Search PubMed⌕ Search

Biomedical subjects

W Hiddemann

Publications and source records attributed to W Hiddemann.

At least 37 records · Page 2Linked to original sources
PubMed2005

New insights into MLL gene rearranged acute leukemias using gene expression profiling: shared pathways, lineage commitment, and partner genes.

Rearrangements of the MLL gene occur in both acute lymphoblastic and acute myeloid leukemias (ALL, AML). This study addressed the global gene expression pattern of these two leukemia subtypes with respect to common deregulated pathways and lineage-associated differences. We analyzed 73 t(11q23)/MLL leukemias in comparison to 290 other acute leukemias and demonstrate that 11q23 leukemias combined are characterized by a common specific gene expression signature. Additionally, in unsupervised and supervised data analysis algorithms, ALL and AML cases with t(11q23) segregate according to the lineage they are derived from, that is, myeloid or lymphoid, respectively. This segregation can be explained by a highly differing transcriptional program. Through the use of novel biological network analyses, essential regulators of early B cell development, PAX5 and EBF, were shown to be associated with a clear B-lineage commitment in lymphoblastic t(11q23)/MLL leukemias. Also, the influence of the different MLL translocation partners on the transcriptional program was directly assessed. Interestingly, gene expression profiling did not reveal a clear distinct pattern associated with one of the analyzed partner genes. Taken together, the identified molecular expression pattern of MLL fusion gene samples and biological networks revealed new insights into the aberrant transcriptional program in 11q23/MLL leukemias.

Acute Disease↗
PubMed2005

Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia.

In search for general PCR targets for minimal residual disease (MRD) studies in acute myeloid leukemia (AML), Wilms' tumor gene 1 (WT1) expression was assessed by real-time RT-PCR relative to the control gene ABL in 569 archived samples of AML patients (pts). Pts were analyzed at diagnosis (n=116) and during follow-up (n=105, median 4 times, range 2--17). Median follow-up time was 258 days (range 16--1578 days). In 66 pts, the WT1 expression was analyzed in comparison to a second PCR marker or to multiparameter flow cytometry. Quantitative WT1 levels correlated to the clinical course or a second marker in 83-96% of the cases. Prognostic significance of WT1 levels was analyzed at diagnosis and three intervals: (1) days 16--60, (2) days 61--120, and (3) days 121--180 after start of chemotherapy. Higher levels of WT1 expression were associated with shorter overall survival (OS) and event-free survival (EFS) within intervals 2 and 3 but not at diagnosis or interval 1. In addition, within these intervals, WT1/ABL levels <or=0.4% were associated with improved OS and EFS. An increase of WT1 levels was detected in 16/44 cases, which subsequently relapsed within a median of 38 days (range 8--180 days). In conclusion, quantification of WT1 may be used for MRD studies and for prognostification in AML.

Acute Disease↗
PubMed2005

Genomic gains and losses influence expression levels of genes located within the affected regions: a study on acute myeloid leukemias with trisomy 8, 11, or 13, monosomy 7, or deletion 5q.

We performed microarray analyses in AML with trisomies 8 (n=12), 11 (n=7), 13 (n=7), monosomy 7 (n=9), and deletion 5q (n=7) as sole changes to investigate whether genomic gains and losses translate into altered expression levels of genes located in the affected chromosomal regions. Controls were 104 AML with normal karyotype. In subgroups with trisomy, the median expression of genes located on gained chromosomes was higher, while in AML with monosomy 7 and deletion 5q the median expression of genes located in deleted regions was lower. The 50 most differentially expressed genes, as compared to all other subtypes, were equally distributed over the genome in AML subgroups with trisomies. In contrast, 30 and 86% of the most differentially expressed genes characteristic for AML with 5q deletion and monosomy 7 are located on chromosomes 5 or 7. In conclusion, gain of whole chromosomes leads to overexpression of genes located on the respective chromosomes. Losses of larger regions of the genome translate into lower expression of the majority of genes represented by only one allele. The reduced expression of these genes is the most characteristic difference in gene expression profiles between AML with monosomy 7 and AML with deletion 5q, respectively, and other AML subtypes. Therefore, these data provide evidence that gene dosage effects gene expression in AML with unbalanced karyotype abnormalities. Losses of specific regions of the genome determine the gene expression profile more strongly than the gain of whole chromosomes.

