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Michael Fiegl

Publications and source records attributed to Michael Fiegl.

At least 19 recordsLinked to original sources
PubMed2006

Prognostic relevance of cytogenetics determined by fluorescent in situ hybridization in patients having myelofibrosis with myeloid metaplasia.

BACKGROUND: In chronic myelofibrosis (MF), distinct recurrent cytogenetic aberrations have been identified but their true prognostic relevance remains uncertain. In this disease, cytogenetic studies as assessed by conventional metaphase karyotyping are limited due to the inherent difficulties in obtaining adequate bone marrow aspirates and the low proliferative capacity of the clonal cells. Interphase fluorescent in situ hybridization (FISH) can partly overcome these limitations and increase the sensitivity of cytogenetic assessment in MF. METHODS: We retrospectively analyzed formalin-fixed, paraffin embedded bone marrow sections of 107 MF patients by FISH and correlated cytogenetic findings with clinical presentation and survival. RESULTS: Chromosomal aberrations were detected in 56% of patients, with 20q- (24.3%) and 13q- (16.8%) being the most frequent ones. Importantly, cytogenetic abnormalities were found in 8/17 patients displaying a normal karyotype as assessed by conventional cytogenetics. CONCLUSIONS: Cytogenetic abnormalities in patients with MF can be detected reliably using FISH. Rare abnormalities confer an adverse outcome, but the main recurrent chromosomal aberrations do not correlate with clinical features and prognosis.

Adult↗
PubMed2006

Routine clinical use of alemtuzumab in patients with heavily pretreated B-cell chronic lymphocytic leukemia: a nation-wide retrospective study in Austria.

BACKGROUND: In previous studies, alemtuzumab demonstrated considerable activity in patients with previously treated B-cell chronic lymphocytic leukemia (CLL), including fludarabine-refractory disease. In this retrospective study, the authors evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced, previously treated CLL who received treatment in the routine clinical setting. METHODS: Data were collected from 115 consecutive patients who received alemtuzumab therapy at 25 participating centers in Austria. Patients received a median of 3 prior lines of therapy (range, 1-11 prior lines of therapy), and 59% had fludarabine-refractory disease. Alemtuzumab was administered intravenously or subcutaneously with a planned schedule of 30 mg 3 times per week for up to 12 weeks. Patients received valacyclovir and trimethoprim/sulfamethoxazole for antiinfective prophylaxis. RESULTS: The overall response rate was 23%, with complete responses achieved in 5% of patients. Stable disease (SD) was achieved in 36% of patients. After a median follow-up of 17.5 months, the median overall survival (OS) was 20.2 months for all patients. A multivariate Cox regression analysis that included pretreatment baseline characteristics, response to therapy, and cumulative dose of alemtuzumab indicated that bulky lymphadenopathy, the administration of > r =3 previous therapies, and lack of response to alemtuzumab remained significant independent risk factors for inferior OS. The median OS had not been reached for responding patients. The median OS was 29.5 months for patients with SD and 10.8 months for patients with progressive disease. CONCLUSIONS: The broad use of alemtuzumab in the routine clinical practice setting is feasible and active in unselected patients with pretreated CLL, and the current results confirmed the activity and safety of this agent, as reported in previously published clinical studies.

Aged↗
PubMed2006

Cytotoxic activity of the third-generation bisphosphonate zoledronic acid in acute myeloid leukemia.

The third-generation bisphosphonate zoledronic acid (ZOL) has recently been shown to be active against human tumour and leukemic cell lines. The purpose of this study was to evaluate the antileukemic potential of ZOL in acute myeloid leukemia (AML). We determined the lethal concentration 50% (LC 50) using the WST-1 assay of ZOL as being 287.9 microg/ml after 24 h and 108.3 microg/ml after 96 h in HL 60 cells and to be 382.4 and 43.2 microg/ml, respectively, in nine samples from patients with AML. The ZOL induced inhibition of proliferative activity of HL 60 cells could not be abrogated by the hematopetic growth factors G-CSF and GM-CSF. ZOL was found to by cytotoxic in HL 60 cells without activation of caspase 3. ZOL was not cross resistant with cytarabine as shown by the linear correlation of LC 50s. Both agents, however, exerted an additive cytotoxicity as revealed by isobologram-analysis and combination index. These data warrant further investigation of ZOL in the treatment of AML.

Acute Disease↗
PubMed2006

Angiogenesis in nodal B cell lymphomas: a high throughput study.

