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Biomedical subjects

W Hiddemann

Publications and source records attributed to W Hiddemann.

At least 199 records · Page 11Linked to original sources
PubMed1998

Clinical outcome and economic impact of aminoglycoside peak concentrations in febrile immunocompromised patients with hematologic malignancies.

The aim of this study was to investigate the clinical and economic significance of aminoglycoside peak concentrations in febrile neutropenic patients with hematologic malignancies. Sixty-one patients were treated according to protocol II of the Paul-Ehrlich-Gesellschaft: initial application of gentamicin or tobramycin in combination with a cephalosporin or ureidopenicillin and, after 3 days, a potential change of antibiosis to be decided in case of nonresponse. At the same time, samples were collected by an independent controller. We found a significant dependence of clinical outcome on aminoglycoside peak concentrations (P = 0.004). Twelve of 17 patients with peak concentrations > 4.8 mg/L, but only 13 of 44 patients with concentrations < or = 4.8 mg/L, responded to initial therapy. Average infection-related costs per patient with peak values > 4.8 mg/L were US$1429, $1790, and $1701 for nursing, diagnostics, and therapeutics, respectively (total $4920). Expenses for patients with peak concentrations < or = 4.8 mg/L were approximately 1.8-fold higher (average total $8718). If all 61 patients had achieved peaks > 4.8 mg/L, the potential savings would have totalled $167,112. We conclude that neutropenic patients form a target group for successful pharmacokinetic intervention and cost saving.

Adult↗
PubMed1998

Interferon alfa for the treatment of follicular lymphomas.

PURPOSE: Recombinant human interferon alfa (rIFN-alpha) has demonstrated significant activity against follicular lymphomas when applied as salvage treatment after the failure of conventional therapy. It has also been shown to exhibit synergistic antitumor activity when given simultaneously with certain cytostatic agents. PATIENTS AND METHODS: Against this background, two major strategies were followed to incorporate rIFN-alpha into the first-line treatment of follicular lymphomas: application simultaneously with initial cytotoxic chemotherapy and application as maintenance treatment after successful initial chemotherapy. RESULTS: Of the five prospective randomized trials performed to assess the activity of rIFN-alpha in combination with initial chemotherapy versus the activity of chemotherapy alone, three studies showed that rIFN-alpha plus chemotherapy yielded no beneficial effect on remission rate, remission duration, or overall survival. In all three of these trials, chemotherapy consisted of a single alkylating agent. In contrast, a significant improvement in remission rate and remission duration was observed in two studies when rIFN-alpha was combined with anthracycline-containing regimens. Five prospective randomized studies have evaluated the role of rIFN-alpha as maintenance therapy after successful cytoreductive chemotherapy. Four of these studies have either found no significant prolongation of the disease-free interval or shown significant improvement in disease-free survival only in patients achieving a complete remission with initial cytoreductive treatment. In all four studies, relatively low doses of rIFN-alpha were administered for a limited time. A different outcome emerged in the fifth study, by the German Low Grade Lymphoma Study Group, in which patients received higher doses of rIFN-alpha with no restriction on duration of therapy. Patients treated with rIFN-alpha had a significantly prolonged median progression-free interval (30 versus 19 months), and at 4 years, 45% of patients receiving rIFN-alpha maintenance therapy remained relapse-free, compared with 26% of patients in the untreated control group (P = 0.003). CONCLUSION: Collectively, these data demonstrate that rIFN-alpha adds substantially to the treatment of follicular lymphomas either when combined with anthracycline-containing cytoreductive chemotherapy or when given as long-term maintenance therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

TGF-beta and its receptor complex in leukemic B-cell precursors.

