[Comparing Community Capacities by Local Actors and External Experts: An Audit of Health Promotion Activities in Lenzsiedlung, Hamburg]. / Evaluation von Gemeinde-Kapazitäten durch Quartiersakteur*innen und externe Expert*innen im Vergleich ­ Ergebnisse der Auditierung der Gesundheitsförderungsaktivitäten in der Hamburger Lenzsiedlung.

AIM: The questionnaire "Capacity building in Neighbourhoods (KEQ)" has five dimensions which are regarded as intermediary outcome results of community health promotion. The questionnaire was to be completed by local actors and thus has some features of self-evaluation. We wanted to find out whether external experts make similar or more critical assessments. METHODS: We conducted an audit of the health promotion activities in our intervention area (Hamburg neighbourhood Lenzsiedlung) in two steps. Five external health promotion experts functioned as auditors with experience in evaluating good practice projects of health promotion. The first part of the audit was a document-based evaluation, the second part a visit-based one during a two-day stay in the intervention area. RESULTS: In the comparison of local actors' assessments (KEQ questionnaire results) with those of external experts in the document-based audit, the judgements of external experts were more positive on all five dimensions of the questionnaire (deviations from +0.1 to +0.9 on a scale from 1 to 5). In the visit-based audit, there was convergence in the assessments of the local actors and the external experts. They were partly identical; only the dimension "local leadership" was viewed slightly more critically by the external experts. CONCLUSIONS: Based on our discussion of the four methodical problems of the comparison, we conclude that, on the whole, local actors do not tend to evaluate their activities too positively. However, if resources are available, one should try to confirm local views of outcomes by external assessments.

Dynamics of mutant BCR-ABL-positive clones after cessation of tyrosine kinase inhibitor therapy.

BACKGROUND: Point mutations of the BCR-ABL tyrosine kinase domain are considered the predominant cause of imatinib resistance in chronic myeloid leukemia. The expansion of mutant BCR-ABL-positive clones under selective pressure of tyrosine kinase inhibition is referred to as clonal selection; there are few data on the reversibility of this phenomenon. DESIGN AND METHODS: The changes of expression of mutant BCR-ABL-positive alleles after cessation of tyrosine kinase inhibitor treatment were examined in 19 patients with chronic myeloid leukemia harboring different mutations in a longitudinal follow-up. The proportion of mutant alleles was quantified by amplification of rearranged ABL sequences followed by mutation-specific restriction digestion, electrophoresis and densitometry. The size of mutant clones was established as a measure of the absolute amount of mutant cells considering the proportion of mutant BCR-ABL transcripts and the total level of BCR-ABL obtained by quantitative reverse transcriptase polymerase chain reaction. RESULTS: The median proportion of mutant transcripts was 97% before and 8% after cessation of tyrosine kinase inhibitor treatment indicating a relative decline of 88% within a median of 6 months. The relative decrease in the size of the mutant clones was 86%. Repeated selection and deselection of the mutant clone after resumption and second cessation of tyrosine kinase inhibitor treatment was observed in individual patients. CONCLUSIONS: Deselection of mutant BCR-ABL-positive clones after cessation of tyrosine kinase inhibitor treatment might be a common, rapid and reproducible phenomenon, although some patients harboring the T315I mutation showed no deselection. Cessation of tyrosine kinase inhibitor treatment may lead to the regression of T315I mutant clones to a level under the limit of detection, offering the therapeutic option of resumed tyrosine kinase inhibitor treatment under close surveillance of the mutation status.

Enhanced Bcr-Abl-specific antileukemic activity of arsenic trioxide (Trisenox) through glutathione-depletion in imatinib-resistant cells.

The development of resistance to imatinib mesylate may partly depend on high Bcr-Abl-expression levels. Arsenic trioxide (ATO) has Bcr-Abl suppressing activity in vitro. Here we investigated means to improve ATO activity in CML by modulating cellular glutathione (GSH), a key regulator of ATO-activity in malignant disease. Our studies demonstrate that depletion of cellular glutathione using dl-buthionine-[S,R]-sulfoximine (BSO) enhances ATO activity against CML cells. GSH-depletion promotes enhanced Bcr-Abl specific activity of ATO through avid repression of Bcr-Abl protein levels and total cellular Bcr-Abl activity. These data provide a rationale for the clinical development of optimized ATO-based regimens through incorporation of GSH-modulators in CML treatment.