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Biomedical subjects

C Schoch

Publications and source records attributed to C Schoch.

At least 37 records · Page 2Linked to original sources
PubMed2004

Clinical, morphological, cytogenetic, and prognostic features of patients with myelodysplastic syndromes and del(5q) including band q31.

We analyzed data of 76 consecutive patients with myelodysplastic syndrome (MDS) and isolated del(5q) (n=66) or del(5q) plus one additional chromosomal abnormality (n=10) included in our MDS database over the last 26 years. The median age of our patient population was 66.8 years. The male to female ratio was 1:1.7. In all, 14 patients (18%) had advanced MDS with an increased medullary blast count. A total of 17 patients (22%) had significant dysplasia in the nonmegakaryocytic cell lines. Nearly half of the study population showed erythroid hypoplasia in the bone marrow. The projected median survival of patients with isolated del(5q) is 146 months for a median follow-up of 67 months. Patients with an increased medullary blast count and those with an additional chromosomal abnormality have a significantly shorter overall survival (24 and 45 months, respectively) than patients with isolated del(5q). We did not find survival differences for different cytogenetic breakpoints, nor did the amount of dysplasia have an impact on survival in our population. In total, 29 patients have died. Deaths occurred primarily due to transformation into acute leukemia, infection, or cardiac failure. Our data support the current definition of a separate entity of MDS with del(5q) that has been suggested by the World Health Organization.

Adult↗
PubMed2003

Myelodysplastic syndrome (RARS) with +i(12p) abnormality in a patient 10 months after diagnosis and successful treatment of a mediastinal germ cell tumor (MGCT).

We report on a 21-year-old man with a mediastinal germ cell tumor (MGCT) who developed a myelodysplastic syndrome (MDS) (refractory anemia with ringed sideroblasts, RARS) 10 months after the start of successful treatment with cisplatin, etoposide, ifosfamide, and paclitaxel. A very rare early occurrence of a therapy-related MDS was suspected. Cytogenetic analysis of the bone marrow revealed an aberrant karyotype, showing a deletion in 12p, an isochromosome 5p, as well as gain of an isochromosome 12p. Isochromosome 12p is a specific aberration frequently observed in MGCT. It also was described in patients who developed hematological transformation of a mediastinal germ cell tumor. In this report the association between mediastinal germ cell tumors and hematological malignancies including the possibility of a common genetic origin is discussed.

Adult↗
PubMed2003

Spontaneous remission in adult acute myeloid leukemia in association with systemic bacterial infection-case report and review of the literature.

Spontaneous remission of acute myeloid leukemia in the adult is a rare event. We report on a 31-year-old male patient suffering from acute myeloid leukemia (AML) M5a according to the French-American-British (FAB) classification with biphenotypic features in flow cytometric examination and severe bacterial infection with group G streptococci at the time of diagnosis. Because of sepsis and stable clinical conditions, chemotherapy was delayed and antibiotics were administered intravenously. Within 6 weeks a spontaneous remission of AML occurred. Remission lasted for about 2 months. At the time of relapse, a change in phenotype of the leukemic blasts with a loss of B-lymphoid markers could be demonstrated by flow cytometry. The patient was treated with an induction therapy according to the multicentric German AMLCG 2000 schedule. To our knowledge, this is the first report of a spontaneous remission in an AML FAB M5a associated with coexpression of myeloid- and lymphoid-associated antigens on the leukemic blasts. Possible mechanisms of this phenomenon are discussed with a review of the literature.

Acute Disease↗
PubMed2003

Inhibitory effects of ketotifen on eotaxin-dependent activation of eosinophils: consequences for allergic eye diseases.