Transforming growth factor beta (TGF-beta) is a highly conserved peptide with growth-inhibitory activity in multiple normal and transformed cell types. Signal transduction is mediated through the receptor complex, consisting of two active seronine or threonine kinases (TGF-beta-receptor I and II) and the receptor-associated proteins betaglycan (TGF-beta-receptor III) and endoglin. In this study, we assessed the analysis of the role of TGF-beta and the transcription of the genes for TGF-beta and its receptor in highly purified leukemic B-cell precursors (BCPs) of patients with common acute lymphoblastic leukemia (cALL). Leukemic BCPs were positive for gene transcription of TGF-beta (9/9), the TGF-beta-receptor I (9/9), the TGF-beta-receptor II (6/6), betaglycan (5/6), and endoglin (6/6). Incubation with TGF-beta significantly reduced the cell viability of leukemic BCPs by a mean of 45% (p = 0.0009). The reduction of cell viability was associated with the induction of apoptosis by a mean of 31%. TGF-beta caused significant suppression of the S phase (p = 0.002) and accumulation in the G0/G1 phase (p = 0.0005). It also reduced expression of the adhesion surface receptor CD18 and the Fas antigen CD95 from 58% to 40% and from 48% to 27%, respectively. The data indicate that TGF-beta is a negative growth signal in leukemic BCPs and point to an additional role of TGF-beta as an immunomodulatory cytokine, suggesting a complex role of TGF-beta in the leukemogenesis of cALL.

Adjuvants, Immunologic↗
PubMed1997

Alterations of the cyclin D1/p16-pRB pathway in mantle cell lymphoma.

Mantle cell lymphoma (MCL) has recently become generally accepted as a subentity of malignant lymphomas that is characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in the overexpression of cyclin D1. Cyclin D1 forms a complex with cell cycle-dependent kinase (cdk) 4, which inactivates the retinoblastoma protein (pRB) via phosphorylation. However, in transgenic mice, the overexpression of cyclin D1 alone is not sufficient for the development of malignant lymphoma. To determine whether other members of the pRB pathway contribute to the malignant transformation of MCL, we analyzed 37 cases of MCL that were well characterized by morphology, immunophenotype, and/or interphase cytogenetics [detection of t(11;14)(q13;q32)]. Interphase fluorescence in situ hybridization was performed using a cosmid contig (250 kb) of the CDKN2/p16 region (encoding an inhibitor of the cyclin D1/cdk4 complex) and a phage contig (200 kb) of the Rb region. CDKN2/p16 deletion was detected in 15 cases (41%), including 6 homozygous deletions; Rb was deleted in 15 cases (41%), all of which were hemizygous deletions. Nine cases (24%) had deletions of both CDKN2/p16 and Rb. Further analysis of a subset of 17 MCLs revealed a highly significant correlation between CDKN2/p16 deletion and proliferation index, determined by the rate of Ki67 expression (P = 0.014; t test). No significant correlation was found between CDKN2/p16 deletion and the blastoid variant of MCL (P = 0.23; Fisher's test) or between proliferation index and blastoid morphology (P = 0.51; t test). Deletion of Rb did not have any impact on cell proliferation in addition to CDKN2/p16 deletion (P = 0.76; t test). Additional analysis of 13q14 deletions suggests that these deletions may target another gene telomeric to Rb. We conclude that deletion of CDKN2/p16 occurs in approximately one-half of MCLs and is a more relevant indicator of the proliferative features as compared to morphological criteria. In contrast, although deletions of chromosomal band 13q14 are frequent in MCL, inactivation of Rb seems not to be involved in the pathogenesis of MCL.

Animals↗
PubMed1997

Influence of cycloheximide-mediated downregulation of glucose transport on TNF alpha-induced apoptosis.