Chromosome Aberrations↗
PubMed2005

Brain metastases in metastatic non-small cell lung cancer responding to single-agent gefitinib: a case report.

Brain metastases are a frequent finding in patients with non-small cell lung cancer (NSCLC). The present case reports the clinical course of a patient who was treated with gefitinib alone for progressive brain metastases after whole-brain irradiation treatment (WBRT). A 50-year-old women with primary stage IV NSCLC (bone metastases) developed brain metastases after 3 cycles of chemotherapy consisting of paclitaxel and carboplatin (CBDA). After completion of the WBRT, magnetic resonance imaging (MRI) indicated further progression. Two cycles of temozolomide and topotecan were applied; this was ineffective in preventing central nervous system progression. For symptomatic brain metastatic disease the patient received gefitinib as single-agent treatment. Within a few weeks of treatment there was an obvious clinical improvement. Follow-up of the brain 2 months after the start of treatment showed a decrease in both the size and number of brain metastases. Additional manifestations in the lungs and the skeletal system were re-assessed as stable disease during the treatment with gefitinib. Within 4 months of treatment there were no side-effects such as skin rash or any other systemic toxicity. Gefitinib may therefore have a role in the treatment of brain metastases from NSCLC.

Antineoplastic Agents↗
PubMed2004

[Current strategies in the treatment of advanced stage mantle cell lymphoma].

Advanced stage mantle cell lymphoma (MCL) with a median survival of only three years and virtually no long-term survivors represents the lymphoma subtype with the poorest prognosis and remains incurable with conventional chemotherapy. Recently two randomized trials of the German Low Grade Lymphoma Study Group (GLSG) demonstrated the superiority of a combined immunochemotherapy with the anti-CD20 antibody rituximab in first-line therapy (R-CHOP) as well as in relapsed disease (R-FCM). In addition, in a trial of the European MCL Network, intensified-consolidation with high-dose radiochemotherapy followed by autologous stem cell transplantation significantly improved the progression-free survival in patients up to 65 years of age. However, the vast majority of patients with MCL will eventually relapse. Thus, new strategies such as allogenic transplantation after dose-reduced conditioning or novel molecular targeting agents (e. g. proteasome inhibitors or radiolabeled antibodies) are urgently warranted to further improve the long-term outcome of MCL.

Age Factors↗
PubMed2004

Discrimination of chronic lymphocytic leukemia (CLL) and CLL/PL by cytomorphology can clearly be correlated to specific genetic markers as investigated by interphase fluorescence in situ hybridization (FISH).

Although interphase fluorescence in situ hybridization (FISH) is routinely used in chronic lymphocytic leukemia (CLL), differences in the chromosomal pattern with respect to morphological subtypes of CLL (typical CLL, CLL/PL, PLL) are still under debate. We studied 153 patients with CLL and correlated cytomorphology on peripheral blood stains with FISH analysis and other prognostic markers. The percentage of prolymphocytes was calculated as a continuous variable and followed published thresholds in parallel while being correlated to FISH analysis. Higher percentages of prolymphocytes were associated significantly with deletion of 17p13. Deletion of 17p13 was most frequently observed in patients with more than 30% prolymphocytes. Trisomy 12 was found mainly in cases with 6-30% prolymphocytes. The percentage of prolymphocytes did not correlate with deletions of 11q23 or with 13q14 abnormalities. In conclusion, we suggest that further research focus on the percentage of prolymphocytes in CLL. Doing so, biologically relevant thresholds for the percentages of prolymphocytes in the peripheral blood and their association to underlying genetic markers could be investigated together with other biologically and especially prognostic markers.