BACKGROUND: The aim of this study was to investigate the effects of ketotifen on different parameters of human eosinophil functions, namely chemotaxis, oxidative metabolism and mediator release, induced after activation. METHODS: Eosinophils from hypereosinophilic patients or normal donors were purified by Percoll gradient and the magnetic cell separation system. Chemotaxis was studied using the Boyden chamber technique using three potent chemoattractants: formyl-methionine-leucine-phenylalanine (fMLP), interleukin (IL)-5 and eotaxin. Oxidative metabolism was determined by a luminol-dependent chemiluminescence assay after activation with eotaxin or secretory immunoglobulin A (sIgA). The release of eosinophil cationic protein (ECP) and eosinophil derived neurotoxin (EDN) was measured by radioimmunoassay after activation with sIgA. RESULTS: At pharmacologically active concentrations and in a dose-dependent manner, ketotifen significantly inhibited the chemotaxis of eosinophils to fMLP, IL-5 and eotaxin. The production of reactive oxygen species induced by eotaxin and sIgA was decreased by ketotifen, showing a more pronounced effect when cells were activated by eotaxin. Activation by sIgA resulted in ECP and EDN release, which was partially inhibited by ketotifen. CONCLUSIONS: Through inhibition of chemotaxis, ketotifen might limit the number of eosinophils at the inflammation site during allergic reaction. Furthermore, inhibition by ketotifen of main inflammatory mediators release suggests a potential role of the drug in limiting the pathological potential of eosinophils.

Anti-Allergic Agents↗
PubMed2003

Molecular monitoring of response to imatinib (Glivec) in CML patients pretreated with interferon alpha. Low levels of residual disease are associated with continuous remission.

A significant proportion of chronic myeloid leukemia (CML) patients achieve a major cytogenetic remission (MCR) to imatinib therapy after failing interferon (IFN) alpha-based protocols. We sought to determine levels of residual disease in patients with MCR using various molecular methods and to establish a relation between residual BCR-ABL transcript levels and rate of relapse in complete cytogenetic remission (CCR). Response was measured by conventional cytogenetic analysis, hypermetaphase and interphase fluorescence in situ hybridization (HM-FISH, IP-FISH) of bone marrow (BM) cells, qualitative nested and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for BCR-ABL transcripts. We investigated 323 peripheral blood (PB) and BM samples from 48 CML patients who achieved a complete (Ph+ 0%; n=41) or partial (Ph+ 1-34%; n=7) cytogenetic remission after 3-20 months of imatinib therapy. Prior to imatinib, 35 patients were in chronic phase (CP), eight in accelerated phase (AP), four in myeloid and one in lymphoid blast crisis. HM-FISH results correlated with ratios BCR-ABL/ABL in PB and BM. In patients with CCR, residual disease was detectable by HM-FISH (31%), IP-FISH (18%), and RT-PCR (100%). During follow-up, BCR-ABL became undetectable in two patients (one CP, one AP) by both nested and quantitative RT-PCR. CCR is ongoing in 30 evaluable patients, 11 patients have relapsed. At the time of best response, median ratios BCR-ABL/ABL were 2.1% (range 0.82-7.8) in patients with subsequent relapse and 0.075% (range 0-3.9) in patients with ongoing remission (P=0.0011). All 16 CP patients, who achieved ratios BCR-ABL/ABL <0.1% as best molecular response are in continuous remission, while 6/13 patients (46%) with ratios >/=0.1% have relapsed (P=0.0036). We conclude that: (i) in patients with CCR to imatinib, HM-FISH and RT-PCR usually reveal residual BCR-ABL+ cells; (ii) RT-PCR results derived from PB and BM are comparable in CP CML; and (iii) low levels of residual disease with ratios BCR-ABL/ABL &<0.1% are associated with continuous remission.

Adult↗
PubMed2003

In vitro inhibition of human conjunctival mast-cell degranulation by ketotifen.

Ketotifen relieves the symptoms of allergic conjunctivitis through multiple mechanisms of action. One such mechanism may involve stabilization of conjunctival mast cells. Because of inter- and intra-species variation, however, this hypothesis cannot be adequately tested using mast cells from animals or other human tissues. We therefore employed human conjunctival mast cells. The mast cells were prepared using human conjunctival tissues obtained from US eye banks. Cell suspensions were sensitized with human IgE and incubated with ketotifen fumarate or control. After antigenic challenge of sensitized cells with anti-IgE, levels of histamine and tryptase, two mast-cell granule markers, were measured in the supernatant fluid. Cell viability was assessed with a Trypan Blue assay. Ketotifen at concentrations of approximately 10(-11) to 10(-4) M inhibited mast-cell histamine release by 90% or more. Similarly, ketotifen at approximately 10(-10) to 10(-4) M inhibited tryptase release by 90% or more (apart from a single anomalous reading). At all ketotifen concentrations that stabilized mast cells, cell viability was preserved. Moreover, ketotifen did not impair cell viability unless concentrations were increased above the clinically relevant range, i.e., above the order of magnitude of 10(-4) M. These data demonstrate that ketotifen can stabilize human conjunctival mast cells, without impairing cell viability.