Enhancement of cellular sensitivity to TNF alpha-induced apoptosis by cycloheximide (CX) has been attributed to its quality as an inhibitor of protein synthesis, presumably by prevention of the synthesis of short-lived death antagonists. CX is also known to interfere with glucose transport, which in turn influences cell death. Hexose uptake, expression of glucose transporter (Glut) mRNAs and proteins, and other related factors were therefore examined upon induction of apoptosis with TNF alpha and CX in breast cancer cell lines. In the early phase of apoptosis, a dramatic decrease in glucose transport was observed, preceded by stimulation of Glut 1 and 3 mRNAs. Transport downregulation was also detectable upon incubation with CX alone, albeit to a lesser extent. With the doses used, TNF alpha had no such effect. Protein synthesis was inhibited to the same degree in TNF alpha/CX-treated apoptotic cells compared to viable CX-treated cells. Diminished hexose uptake was associated with decreased Vmax, while Glut affinity remained unaffected. As there was no evidence for changes in total cellular Glut content or for Glut translocation from the plasma membrane, a diminished intrinsic activity of Gluts must be postulated. In conclusion, CX is proposed to contribute to TNF alpha-induced apoptosis predominantly by interference with glucose transport; the exact nature of this effect remains to be elucidated.

Adenosine Triphosphate↗
PubMed1997

["Medical Ethics Patient Forum". Results of a model project].

BACKGROUND: The patients' forum Medical Ethics is an innovative model project, which aims at intensifying the dialogue between health care professionals and patients as well as their relatives. METHODS AND RESULTS: Practical experiences and data from a complementing evaluative study are reported. By means of a sophisticated instrument of moral psychology, the Moralisches-Urteil-Test (M-U-T), differences are revealed between the participating groups--doctors, health care professionals, patients, medical students etc.--referring to more cognitive or emotional orientations in moral judgment, respectively. These differences contradict common assumptions. CONCLUSION: On the ground of the data presented as well as by subjective estimations of participants it is shown that the ethics discussion with patients is not only successful, but that it is also valuable for teaching by fostering new insights and experiences.

Education, Medical↗
PubMed1997

Activity of thymidine kinase and of polymerase alpha as well as activity and gene expression of deoxycytidine deaminase in leukemic blasts are correlated with clinical response in the setting of granulocyte-macrophage colony-stimulating factor-based priming before and during TAD-9 induction therapy in acute myeloid leukemia.

The present study was undertaken to assess the predictive value of pretherapeutic determinants of ara-C metabolism and proliferative activity of leukemic blasts for early response to antileukemic therapy in the setting of granulocyte-macrophage colony-stimulating factor (GM-CSF)-based priming before and during TAD-9 induction in 36 consecutive patients with de novo acute myeloid leukemia (AML). Ara-C metabolism was assessed by the activities of deoxycytidine kinase (DCK), deoxycytidine deaminase (DCD), DNA polymerase alpha (Poly alpha), and overall polymerase (overall Poly). The fraction of cells in S phase (%S phase) and thymidine kinase (TK) activity were determined as a measure of proliferative activity. Early response to therapy was defined by the percentage of leukemic blasts in the bone marrow 5 to 7 days after completion of TAD-9 with less than 5% signaling an adequate response and greater than 5% indicating an inadequate early reduction, respectively. While neither %S phase, DCK, nor overall Poly activity were predictive for early response, TK and Poly alpha activities were significantly higher for cases with adequate blast cell clearance. The respective median values were for TK 3.8 versus 1.85 pmol/min/mg protein (P = .012), and for Poly alpha 1.9 versus 0.69 pmol/min/mg protein (P = .014). An inverse relation was detected for DCD activity which was significantly lower in responding patients with a median of 0.33 nmol/min/mg protein (range, 0.0 to 29.5) as compared to a median of 5.1 nmol/min/mg protein (range, 0.11 to 8.45) in early nonresponders, (P = .009). Taking the respective median values as arbitrary cut-points for high or low enzyme activities, responders and nonresponders could be discriminated prospectively. Hence, 14 of 16 cases (88%) with DCD activities below the median of 1.56 nmol/min/mg protein responded as compared to only 3 of 14 (22%) patients with higher DCD activities (P = .0004). From the 15 patients with TK activity above the overall median of 3.2 pmol/min/mg protein, 11 cases (73%) achieved an adequate blast cell clearance while only 6 of 17 cases (35%) with lower values responded (P = .035). Similarly, 12 of 15 patients (80%) with high Poly alpha levels (>1.22 pmol/min/mg protein) responded to induction therapy as compared to only 5 of 14 patients (36%) with lower enzyme activities (P = .02). By logistic regression analysis of enzyme activities, DCD activity was found to be the most sensitive parameter to predict an adequate blast cell clearance (P = .032). Activities of DCD and TK were not only associated with initial response but were also found predictive for remission duration. Hence, from 11 patients with low TK levels 8 (73%) relapsed within 1 year, whereas only 2 of 11 (18%) patients with high TK activity experienced a recurrence of their disease (P = .015). Six of 9 (66%) patients with higher than median DCD levels relapsed within 1 year, whereas 10 of 14 patients (71%) with lower DCD levels had a longer remission duration (P = .085). Analysis of DCD gene expression at the mRNA level by a semi-quantitative reverse transcriptase-polymerase chain reaction method showed that a high transcription rate of the DCD gene was associated with high enzyme activities and vice versa. Hence, the observed intraindividual differences in DCD activity are a reflection of differences in gene activity and transcription rate rather than of variants in translation. Although further analyses are needed to elucidate the molecular mechanisms that determine the variation of enzyme activities in individual patients, the present study strongly suggests that pretherapeutic determination of TK and Poly alpha as well as of DCD allows to predict response to TAD-9 + GM-CSF induction therapy and may provide the means for the development of a risk adapted treatment strategy.

