively. Patients with primary refractory disease or resistant relapse had a poor prognosis. High-dose carboplatin, etoposide and ifosfamide plus autologous stem cell rescue represents an effective, potentially curative salvage treatment with acceptable toxicities.
Adolescent↗
Lymphocyte apoptosis: induction by gene transfer techniques.
Efficient gene transfer of lymphocytes has been shown to be extremely difficult. The molecular background for this gene transfer resistance is not completely understood. We reasoned that apoptosis may play a role in this gene transfer resistance of lymphocytes. We show that transfection of lymphocytes via nonviral vectors leads to induction of apoptosis in a significant proportion of cells. Since apoptosis may be mediated via the TNF alpha and TNF alpha receptor pathway, we studied the amount of TNF secreted by transfected lymphocytes. The percentage of apoptotic lymphocytes correlated well with TNF alpha secretion. TNF secretion was dependent on the gene transfection method used. High amounts of TNF secretion were detected using receptor-mediated gene transfer and lipofection. In contrast, only low amounts of TNF were detected after electroporation and retroviral gene transfer. In receptor-mediated gene transfer, TNF secretion was due to the use of anti-CD3 antibody. Induction of apoptosis and increase in necrosis was blocked using an anti-TNF antibody. This blockage led to a significant increase in the proliferation rate of lymphocytes transfected with the interleukin-2 or interleukin-7 gene. In conclusion, gene transfer techniques led to TNF secretion, apoptosis and necrosis of lymphocytes. This could be blocked using an anti-TNF antibody. Blockage of apoptosis after gene transfer should have an impact on the use of lymphocytes transfected with cytokine genes as immunologic effector cells in cancer gene therapy protocols.
Antibodies, Monoclonal↗
Pulsed high-dose dexamethasone in chronic autoimmune haemolytic anaemia of warm type.
The management of patients with autoimmune haemolytic anaemia of warm type (AIHA) is often problematic. Recently, pulsed high-dose dexamethasone (HDD) has been shown to be effective in the treatment of autoimmune thrombocytopenic purpura (AITP). In this study we treated seven patients with AIHA with HDD. The regimen recommended for treatment of refractory AITP (40 mg dexamethasone for 4 d at the beginning of each 28 d cycle) was employed in almost all cases. Prior to dexamethasone administration, haemolysis was decompensated in all seven patients. HDD was well tolerated and led to an improvement of haemolysis in all cases.
Adult↗
Two subsets of peripheral blood plasma cells defined by differential expression of CD45 antigen.
The purpose of this study was to optimize the flow cytometric determination of circulating normal and malignant plasma cells (PC). We investigated peripheral blood (PB) samples of 65 patients with multiple myeloma or monoclonal gammopathy of unknown significance and 47 control subjects using CD38, CD45, B-B4, CD56, VLA-4, VLA-5 and CD19 monoclonal antibodies (MoAbs). Mono- or polyclonality was determined by staining of intracellular kappa and lambda light chains. Two subpopulations of PBPC were distinguished by differential expression of CD45. CD45 positive (CD45+) PC showed a more immature morphology and were detected in all groups. They were polyclonal in the control subjects and either poly- or monoclonal in the myeloma patients. In contrast, CD45 negative (CD45-) PBPC only occurred in myeloma patients and were consistently monoclonal, their presence being significantly associated with high disease activity (P < 0.001). Although detection of CD45- PBPC using CD38 or B-B4 MoAbs lead to similar results. CD45+ PBPC often were recognized to a lesser extent by B-B4 than by CD38 MoAbs. In conclusion, normal and malignant circulating PC can reliably be identified using CD38 and CD45 MoAbs. CD45 expression separates PBPC into two subsets of which the CD45- one only occurs in myeloma patients.
ADP-ribosyl Cyclase↗
Peripheral blood progenitor cell collection during hematopoietic recovery following autologous blood progenitor cell transplantation.