Anti-Allergic Agents↗
PubMed2003

Bioinformatics for medical diagnostics: assessment of microarray data in the context of clinical databases.

MOTIVATION: To identify genes suitable for medical diagnostics microarray data is assessed in the context of clinical databases, which store complex information about the patient phenotype. The wealth of data and lacking standards make it difficult to analyse this kind of data. RESULTS: We present a workflow for exploratory analysis of microarray data together with clinical data consisting of four steps: definition of clinically meaningful research questions in a masterfile, generation of analysis files, selection and characterization of differentially expressed genes, and estimation of classification accuracy. We applied this workflow to large data sets from the field of cardiology and oncology (n~500 patients). Systematic data management of microarray data and clinical data helps to make results more transparent and comparable.

Cardiology↗
PubMed2003

New insights into the biology of acute myeloid leukemia and their impact on treatment.

Acute myeloid leukemia (AML) is a heterogeneous group of disorders that can be discriminated by morphology, immunophenotyping or more recently by cytogenetic and molecular techniques. By cytogenetics two major groups of AML can be discriminated: One group with detectable chromosomal aberrations accounting for approximately 52 % of all de novo AML and the second group without cytogenetically detectable karyotype abnormalities. In the first group two major subtypes can be further distinguished. The first group comprises AML with balanced aberrations mainly consisting in t(8;21), t(15;17) and inv(16). The second group comprizes cases with unbalanced aberrations including particularly 5q-, 17q- -5 and AML with complex karyotypes. AMLs with balanced aberrations have a good prognosis with long term survival being achieved in approximately 60 %-80 % of cases. AMLs with non-balanced aberrations on the other hand have a poor prognosis with only 10 %-15 % long-term survivors. AMLs with no detectable abnormalities or other cytogenetic aberrations comprise a group with an intermediate prognosis in which long term survival is achieved in approximately 25 %-30 % of cases. Biologically, AMLs with balanced aberrations regularly involve the deregulation of transcription factors resulting in an impairment of cell differentiation and proliferation. AMLs with unbalanced aberrations are mostly characterized by a loss of genetic material resulting in an alteration of cell cycle control and DNA repair. A new view on the biology of AML has recently been made possible through the analysis of gene expression profiles. This technique is still under investigation. First results, however, already show that gene expression patterns have a high diagnostic potential and allow to detect biology subgroups with a high accuracy. Furthermore, by this technique pathways can be identified that are altered in the leukemic process. Gene expression profiling therefore opens a new and exciting perspective in leukemia biology and therapy that may have substantial impact on the improvement of diagnosis and more importantly may guide therapeutic strategies.

Acute Disease↗
PubMed2002

Comparison of chromosome banding analysis, interphase- and hypermetaphase-FISH, qualitative and quantitative PCR for diagnosis and for follow-up in chronic myeloid leukemia: a study on 350 cases.

For the diagnosis of CML and for monitoring of treatment response the detection of the t(9;22)(q34;q11) or the BCR-ABL rearrangement is necessary. Chromosome banding analysis (CA) is still the gold standard but other techniques like Southern blot, fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) are available. We analyzed 350 CML patients at different stages of disease in parallel with CA, interphase-FISH (IP-FISH), hypermetaphase-FISH (HM-FISH) and RT-PCR. In 20 cases with no Ph(+) metaphases in CA, HM-FISH detected 0.2 to 10% BCR-ABL(+)metaphases. After IP-FISH 107 samples were judged as negative. However, in 17 of these samples HM-FISH detected BCR-ABL(+) metaphases (0.3-11%), and in eight cases CA detected Ph(+) metaphases (2.5-25%). A comparison of IP-FISH performed on uncultivated cells vs cells cultivated for 48 h in 70 cases revealed a higher proportion of BCR-ABL+ cells in the cultivated samples. If nested PCR was negative, all other methods were negative in all cases too. In addition, 94 cases were evaluated using real-time PCR (LightCycler technology). The BCR-ABL/cABL ratio measured showed a high correlation with all other methods. Interestingly, a wide range in the BCR-ABL/ABL ratio was observed especially in patients who showed 100% Ph-positive metaphases in CA. In conclusion, CA, IP-FISH, HM-FISH and real-time PCR give reliable results but differences due to measurement of different target structures have to be kept in mind when using these data for definition of remission status.