AIM: To assess the biological significance of vascular endothelial growth factor (VEGF) A, VEGF receptor (Flk-1) and cyclooxygenase 2 (COX2) expression with respect to microvessel density (MVD), proliferative activity (Ki-67), expression of p53 and clinical presentation in a large cohort of nodal B cell lymphomas. METHODS: An immunohistochemical and morphometric study was performed on a validated tissue microarray containing 271 B cell lymphoma specimens, 197 of which included follow-up data. Statistical assessment was done by Pearson's chi(2) test, Spearman's rank correlation coefficient, analysis of variance and survival analysis. RESULTS: 266 (98%) cases were evaluable. Strong VEGF expression was observed in only 20 diffuse large B cell lymphomas (DLBCLs). Flk-1 and COX2 were expressed in 53 and 21 cases, respectively, mainly in DLBCLs, follicular lymphoma (FL) grade 3 and mantle cell lymphomas (MCLs), in a low proportion of cells. MVD decreased in the following order: DLBCLs, FLs, MCLs and small lymphocytic lymphomas/chronic lymphocytic leukaemia (SLL/CLLs). VEGF expression correlated with Ki-67, p53 and COX2 expression in the whole cohort and in DLBCLs. Flk-1 expression correlated with Ki-67 in the cohort and in SLL/CLL and FL grade 1 and 2. COX2 expression correlated with Ki-67 and p53. The analysed angiogenesis parameters did not correlate with clinical parameters or survival. CONCLUSIONS: Angiogenesis plays a differential role in various B cell lymphomas. Aggressive lymphomas express the potential molecular therapeutic targets VEGF and COX2, and have higher MVD. In a few low proliferation-fraction lymphomas, Flk-1 might have a role in proliferative advantage. Therapeutic strategies aimed at angiogenesis should take into account lymphoma heterogeneity.

Aged↗
PubMed2006

Diffuse large B-cell lymphoma with overexpression of cyclin e substantiates poor standard treatment response and inferior outcome.

PURPOSE: Gold standard to predict survival and stratify patients for risk-adapted therapy in diffuse large B-cell lymphoma (DLBCL) is the international prognostic index, although it does not consider the molecular heterogeneity of DLBCL. Deregulation of cyclin E (CCNE) is a strong predictor of poor prognosis in some neoplastic diseases. In tumor cells, it induces chromosomal instability with an increased rate of aneuploidy/polyploidy. EXPERIMENTAL DESIGN: We analyzed in this retrospective study the prognostic value of immunohistochemical CCNE expression on a validated tissue microarray containing 101 de novo DLBCLs and, in 9 cases, the CCNE-induced chromosomal instability as assessed by cytometry. RESULTS: Forty-six of 98 evaluable DLBCLs expressed CCNE in a mean proportion of 20 +/- 29% of tumor cells; 38 cases expressed CCNE in >/=20% of tumor cells. CCNE-positive samples were aneuploid compared with near tetraploidy in CCNE-negative cases. Multivariate analysis showed CCNE expression in >/=20% of tumor cells to be an international prognostic index-independent, Adriamycin-based treatment-independent, and BCL2-independent prognostic factor for poor disease-specific survival. CCNE expression in >/=80% of tumor cells was associated with dismal short-term prognosis. CCNE expression in >/=50% of tumor cells emerged as an independent predictive factor for standard CHOP treatment resistance. CONCLUSIONS: CCNE expression assessment is easy on paraffin-embedded tissue. The high prognostic value of CCNE expression in DLBCL may be the basis for future prospective trials. In addition, a high CCNE expression hints at the presence of a possible target for individualized cancer therapy.

Aged↗
PubMed2006

Age and hemoglobin level emerge as most important clinical prognostic parameters in patients with osteomyelofibrosis: introduction of a simplified prognostic score.

The course of disease in patients with myelofibrosis is highly variable, with survival ranging from few months to many years. Several prognostic models have been established, with the LILLE score now most commonly used. However, in recent series, the latter scoring system repeatedly failed to discriminate patients with intermediate and poor prognosis. In the present study, we re-evaluated previous prognostic models in a separate patient population. We have studied 107 patients with myelofibrosis and correlated clinical parameters at the time of diagnosis with survival. Previous scoring systems were applied to allocate patients to subgroups with distinct prognosis. Most previous scoring systems failed to clearly discriminate an intermediate and poor prognostic group. By contrast, age and hemoglobin level emerged as most significant parameters in multivariate analysis. By allocating one risk point each for hemoglobin < 10 g/dl and age >60 years, three subgroups of patients with distinct prognosis could be identified in our cohort. The overall model and the difference between each of the subgroups were statistically significant in a training group, a test group, the overall cohort of patients and the group of patients with chronic idiopathic myelofibrosis. In summary, we propose an alternative prognostic model for patients with myelofibrosis that reliably identifies three groups of patients with highly different outcome. This is in contrast to previous prognostic scores, in which the poor prognosis group was often very small and/or could not be consistently differentiated from patients with an intermediate prognosis.