BACKGROUND AND OBJECTIVES: Peripheral blood progenitor cells (PBPC) are increasingly used for autologous transplantation after high-dose radio/chemotherapy in patients suffering from cancer. PBPC are usually collected after mobilization with conventional-dose chemotherapy plus growth factor. However, it is conceivable to perform leukapheresis for the second autograft during recovery of hematopoiesis after the first course of HDCT/ABPCT. MATERIALS AND METHODS: We treated two patients this way. In the first, with germ cell cancer, six 12-liter leukaphereses yielded 1.8 x 10(6) CD34+ cells/kg after mobilization with cis-platinum, etoposide and ifosfamide (PEI) plus granulocyte colony-stimulating factor (G-CSF). The second patient, with relapsed Hodgkin's disease, underwent PBPC collection after treatment with dexamethasone, carmustine, etoposide, cytarabine and melphalan (DexaBEAM) plus G-CSF. Due to excellent mobilization, 8.5 x 10(6) CD34+ cells/kg were collected by one 12-liter leukapheresis. Both patients then underwent PBPC collection during hematopoietic recovery following HDCT and ABPCT. RESULTS: In patient 1, following HDCT and ABPCT, three 12-liter aphereses resulted in 0.7 x 10(6) CD34+ cells/kg. In patient 2, also after HDCT and ABPCT, a second autograft with 3.2 x 10(6) CD34+ cells/kg was harvested by a single 10-liter apheresis. No adverse effects were seen in either patient during apheresis following ABPCT. To our knowledge this is the first report dealing with PBCT collection during hematopoietic recovery following HDCT and ABPCT. CONCLUSIONS: (1) PBPC harvesting is feasible and well tolerated in this setting. (2) In appropriate patients with efficient PBPC mobilization after conventional-dose chemotherapy, a further PBPC autograft can be collected during recovery of hematopoiesis after ABPCT, serving as a rescue for a second course of HDCT.
Adult↗
Increased diversity within the HLA-A*66 group: implications for matching in unrelated bone marrow transplantation.
We have identified a new A*66 allele (A*6603) in three related individuals, an Arabic patient suffering from acute myeloid leukemia and two of her relatives. The A*66 alleles differ in three amino acid residues at positions 70, 90 and 163. The closer relationship between A*6602 and A*6603, which only differ at amino acid 70, replacing GLN with HIS, suggests that the alloreactive potential in this mismatch combination is lower than in all other mismatched A*66 donor-recipient combinations, which exhibit two (A*6601 versus A*6602) and three (A*6601 versus A*6603) differences at the pivotal positions, respectively. This emphasizes the potential role of the A*66 subtypes in bone marrow transplantation with alternative donors. For that reasons, allelic subtyping should be considered in donor-recipient matching to identify the kind of disparity.
Amino Acid Sequence↗
Recent progress on the role of Axl, a receptor tyrosine kinase, in malignant transformation of myeloid leukemias.
Receptor tyrosine kinases (RTK) play an important role in the signal transduction of normal and malignant cells. There are different families of RTKs which are mainly characterized by differences in the ligang-binding extracellular domains. Axl (or UFO/Ark) is the first member of a new class of RTK with two fibronectin type III domains and two immunoglobulin-like domains present at the extracellular domain. The axl-gene has been isolated by means of gene transfection studies using DNA of patients with chronic myelogeneous leukemia. For a previous and the present study, we used a sensitive reverse-transcriptase polymerase chain reaction assay to detect axl's mRNA in cells from normal and malignant hematopoietic tissue. Axl's mRNA expression was mainly detected in myelo-monocytic cells, whereas much weaker transcription was seen in lymphatic cells and in lymphatic leukemias. In normal bone marrow, axl was heavily transcribed in marrow stromal cells. Further, we analysed Axl protein expression using monoclonal antibody M50 in peripheral stem cell harvests; in most harvests, no co-expression of CD34 and Axl was detected. However, in one patient with AML in complete remission, Axl was co-expressed on 80% of the CD34-positive population. These data show that axl is preferentially expressed in monocytes and stromal cells. Furthermore, a fraction of CD34-positive progenitor cells may express Axl. The exact mechanism for transformation of myeloid progenitor cells through Axl, however, remains to be determined.
Flow Cytometry↗
[Pelvic vein thrombosis despite anticoagulant therapy in a 17-year-old patient].
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Adolescent↗
Quantification of Bcr-Abl transcripts in chronic myelogenous leukemia (CML) using standardized, internally controlled, competitive differential PCR (CD-PCR).
The quantification of Bcr-Abl transcript numbers in chronic myelogenous leukemia (CML) patients described here uses simultaneous competitive PCR amplification of the target gene (Bcr-Abl) and a reference gene (porphobilinogen deaminase; Pbgd) together with a single composite competitor molecule for both targets based on heterologous sequences. Using this technique, Bcr-Abl transcript numbers could be reproducibly determined even in clinical samples known to harbour poor quality RNA.
DNA Primers↗
Clinical experiences with magnetic drug targeting: a phase I study with 4'-epidoxorubicin in 14 patients with advanced solid tumors.
