Das kleinzellige Bronchialkarzinom – neue Entwicklungen nach ASCO 2007

Wiener Medizinische Wochenschrift - Aggressives Tumorwachstum, frühe Metastasierung und hohe Assoziation mit intensivem Nikotinkonsum sind die Charakteristika des kleinzelligen...     

Increase of regulatory T cells in the peripheral blood of cancer patients.

PURPOSE: T cells constitutively expressing both CD4 and CD25are essential for maintenance of self-tolerance and therefore have been referred to as regulatory T cells (Treg). Experimental tumor models in mice revealed that Tregs are potent inhibitors of an antitumor immune response. The current study was designed to determine whether cancer patients exhibit an expanded Treg pool. EXPERIMENTAL DESIGN: The frequency of Tregs in the peripheral blood of 42 patients suffering from epithelial malignancies and from 34 healthy controls was determined by flow cytometry. The immunoregulatory properties of CD4(+)CD25(+) and CD4(+)CD25(-) T cells were characterized by proliferation and suppression assays. Cocultures with natural killer (NK) cells were performed to determine the impact of Tregs on NK-mediated cytotoxicity. RESULTS: Patients with epithelial malignancies show an increase of CD4(+)CD25(+) T cells in the peripheral blood with characteristics of Tregs, i.e., they are CD45RA(-), CTLA-4(+), and transforming growth factor beta(+). Notably, CD4(+) T cells from cancer patients are characterized by an impaired proliferative capacity, which is restored to the extend of CD25-depleted CD4(+) T cells from control persons by prior removal of CD25(+) T cells. In contrast to CD4(+)CD25(-) T cells, isolated CD4(+)CD25(+) T cells from cancer patients were anergic towards T cell receptor stimulation. In addition, CD4(+)CD25(+) T cells suppressed the proliferation of CD4(+)CD25(-) T cells. When cultured together with CD56(+) NK-cells, CD4(+)CD25(+) T cells from cancer patients effectively inhibited NK-cell-mediated cytotoxicity. CONCLUSIONS: Thus, we provide evidence of an increased pool of CD4(+)CD25(+) regulatory T cells in the peripheral blood of cancer patients with potent immunosuppressive features. These findings should be considered for the design of immunomodulatory therapies such as dendritic cell vaccination.     

Fungal colonization in neutropenic patients: a randomized study comparing itraconazole solution and amphotericin B solution

We assessed the impact of prophylaxis with the oral itraconazole solution and amphotericin B solution on fungal colonization and infection in a randomized study among patients with hematological malignancies and neutropenia. Infecting and colonizing Candida strains of patients suffering from candidiasis were genotyped by random amplification of polymorphic DNA (RAPD) analysis. A total of 106 patients were evaluated in this study: 52 patients in the itraconazole and 54 in the amphotericin B arm. During neutropenia fungal colonization in the oropharynx occurred in 11 (19.6%) and 24 (40.6%) and in the rectum in 11 (19.6%) and 23 (38.9%) courses in the itraconazole and amphotericin B groups (P<0.05), respectively. Candida albicans was the most prevalent species in both study groups. Mixed fungal colonization with Candida krusei and Candida glabrata was increased in the amphotericin B group, yet without clinical importance since infections were due to C. albicans. The occurrence of invasive candidiasis was significantly increased in multicolonized compared to monocolonized patients. In the amphotericin B group 20 and in the itraconazole group 2 neutropenic patients showed multicolonization with Candida spp. (P<0.05). Overall fungal infections were 3.8% in the itraconazole and 14.8% in the amphotericin B group (P<0.05). RAPD typing showed oropharynx strains involved in superficial infections in four of five patients. In all four patients with deep fungal infections, it appears that the colonizing rectum strains were identical to infecting strains of Candida spp. Itraconazole solution significantly reduced Candida colonization and infection compared to amphotericin B solution. Most patients remained infected with the colonized strains for the entire study period, irrespective of antifungal prophylaxis.     

Impact of natural killer cell dose and donor killer-cell immunoglobulin-like receptor (KIR) genotype on outcome following human leucocyte antigen-identical haematopoietic stem cell transplantation