B-Lymphocytes↗
PubMed2002

Karyotype instability between diagnosis and relapse in 117 patients with acute myeloid leukemia: implications for resistance against therapy.

The instability of the karyotype may play a role in the development of refractoriness of acute myeloid leukemia (AML) to anti-leukemic therapy. Therefore, in the current study cytogenetic analyses were performed in 117 patients with AML both at diagnosis and at relapse. Changes in karyotype were observed in 38% (36% of initially normal karyotypes, 39% of initially aberrant karyotypes). An evolution of karyotype, ie the acquisition of further aberrations in addition to those present at diagnosis, occurred more frequently in patients with unfavorable karyotypes at diagnosis as compared to all others (60% vs 32%, P = 0.0095). The duration from initial diagnosis to relapse was significantly shorter in cases with an evolution of the aberrant karyotype as compared to cases with no changes in the aberrant karyotype between diagnosis and relapse or with solely regression of aberrations at relapse (9.2 +/- 4.4 vs14.0 +/- 8.5 months, P = 0.0081). In an additional analysis, another cohort of 120 patients with refractory and relapsed AML who were treated uniformly within the respective trial of the German AML Cooperative Group was analyzed cytogenetically at diagnosis and at relapse to further prove the prognostic impact of karyotype aberrations at relapse. Karyotypes were prognostically favorable, intermediate, unfavorable and not available in 8%, 50%, 17% and 25% at diagnosis and in 8%, 49%, 21% and 22% at relapse, respectively. Karyotype aberrations at diagnosis had no impact on response to therapy (P = 0.32) but influenced survival and event-free survival significantly (P = 0.03 and P = 0.02). In contrast, karyotype aberrations at relapse strongly influenced response to therapy (P = 0.05), survival (P = 0.01), and event-free survival (P = 0.002). These data suggest that the instability of the karyotype between diagnosis and relapse and thus karyotype aberrations at relapse in particular contribute to the refractoriness of AML to anti-leukemic therapy.

Acute Disease↗
PubMed2002

Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon alpha.

The degree of tumor load reduction as measured by cytogenetic response is an important prognostic factor for chronic myelogenous leukemia (CML) patients on therapy. We sought to determine whether BCR-ABL transcript levels can predict chromosomal response. Residual disease was evaluated in 120 CML patients in chronic phase (CP) treated with the selective tyrosine kinase inhibitor imatinib after resistance or intolerance to interferon alpha (IFN). Median time of therapy was 401 days (range 111-704). BCR-ABL and total ABL transcripts were measured in 486 peripheral blood (PB) specimens with a real time RT-PCR approach using fluorescent-labeled hybridization probes (LightCycler technology) and results were expressed as the ratio BCR-ABL/ABL. Cytogenetic response was determined in 3-monthly intervals: From 101 evaluable patients, 42 achieved a complete (CR, 0% Philadelphia chromosome (Ph)- positive metaphases), 18 a partial (PR, 1-34% Ph+), 13 a minor (MR, 35-94% Ph+), and 26 no response (NR, >94% Ph+). All PB samples were RT-PCR positive. The proportion of Ph+ metaphases and simultaneous BCR-ABL/ABL ratios correlated with r = 0.74, P < 0.0001. In order to investigate whether early molecular analysis may predict cytogenetic response, quantitative RT-PCR data obtained after 1 and 2 months of therapy were compared with cytogenetic response at 6 months. BCR-ABL/ABL ratios after 1 month were not predictive, but results after 2 months correlated with the consecutive cytogenetic response (P = 0.0008). The probability for a major cytogenetic response was significantly higher in patients with a BCR-ABL/ABL ratio <20% after 2 months of imatinib therapy. We conclude that: (1) quantitative determination of residual disease with real time RT-PCR is a reliable and sensitive method to monitor CML patients on imatinib therapy; (2) BCR-ABL/ABL ratios correlate well with cytogenetic response; (3) in IFN-pretreated patients all complete responders to imatinib have evidence of residual disease with the limited follow-up available; and (4) cytogenetic response at 6 months of therapy in CP patients is predictable with real time RT-PCR at 2 months.

Adult↗