Acute Disease↗
PubMed1997

[Therapy of infections in patients with acute leukemia].

BACKGROUND: Infections are the major cause for treatment failure in acute leukemias. They mostly present as fever of unknown origin (FUO), a smaller but prognostically unfavorable group are pneumonias. The effective management of infectious complications requires a symptom and response adapted interventional strategy. THERAPEUTICAL APPROACH: In case of FUO standard therapy consists of the two drug combination of aminoglycoside plus acylaminopenicillin or third generation cephalosporine. In case of non-response carbapenems and a glycopeptide should be applied and a systemic antifungal treatment must be initiated. In pneumonia amphotericin B should be added to antibiotics already initially. Potent single agents with a broad spectrum of activity as well as new antifungal drugs provide attractive perspectives for future evaluations. CONCLUSIONS: By a consequent step-wise oscalating interventional treatment strategy infections in patients with acute leukemias can be successfully treated.

Acute Disease↗
PubMed1997

Detection of trisomy 12 and Rb-deletion in CD34+ cells of patients with B-cell chronic lymphocytic leukemia.

B-cell chronic lymphocytic leukemia (B-CLL) is a slowly progressive disease characterized by the clonal expansion of CD5+/CD23+ B lymphocytes. The malignant transformation is assumed to occur at the level of mature B lymphocytes. We asked whether CD34+ progenitor cells are involved in the malignant process in B-CLL. Furthermore, we investigated the possibility of aberrant CD34 expression by the malignant B-cell clone. Bone marrow and peripheral blood samples from 75 patients with B-CLL were tested for the presence of trisomy 12 and deletion of the retinoblastoma gene (Rb) by fluorescence in situ hybridization. CD34+ subpopulations were isolated by fluorescence-activated cell sorting and analyzed for the presence of the informative genetic marker. Bone marrow and peripheral blood samples of 10 B-CLL patients were analyzed for coexpression of CD34/CD5/CD20. Trisomy 12 was detected in 15 of 75 (20%) and Rb-deletion was detected in 6 of 30 patients (20%). In 7 patients with trisomy 12, hematopoietic progenitor cells were sorted, with the sort purity being between 85% and 99.8%. The genetic marker was detected in the CD34+/CD38+ cells as well as in the CD34+/38- subsets in 3 patients. Progenitor cells were also sorted in 2 patients with Rb-deletion. In 1 patient, Rb-deletion was present in 10% of CD34+/38+ cells. In the other patient, Rb-deletion was neither detected in the CD34+/38+ nor in the CD34+/CD38- subsets. In all 10 patients investigated for coexpression of CD34/CD5/CD20, we could not find a subpopulation coexpressing these markers. We conclude that trisomy 12 and Rb-deletion are present in a considerable subset of patients with B-CLL. In part of these patients, the genetic marker was detected at the level of CD34+ stem cells. CD34 expression is not related to an aberrant phenotype of the malignant B-cell clone. These results suggest that the malignant transformation in B-CLL may involve early hematopoietic stem cells and place a note of caution on future strategies using autologous stem cell transplantation.

