Chronic myeloid leukemia (CML) starts with the acquisition of a BCR-ABL fusion gene in a single hematopoietic stem cell, but the time to progression is unpredictable. Although the tyrosine kinase ...inhibitor imatinib mesylate is highly effective in the treatment of CML, its continuous administration is associated with development of resistance, particularly in advanced phase or blast crisis. We investigate here whether a feature of disease progression (i.e., elevated expression of Bcr-Abl in CD34+ progenitor cells from CML patients in blast crisis) has any bearing on the kinetics of resistance to imatinib. By studying cell lines that exogenously express Bcr-Abl over the range found from chronic phase to blast crisis of CML, we show that cells expressing high amounts of Bcr-Abl, as in blast crisis, are much less sensitive to imatinib and, more significantly, take a substantially shorter time for yielding a mutant subclone resistant to the inhibitor than cells with low expression levels, as in chronic phase. Our data suggest that the differential levels of the Bcr-Abl oncoprotein expressed by CD34+ CML cells may reflect the extent and duration of their response to imatinib; the relatively high levels of oncoprotein in advanced-phase disease may underlie the observed rapid development of resistance.
This randomized study was designed to investigate the superiority of gemcitabine (gem) plus nimotuzumab (nimo), an anti-epidermal growth factor receptor monoclonal antibody, compared with gem plus ...placebo as first-line therapy in patients with advanced pancreatic cancer.
Patients with previously untreated, unresectable, locally advanced or metastatic pancreatic cancer were randomly assigned to receive gem: 1000 mg/m2, 30-min i.v. once weekly (d1, 8, 15; q29) and nimo: fixed dose of 400 mg once weekly as a 30-min infusion, or gem plus placebo, until progression or unacceptable toxicity. The primary end point was overall survival (OS), secondary end points included time to progression, overall response rate, safety and quality of life.
A total of 192 patients were randomized, with 186 of them being assessable for efficacy and safety (average age 63.6 years). One-year OS/progression-free survival (PFS) was 34%/22% for gem plus nimo compared with 19%/10% for gem plus placebo (HR = 0.69;P = 0.03/HR = 0.68;P = 0.02). Median OS/PFS was 8.6/5.1 months for gem plus nimo versus 6.0/3.4 mo in the gem plus placebo group (HR = 0.69;P = 0.0341/HR = 0.68;P = 0.0163), with very few grade 3/4 toxicities.KRAS wildtype patients experienced a significantly better OS than those withKRAS mutations (11.6 versus 5.6 months,P = 0.03).
This randomized study showed that nimo in combination with gem is safe and well tolerated. The 1-year OS and PFS rates for the entire population were significantly improved. Especially, those patients withKRAS wildtype seem to benefit.
The study was registered as protocol ID OSAG101-PCS07, NCT00561990 and EudraCT 2007-000338-38.
Chronic myeloid leukemia (CML) is caused by Bcr-Abl, an activated tyrosine kinase. The amounts of Bcr-Abl mRNA and protein in cells from patients in blast crisis (BC) are higher than in those chronic ...phase (CP), indicating that their expression rises with disease progression. In order to study this phenomenon on cells with the same genetic background, we transfected the 32D cell line with the BCR-ABL transgene and selected clones with graded expression of Bcr-Abl within the range found in cells from CP to BC. In vitro, we found that Bcr-Abl exerted dose-dependent effects upon growth factor dependence, clonogenicity and migration. However, the relationship between Bcr-Abl expression and cellular adhesion to fibronectin was more complex: rather than a direct positive correlation, clones that expressed low, but not high, levels of Bcr-Abl were less adhesive than growth factor stimulated, parental BCR-ABL-negative 32D cells. This finding parallels the situation with normal and CML-CP progenitors where the latter exhibit defective adhesion to fibronectin. Treatment with the tyrosine kinase inhibitor imatinib mesylate reversed the adhesion deficient phenotype of clones expressing low levels of Bcr-Abl. When injected subcutaneously into syngeneic mice, cell lines expressing high levels of Bcr-Abl rapidly induced tumors, whereas low-expressing clones led to tumor formation only after a prolonged latency. These findings suggest that the level of Bcr-Abl may be essential in determining the phenotype of the leukemic clone at different stages of the disease.
Fragestellung:
Inwieweit kann die Einrichtung eines ambulanten Palliativnetzes die Chancen für eine poststationäre Versorgung von Palliativpatienten im häuslichen Umfeld vergrößern?
Methodik:
Die ...Patientendokumentationen der 2008 eingerichteten interdisziplinären (Anästhesie, Onkologie, Geriatrie) Palliativstation werden retrospektiv im Hinblick darauf analysiert, welche Gründe einer weiteren häuslichen Versorgung der Patienten entgegenstehen. Verglichen werden die erhobenen Daten des Zeitraumes von November 2008 bis zur Gründung des Palliativnetzes im Juni 2009 (Gruppe 1) mit denen von Juli 2009 bis März 2010 (Gruppe 2).
Ergebnis:
Von 11/2008 bis 03/2010 wurden insgesamt 227 stationäre palliativmedizinische Behandlungen dokumentiert. Von diesen Patienten wurden 73 (32%) in Ihre häusliche Umgebung, 6 Patienten (3%) in eine Pflegeeinrichtung und 30 Patienten (13%) in ein stationäres Hospiz entlassen. 118 Patienten (52%) verstarben während des stationären Aufenthaltes. In Gruppe 1 verhinderten bei 5 Patienten (29%) medizinische Gründe, bei 3 Patienten (18%) ein komplexer pflegerischer Aufwand und bei 9 Patienten (53%) psychosoziale Gründe (z.B. allein lebend, Überforderung der Familie etc.) eine ambulante palliativmedizinische Versorgung. Nach Gründung des Palliativnetzes erforderten bei 3 der Patienten (16%) medizinische Gründe, bei 1 Patienten (5%) der pflegerische Aufwand und bei 15 Patienten (79%) psychosoziale Gründe eine weitere stationäre palliativmedizinische Betreuung.
Schlussfolgerung:
Der Aufbau eines ambulanten Palliativnetzes erhöht nicht unmittelbar die Chance einer ambulanten häuslichen Palliativbetreuung. Vorwiegend psychosoziale Ursachen begründen die Notwendigkeit einer stationären Palliativbehandlung (in der Regel im Hospiz). Dies betrifft vor allem allein lebende Patienten oder Überforderungssituationen des unmittelbar versorgenden Lebensumfeldes.
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