Anticancer drugs reversibly bound to magnetic fluids (ferrofluids) could be concentrated in locally advanced tumors by magnetic fields that are arranged at the tumor surface outside of the organism. If certain requirements are met, systemic toxicity might be minimized, and local tumor efficacy might be increased. We have conducted a Phase I clinical trial using this approach in patients with advanced and unsuccessfully pretreated cancers or sarcomas. Nine such patients received two treatment courses, 3 patients received one course, and 2 patients received three courses of magnetic drug targeting consisting of the infusion of epirubicin in increasing doses (from 5 to 100 mg/m2) that had been chemically bound to a magnetic fluid and the application of magnetic fields to the tumors for 60-120 min. In 2 of 14 patients, the same dose of epirubicin not bound to a magnetic fluid was administered systemically 3 weeks after drug targeting for intraindividual comparisons. Magnetic drug targeting with epirubicin was well tolerated. In one case, a planned second treatment was withdrawn, because of an episode of chills 130 min after infusion of the magnetic drug. Two patients received a third treatment because of good responses after the first two therapies. Based on magnetic resonance tomographic techniques, pharmacokinetics, and the histological detection of magnetites, it was shown that the ferrofluid could be successfully directed to the tumors in about one-half of the patients. Organ toxicity did not increase with the treatment, but epirubicin-associated toxicity appeared at doses greater than 50 mg/m2. Although treatment with magnetic drug targeting seems safe, improvements are necessary to make it more effective and independent of patient- or disease-related problems. A study design to compare conventional treatments with the new treatment form within one patient seems crucial to eliminate interindividual differences.
Adolescent↗
Preclinical experiences with magnetic drug targeting: tolerance and efficacy.
Although site-specific direction of drugs within an organism would benefit patients with many diseases, active drug targeting is clinically not yet possible. To overcome some of the problems associated with active drug targeting, we have developed a magnetic fluid to which drugs, cytokines, and other molecules can be chemically bound to enable those agents to be directed within an organism by high-energy magnetic fields. In the first part of this study, various concentrations of the magnetic fluid were tested in rats and immunosuppressed nude mice with regard to subjective and objective tolerance. In the second part, the same parameters were evaluated after administration of the ferrofluid to which epirubicin (4'-epidoxorubicin) was chemically bound. Finally, two forms of therapy with the magnetic fluid were tested: tumor treatment by mechanical occlusion with the ferrofluid in high concentrations; and magnetic drug targeting, using small amounts of the ferrofluid as a vehicle to concentrate epirubicin locally in tumors. As a result, the ferrofluid did not cause major laboratory abnormalities; there was no LD50. With very high concentrations of the ferrofluid, animals showed lethargy for 1-2 days. There were no intolerances with the epirubicin-bound ferrofluid as well. Both forms of treatment led to complete tumor responses in an experimental human kidney as well as in a xenotransplanted colon carcinoma model. Thus, the magnetic fluid is a safe agent, which can be used in different ways for local forms of cancer treatment in conjunction with high-energy magnetic fields.
Animals↗
Expression of class I, II and III epitopes of the CD34 antigen by normal and leukemic hemopoietic cells.
Peripheral blood samples from 115 consecutive patients and bone marrow samples from 9 healthy donors were studied for percentages of CD34-expressing cells, quantitative expression of various CD34 epitopes as defined by fluorescence mean channel, and mutual inhibition of the different CD34 monoclonal antibodies detecting the various CD34 epitopes. The study focused only on samples from patients with presumably elevated numbers of CD34-expressing cells, due to the nature of the disease. Samples from patients with chronic myeloproliferative syndromes, acute leukemias from nonhematological cancer patients during mobilization with filgrastim, and normal bone marrow samples were studied. Elevated numbers of CD34-expressing cells (> 0.04% of all nucleated cells) were detected in 111 of 124 patients. An almost identical expression of CD34 epitopes as detected by phycoerythrin-conjugated monoclonal antibodies QBEND-10, 8G12, and ICH3 were detected, whereas expression of the IMMU409 epitope was detected in only a few samples (19 of 111). Reactivity of IMMU-133 was almost identical to that of QBEND-10. Reactivity of BIRMA-K3, the only CD34 monoclonal used in this study, but not described in previous workshops, was almost identical to that of 8G12. From studies on mutual inhibition of binding, two families of CD34 epitopes are defined. The first family is comprised of QBEND-10, IMMU-133, My-10, and ICH-3, and the second one is comprised of only 8G12 and BIRMA-K3.
Antigens, CD34↗