Adult↗
PubMed2005

Identification of glucocorticoid-response genes in children with acute lymphoblastic leukemia.

The ability of glucocorticoids (GCs) to kill lymphoid cells led to their inclusion in essentially all chemotherapy protocols for lymphoid malignancies, particularly childhood acute lymphoblastic leukemia (ALL). GCs mediate apoptosis via their cognate receptor and subsequent alterations in gene expression. Previous investigations, including expression profiling studies with subgenome microarrays in model systems, have led to a number of attractive, but conflicting, hypotheses that have never been tested in a clinical setting. Here, we present a comparative whole-genome expression profiling approach using lymphoblasts (purified at 3 time points) from 13 GC-sensitive children undergoing therapy for ALL. For comparisons, expression profiles were generated from an adult patient with ALL, peripheral blood lymphocytes from GC-exposed healthy donors, GC-sensitive and -resistant ALL cell lines, and mouse thymocytes treated with GCs in vivo and in vitro. This generated an essentially complete list of GC-regulated candidate genes in clinical settings and experimental systems, allowing immediate analysis of any gene for its potential significance to GC-induced apoptosis. Our analysis argued against most of the model-based hypotheses and instead identified a small number of novel candidate genes, including PFKFB2, a key regulator of glucose metabolism; ZBTB16, a putative transcription factor; and SNF1LK, a protein kinase implicated in cell-cycle regulation.

Adolescent↗
PubMed2005

Modeling the pharmacodynamics of highly schedule-dependent agents: exemplified by cytarabine-based regimens in acute myeloid leukemia.

BACKGROUND: Many agents in antineoplastic chemotherapy are highly schedule dependent. Therefore, variables such as total dose and also the area under the curve (AUC) that are schedule insensitive are generally insufficient to adequately represent treatment strength. PURPOSE: To establish a descriptor of treatment strength that takes into account the differential contribution of plasma concentrations (C) and exposure times (T) towards the cytotoxic effect and to investigate whether such a pharmacodynamically weighed descriptor is better correlated to the clinical effect than conventional variables. PATIENTS AND METHODS: The paradigm "C(N) x T = constant" (for an isoeffect) incorporates a weighing factor N (concentration coefficient) into the conventional description of the AUC that quantitates the differential contribution of C and T towards the cytotoxic effect. N was to be numerically derived from a multitude of in vitro isoeffect analyses of the major agents in acute myeloid leukemia (AML) therapy from patient samples (n = 57). RESULTS: For cytarabine, N was 0.45, numerically expressing the substantially higher relevance of T versus C for its cytotoxic effect. In a meta-analysis of 49 study arms involving >10,000 patients, neither total dose, dose intensity, nor AUC was correlated to the clinical effect. However, when AUC was pharmacodynamically weighed (N-weighed AUC, N-AUC = C(0.45) x T), this new descriptor was highly significantly correlated to the clinical effect (P < 0.001). CONCLUSION: The N-AUC concept is able to characterize schedule-dependent agents and is the only descriptor of cytarabine treatment strength actually correlated to the clinical effect in AML.

Acute Disease↗
PubMed2005

Recovery from CMV esophagitis after allogeneic bone marrow transplantation using non-myeloablative conditioning: the role of immunosuppression.

Cytomegalovirus (CMV) positive recipients of CMV negative bone marrow bear a significantly higher risk of developing CMV disease compared to all other constellations. Here, we report a case of severe CMV induced esophagitis after allogeneic bone marrow transplantation for paroxysmal nocturnal hemoglobinuria. The patient developed the first symptoms between day 10 and 20 after dose reduced conditioning and HLA-matched unrelated stem cell transplantation. Esophageal tissue biopsies as well as peripheral blood proved positive for CMV DNA by PCR. Treatment with acyclovir, ganciclovir, foscarnet, cidofovir, and immunoglobulines resulted in elimination of CMV in peripheral blood but not in clinical improvement. Only tapering of cyclosporine at day +120 eventually led to the development of CMV-specific T-cells and resolution of esophagitis.

Antiviral Agents↗
PubMed2005

The utility of fluorescence in-situ hybridization in the diagnosis of malignant pleural effusion.