To define the role of quantitative graft composition and donor killer-cell immunoglobulin-like receptor (KIR) genotype in clinical outcome following unmanipulated peripheral blood stem cell transplantation (PBSCT) from human leucocyte antigen (HLA)-identical siblings, 43 consecutive transplants for haematological malignancies were analysed retrospectively. Twenty-four patients underwent myeloablative conditioning and 19 received busulphan/fludarabine-based reduced intensity conditioning (RIC). In patients with acute myelogenous leukaemia or myelodysplastic syndrome (AML/MDS; n = 18), no relapse occurred following transplants meeting both a high (above median) natural killer (NK) cell count and missing HLA-ligand(s) to donor's KIR(s), compared to all other AML/MDS patients (0% versus 44%; P = 0.049). Missing HLA-B and/or HLA-C ligand combined with missing HLA-A3/11 (KIR3DL2 unblocked) predicted for reduced relapse incidence regardless of diagnosis or conditioning type (P = 0.028). Moreover, in AML/MDS patients, this constellation predicted superior overall survival (OS) (P = 0.046). Transplants with more than two different activating donor KIRs were associated with an increased risk for non-relapse mortality (NRM), both by univariate and multivariate analysis. Quantitative graft composition had a significant impact exclusively in RIC transplants. Here, a trend towards reduced relapse incidence was found in patients receiving high numbers of NK cells (16% versus 54%; P = 0.09). In patients receiving high versus low T cell numbers, OS was superior (83% versus 37%; P = 0.01), due mainly to reduced NRM (0% versus 33%; P = 0.046). By multivariate analysis, relapse risk was decreased significantly in patients receiving high NK cell numbers (P = 0.039). These data suggest that both the number of transplanted NK cells and the donor KIR genotype play a role in graft-versus-malignancy mechanisms in HLA-identical PBSCT.     

Myelodysplastic/myeloproliferative disease with erythropoietic hyperplasia (erythroid preleukemia) and the unique translocation (8;9)(p23;p24): first description of a case

We report on a patient fulfilling the diagnostic criteria of unclassifiable myelodysplastic/myeloproliferative diseases with prominent erythropoietic hyperplasia/dysplasia (erythroid preleukemia) and the unique translocation (8;9)(p23;p24). The patient presented with B-symptoms, erythroblastemia, thrombopenia, marked eosinophilia, presence of myeloid precursors in the peripheral blood, and decreased erythropoietin level. Nodular peritrabecular polymorphous blasts, dysplastic megakaryocytes, and a diffuse argyrophilic fibrosis were detected in the trephine bone marrow biopsy. Immunohistochemically, the blasts stained positively for glycophorin C and hemoglobin A; the proliferation fraction was nearly 90% in the Ki-67 stain. Expression of the phosphorylated Janus kinase 2 was detected in almost all megakaryocytes and in isolated erythroblast islets, suggesting a probable activation of Janus kinase 2, the jak-2 gene being mapped on 9p24. Ten months after initial diagnosis, the disease progressed to frank acute erythroid leukemia. We report for the first time a myelodysplastic/myeloproliferative disease (erythroid preleukemia) accompanied by the specific chromosomal aberration t(8;9)(p23;p24), distinct histopathology, and clinical and laboratory symptoms, and progress to acute erythroid leukemia.     

Das kleinzellige Bronchialkarzinom

With about 20% of all lung cancers small cell lung cancer (SCLC) represents a major subset of this entity. Although therapeutic improvements did not receive as much attention as in non small cell lung cancer (NSCLC), many small steps of clinical progress have been achieved within the last 20 years. An optimal treatment should be based on an interdisciplinary treatment plan. The standard treatment in localized stages represents combined radiation and chemotherapy. Cisplatin and etoposide are in this concern considered as a gold standard. 3D-planned conformal radiotherapy should start as early as possible and should be applied concomitantly to chemotherapy and in certain cases even in a hyperfractionated treatment protocol. In very early stages surgical resection could be an option in selected cases. In advanced stages a platinum-based doublet offers high response rates. As already established in limited disease prophylactic cranial irradiation is now also indicated in extensive disease in case of any tumor remission. In the second line treatment and in patients with reduced performance status topotecan is recommended. Similar as in NSCLC pemetrexed might become an alternative treatment option in the second line setting. In the field of new targeted therapies bevacizumab achieved the most promising results. The present review highlights historical milestones and up-to-date trends in radiotherapy, chemotherapy and surgery. Furthermore, the role of experimental strategies and the management of certain special clinical situations are discussed.     

Low concentrations of STI571 in the cerebrospinal fluid: a case report

We report a 53-year-old man with lymphoid blast crisis of Ph+ chronic myeloid leukaemia who was treated with STI571, a selective inhibitor of the enzymatic activity of BCR-ABL. He responded excellently to STI571 (600 mg/d), obtaining a complete cytogenetic remission after 3 months of therapy. Although remission in the bone marrow was sustained, the patient developed an isolated central nervous system relapse. Subsequent analyses of STI571 concentrations in the cerebrospinal fluid (CSF) revealed 2-log lower CSF levels of STI571 than corresponding plasma levels. These are the first data demonstrating a low penetration of orally administered STI571 into the CSF in humans.