Adult↗
PubMed2004

[Monoclonal antibody treatment of malignant lymphoma].

In the last years monoclonal antibodies directed against B-cell associated epitopes have enriched our armentarium of therapeutic strategies against malignant B-cell lymphoma. Monoclonal antibodies are characterized by a different mode of action compared to chemotherapy, thereby opening new avenues in lymphoma treatment. These monoclonal antibodies can exert their anti-lymphoma activity directly by an intrinsic cytotoxic effect or indirectly as a carrier of cytotoxic drugs or radioisotopes. Rituximab, an anti-CD20 monoclonal antibody, was proven to be highly active in indolent as well as aggressive lymphoma, in particular when combined with chemotherapy. The anti-CD52 antibody alemtuzumab was shown to induce remissions in high risk CLL. Furthermore, clinical trials have demonstrated promising activity of monoclonal antibodies conjugated to radioisotopes such as the (131)iodine anti-CD20 antibody tositumomab or the (90)yttrium anti-CD20 antibody ibritumomab tiuxetan.

Alemtuzumab↗
PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗
PubMed2004

Pediatric acute lymphoblastic leukemia (ALL) gene expression signatures classify an independent cohort of adult ALL patients.

Recent reports support a possible future application of gene expression profiling for the diagnosis of leukemias. However, the robustness of subtype-specific gene expression signatures has to be proven on independent patient samples. Here, we present gene expression data of 34 adult acute lymphoblastic leukemia (ALL) patients (Affymetrix U133A microarrays). Support Vector Machines (SVMs) were applied to stratify our samples based on given gene lists reported to predict MLL, BCR-ABL, and T-ALL, as well as MLL and non-MLL gene rearrangement positive pediatric ALL. In addition, seven other B-precursor ALL cases not bearing t(9;22) or t(11q23)/MLL chromosomal aberrations were analyzed. Using top differentially expressed genes, hierarchical cluster and principal component analyses demonstrate that the genetically more heterogeneous B-precursor ALL samples intercalate with BCR-ABL-positive cases, but were clearly distinct from T-ALL and MLL profiles. Similar expression signatures were observed for both heterogeneous B-precursor ALL and for BCR-ABL-positive cases. As an unrelated laboratory, we demonstrate that gene signatures defined for childhood ALL were also capable of stratifying distinct subtypes in our cohort of adult ALL patients. As such, previously reported gene expression patterns identified by microarray technology are validated and confirmed on truly independent leukemia patient samples.

Adult↗
PubMed2004

Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML.

The aim of this study was to compare the pattern of karyotype abnormalities of therapy-related acute myeloid leukemia (t-AML) (n=93) with de novo AML (n=1091), and to evaluate their impact on prognosis. Favorable, intermediate, and unfavorable cytogenetics were observed in 25.8, 28.0, and 46.2% of t-AML, and in 22.2, 57.3, and 20.4% of de novo AML. The median overall survival (OS) was shorter in t-AML than in de novo AML (10 vs 15 months, P=0.0007). Favorable and unfavorable cytogenetics had a prognostic impact with respect to OS in both t-AML (P=0.001 and 0.0001) and de novo AML (P<0.0001 and <0.0001). To define the overall prognostic impact of cytogenetics and t-AML, a multivariate Cox's regression analysis was performed for OS with favorable cytogenetics, unfavorable cytogenetics, t-AML, age, and white blood cell (WBC) count as covariates. All parameters proved to be independently related to OS (P=0.001 for t-AML, P<0.0001 for all other parameters). Within patients with t-AML, there were significant correlations between OS and both unfavorable (P<0.0001) and favorable cytogenetics (P=0.001), while age and WBC count had no impact on OS. In conclusion, these data indicate that cytogenetics are an important prognostic parameter in t-AML. Furthermore, t-AML is an unfavorable factor independent of cytogenetics with respect to survival.

Acute Disease↗