PURPOSE OF REVIEW: Molecular tools are used to refine the diagnosis of malignancy in pleural fluids. This review discusses the rationale and recent findings of the application of one of these tools, fluorescence in-situ hybridization, in pleural effusions. RECENT FINDINGS: Aneuploidy (i.e., pronounced numeric and structural chromosomal changes) is a recurrent finding in cells of solid tumors. Different methods attempt to detect tumor-associated aneuploidy to prove micrometastasis in different compartments, such as urine, cerebrospinal fluid, bone marrow, and body fluids. In recent years, fluorescence in-situ hybridization analysis has proved viable for detecting metastasis based on the observation of matching patterns of chromosomal aneusomies in primary tumors and corresponding metastasis. SUMMARY: Fluorescence in-situ hybridization analysis using specific probes for visualizing numeric aberrations in a microscopic evaluation (thus complementing routine cytologic evaluation) has been shown to be relatively simple, very robust, and thus applicable in material of lesser quality and more sensitive than routine cytology. Remarkably, dual-color fluorescence in-situ hybridization analysis allows for an efficient analysis in effusions, and the approach presented in this review proved to be more specific than other molecular procedures applied in effusions to detect malignancy, such as polymerase chain reaction. Prospective studies are needed to demonstrate that refinement of staging by fluorescence in-situ hybridization or polymerase chain reaction ('molecular upstaging') will translate into meaningful therapeutic consequences.

Aneuploidy↗
PubMed2004

A phase I/II study of oral etoposide and idarubicin in elderly patients with high-risk acute myeloid leukemia unable to undergo intensive chemotherapy.

Acute myeloid leukemia (AML) is a disease of mostly elderly patients who are often unable to undergo intensive intravenous chemotherapy. In an attempt to provide an all-oral regimen suitable for palliative treatment, we assessed the antileukemic efficacy of combination therapy of idarubicin 20 mg/m(2) (days 1, 3, and 5) and etoposide (EI) in increasing doses (75-125 mg/m(2)) on days 1-5. Eleven patients were included (median age 69 years, range: 56-77) with prognostically unfavorable characteristics (myelodysplastic syndrome, relapse, or unfavorable karyotypes). No complete remission and five partial remissions were observed whereas four patients had persistent leukemia. There were two patients who succumbed to early death. Median overall survival was 100 days (range: 8-493 days). Nonhematological toxicities were acceptable with nausea/vomiting being the predominant side effect. Hematological toxicity with grade III/IV aplasia was seen in all patients. In this study EI did not show convincing antileukemic efficacy and was unable to induce clinically useful complete remissions, with a substantial risk profile. In contrast to the situation of elderly patients with standard-risk AML in which similar oral treatment has shown promising activity, EI cannot be recommended for elderly patients with high-risk AML.

Acute Disease↗
PubMed2004

Transendothelial migration of myeloma cells is increased by tumor necrosis factor (TNF)-alpha via TNF receptor 2 and autocrine up-regulation of MCP-1.

The proinflammatory cytokine tumor necrosis factor (TNF)-alpha has been shown to facilitate leukocyte transendothelial migration. In multiple myeloma, TNF-alpha is an important factor in the promotion of growth and survival of the malignant cells. Studies have shown that enhanced TNF-alpha levels in myeloma patients correlated with aggressive disease. Therefore, we investigated the effect of recombinant human TNF-alpha on the migrational behavior of myeloma cells across the physiological barrier of the major disease compartment, i.e., human bone marrow endothelial cells. In the presence of TNF-alpha, we observed significantly increased migration both in established myeloma cell lines and in plasma cells from myeloma patients. Expression of TNF-receptor 2 (TNF-R2) but not TNF-receptor 1 (TNF-R1) was detected in myeloma cell lines. Myeloma cells of patients also showed expression of TNF-R2 but not TNF-R1. The effect of TNF-alpha could not be explained by altered expression of adhesion molecules or metalloproteases. Instead, we found an up-regulation of monocyte chemoattractant protein (MCP)-1 and confirmed that myeloma cells express the relevant receptor C-C chemokine receptor 2. Preincubation of myeloma cells with recombinant human MCP-1 also enhanced cell migration, and this effect, as well as the effect of TNF-alpha, was abolished by treatment with anti-MCP-1 antibody. In contrast, migration of myeloma cells in the direction of an MCP-1 gradient, i.e., chemotaxis, could not be observed in the cell lines investigated. Additionally, the mRNA level of TNF-alpha was up-regulated by the cytokine treatment, which points to an autocrine loop augmenting and/or stabilizing the TNF-alpha-MCP-1 pathway. In summary, our data clearly support additional investigations using anti-MCP-1 antibodies in myeloma progression.