Adult↗
PubMed1997

Differential regulation of phospholipase A2 in human leukemia cells by the etherphospholipid analogue hexadecylphosphocholine.

Hexadecylphosphocholine (HePC) is the main representative of a new group of antineoplastic agents, the alkylphosphocholines, which were originally derived from cytotoxic etherlysophospholipids. HePC shows antiproliferative action against a whole variety of tumor cells and tumors in vitro and in vivo. Furthermore, it also induces differentiation in some hematologic cell lines and prevents invasive growth of neoplastic cells in vitro. To date, the precise molecular mechanisms mediating the biological effects of HePC have not been identified yet. As etherlysophospholipids seem to inhibit some pathways of lipid-dependent intracellular signalling, similar effects may be relevant for HePC. We therefore investigated the influence of HePC on phospholipase A2 (PLA2-EC 3.1.1) in the human leukemia cell line U 937. HePC seems to inhibit enzyme activity independently of protein kinase C (PKC) in differentiated U 937 cells stimulated by tumor necrosis factor alpha (TNFalpha). Inhibition of purified secretory PLA2 from snake venom (EC 3.1.1.4) in vitro shows characteristics of a non-competitive mode. In contrast, HePC leads to an enhancement of PLA2 activity in immature cells which cannot be explained by changes in membrane composition. Our data suggest that PLA, inhibition is most probably not the mechanism by which HePC mediates its antiproliferative effects.

Acylation↗
PubMed1997

High antileukemic activity of sequential high dose cytosine arabinoside and mitoxantrone in patients with refractory acute leukemias. Results of a clinical phase II study.

BACKGROUND: The current study was initiated to assess the efficacy and side effects of a timed sequential application of high dose cytosine arabinoside (AraC) in combination with mitoxantrone (S-HAM) in patients with refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). METHODS: Patients with refractory AML or ALL were eligible for S-HAM salvage therapy, which was comprised of AraC, 1 g/m2 or 3 g/m2 every 12 hours, on Days 1, 2, 8, and 9 and mitoxantrone, 10 mg/m2/day, given on Days 3, 4, 10, and 11. RESULTS: Of 22 fully evaluable patients, 14 patients (64%) achieved a complete remission whereas 5 patients (23%) succumbed to early death and 3 patients (14%) did not respond. Blood counts recovered at a median of 33.5 days after the start of treatment and complete remission was achieved after a median of 38 days. The median duration of complete remission was 4 months (range, 1-14 months) whereas overall survival time lasted for a median of 4.5 months (range, 1-30+ months). Treatment-associated toxicity was comprised predominantly of infection and diarrhea that reached World Health Organization Grades 3 and 4 in 64% and 32% of patients, respectively. Complementary pharmacokinetic evaluations of plasma AraC and AraU levels revealed no impact of initial AraC administration on the pharmacokinetics of subsequent AraC administrations and failed to demonstrate any evidence of self-potentiation. CONCLUSIONS: The clinical data show the S-HAM regimen to be a promising approach for the treatment of patients with advanced acute leukemias. However, further evaluation at earlier stages of treatment is needed.

Acute Disease↗
PubMed1997

Reverse transcriptase/polymerase chain reaction analysis of parathyroid hormone-related protein for the detection of tumor cell dissemination in the peripheral blood and bone marrow of patients with breast cancer.