Apoptosis↗
PubMed2004

Combination of cytology, fluorescence in situ hybridization for aneuploidy, and reverse-transcriptase polymerase chain reaction for human mammaglobin/mammaglobin B expression improves diagnosis of malignant effusions.

PURPOSE: The identification of malignant cells in effusions by conventional cytology is hampered by its limited sensitivity. The aim of this study was to improve tumor cell detection in effusions by molecular approaches. MATERIALS AND METHODS: A total of 157 effusions from patients with tumors and 72 effusions from patients without a history or evidence of malignancy were included in this study. All effusion specimens were evaluated in parallel by cytology, fluorescence in situ hybridization (FISH) for aneuploidy, and reverse-transcriptase polymerase chain reaction (RT-PCR) for expression of human mammaglobin (hMAM) and mammaglobin B (hMAM-B). RESULTS: In effusions from patients with tumors, the sensitivities of tumor cell detection by cytology, FISH, and hMAM and hMAM-B detection were 46.2%, 53.3%, 36.4%, and 57.7%, respectively. The corresponding specificities were 94.4%, 97.0%, 87.1%, and 88.6%. Notably, a high percentage of effusions containing malignant cells were in fact transudates, indicating the necessity for molecular diagnostic work-up of transudates collected from patients with tumors. Dependent on the tumor type, the use of appropriate marker combinations improved tumor cell detection in effusions significantly. By combining all four diagnostic tests, a positive test result indicating the presence of malignancy was achieved in 81.1%, with a fairly good specificity of 70.1%. CONCLUSION: Molecular techniques are definitely useful to detect malignancy in cytologically negative effusions. Tumor cell detection in effusions can be significantly improved by FISH and PCR techniques applying appropriate molecular markers. This finding should help to improve tumor staging, prognostic assessment, and treatment monitoring.

Aneuploidy↗
PubMed2004

FISH cytogenetics and prognosis in breast and non-small cell lung cancers.

BACKGROUND: Interphase cytogenetics by fluorescence in situ hybridization (FISH) has been demonstrated to be a valuable diagnostic tool in effusions from patients with solid tumors. As the next step, we investigated whether certain patterns of numeric aberrations in malignant effusion cells supply prognostic information. METHODS: From a large series of effusions from patients with solid tumors, 55 effusions from breast cancer and 39 effusions from non-small cell lung cancer (NSCLC) were classified as malignant by cytology or FISH. Tumor cells were classified as FISH aneuploid for chromosome 11 and/or 17 or as not aneuploid. Predominant cytogenetic anomalies and patterns of intratumor cytogenetic heterogeneity were brought in relation to overall survival rate. RESULTS: There was no difference with respect to overall survival rate when effusions with or without aneuploidy for chromosomes 11 and 17 were compared. Likewise, in effusions with aneuploidy, there was no difference in overall survival rate among patients with different modal chromosome copy numbers (e.g., trisomy vs. tetrasomy 11) or among patients with a low or high grade of intratumor complexity (defined by the intratumor heterogeneity of FISH aneuploidy). In breast cancer, aneuploidy with gain of chromosome 11 was associated with a significantly superior survival rate, suggesting that amplification of chromosome 11 DNA is associated with a less aggressive phenotype. CONCLUSIONS: Simple chromosomal changes as determined by FISH, such as gain of chromosome 11 copy numbers in breast cancer, may be prognostic. Prospective studies in primary tumors that classify distinct prognostic groups by FISH cytogenetics are warranted.

Aneuploidy↗
PubMed2004

Burkitt's lymphoma of the stomach: a case report with molecular cytogenetic analysis.

In 1974, a 28-year-old man presented with a 12 cm sized ulcerated tumor involving the middle third of the stomach, which was originally diagnosed as "lymphosarcoma". Clinical recurrence of the lymphoma resulted in rapidly progressing disease and the patient died 4 months after initial diagnosis. Retrospective work-up of the 29-year-old tumor blocks revealed the typical histologic appearance and phenotype (CD20, CD10, BCL-6 positive) of Burkitt's lymphoma (BL) with a proliferation rate of 95%. By fluorescence in situ hybridization (FISH). the tumor cells were shown to harbor an IGH-MYC fusion indicating the presence of the hallmark Burkitt-translocation t(8;14)(q24;q32). Considering the typical clinical features of BL requiring appropriate treatment regimes the case presented here highlights the importance of modern histopathologic and molecular cytogenetic techniques for the proper classification of such rare lymphomas presenting at atypical sites.

Adult↗