Tumor cell dissemination in the bone marrow is an independent prognostic marker for relapse and survival for patients with primary breast cancer. Parathyroid-hormone-related protein (PTHrP) is expressed in most primary tumors and bone metastases of patients with breast cancer. PTHrP acts as an autocrine growth factor for breast cancer cells in vitro and there is evidence that it is especially important for osseous metastasis. For a sensitive detection of PTHrP-positive disseminated tumor cells a reverse transcriptase/polymerase chain reaction (RT/PCR) assay for PTHrP transcripts in the peripheral blood (PB) and in the bone marrow (BM) has been established. In mixing studies, the sensitivity of the reverse transcriptase/polymerase chain reaction (RT/PCR) for PTHrP was one tumor cell in 1 x 10(6) mononuclear cells. At this level of sensitivity, transcripts of PTHrP were detected in none of 30 PB samples and in 3 of 25 BM samples of healthy volunteers; there were also no transcripts of PTHrP in the PB and BM of 6 patients with benign breast lesions. The PB samples of 31 patients and the BM samples of 34 patients with predominantly early-stage breast cancer were tested for PTHrP expression along with immunocytology against cytokeratin 18 (CK18) as a standard immunological detection technique. PTHrP expression was shown in 9 of 31 patients in the PB and in 9 of 34 patients in the BM. In 30 patients, PB and BM samples were available simultaneously. There were cases of combined positive findings in the PB and the BM (4/30) and of isolated positivity in the PB (5/30) or in the BM (4/30). Compared to immunocytology, RT/PCR assay of PTHrP assay was significantly more sensitive in the peripheral blood (8/30 by RT/PCR compared to 1/30 by immunocytology). In the bone marrow there were cases of positivity for both markers (2/34), cases of isolated positivity by immunocytology for CK18 (3/34) and cases of isolated positivity for PTHrP transcripts (7/34). In conclusion the RT/PCR assay for PTHrP transcripts is a feasible and very sensitive technique for the detection of tumor cell dissemination in the PB, even in patients with early-stage breast cancer. The specificity of detection of PTHrP transcripts in the bone marrow is limited, possibly because of autochthonous expression of PTHrP in osteoblastic cells. The clinical follow-up of the subgroups of patients at risk, as defined by this assay, will show its prognostic significance for patients with breast cancer.

Blood Cells↗
PubMed1997

Frequency and causes of refractoriness in multiply transfused patients.

The use of leukocyte-depleted blood components has become the standard therapy for multiply transfused patients during the past few years, as a measure to reduce the frequency of alloimmunization and refractoriness. We assessed frequency and causes of refractoriness, defined as a repeated 24-h post-transfusion platelet count below 20,000/microliters, in 145 consecutive patients who received three or more single-donor platelet concentrates during a 1-year period. Flow-cytometric detection of anti-platelet antibodies and a glycoprotein-specific ELISA were applied for the diagnosis of alloimmunization. Forty patients (27.6%) had at least one episode of refractoriness. In 25 of these 40 patients (62.5%), nonimmune factors (fever, sepsis, coagulopathy, splenomegaly) alone were the cause. In 15 refractory patients alloantibodies were detected. In seven patients (17.5%), alloimmunization alone caused an inadequate transfusion response, while in eight refractory patients (20.0%) alloimmunization and fever or sepsis were present. HLA antibodies were detected in 17 patients (11.7%); three patients (2%) had platelet-specific antibodies in addition to HLA antibodies; in two patients panreactive platelet antibodies were detectable. All 17 patients had a history of previous transfusions or pregnancy. We did not observe primary immunization in patients transfused exclusively with filtered (leukodepleted) blood products. Our data suggest that alloimmunization in patients with a negative risk history can be prevented by the exclusive use of leukodepleted blood components.

Antigens, Human Platelet↗