Management of immunosuppression in the treatment of chronic lymphocytic leukemia

In patients with chronic lymphocytic leukemia (CLL), infections exert a substantial influence on morbidity and mortality. Hypogammaglobulinemia is one important predisposing factor for development of infections. The use of purine analogs, such as fludarabine, and monoclonal antibodies, such as rituximab and alemtuzumab, has introduced a new spectrum of infectious complications caused by pathogens such as Pneumocystis jiroveci, mycobacteria, listeria, and herpes viruses, as well as of fungal infections; these infections are mainly related to cellular immunosuppression induced by these agents. This short review focusses on risk factors, the causative spectrum of infectious complications, and possible preventive approaches in CLL patients, including antimicrobial, immunoglobulin prophylaxis, and vaccination strategies.     

Neprilysin, a novel target for ultraviolet B regulation of melanogenesis via melanocortins

Compelling evidence suggest a role for melanocortins in the regulation of melanogenesis by ultraviolet radiation. Within the epidermis, melanocytes and keratinocytes produce alpha-melanocyte-stimulating hormone and adrenocorticotropic hormone. The persistence and the strength of the biologic signal delivered by these peptides depend on their local concentration, which is controlled by the rate of peptide production and by the rate of its degradation. In this study, we investigated the mechanism of melanocortin degradation by melanocytes and the effect of ultraviolet on this process. We have focused our attention on a neutral endopeptidase, neprilysin, which has been implicated in the ending of numerous peptidergic signals. We have shown that this enzyme is expressed at the surface of human melanocytes. Interestingly, its activity and its expression are dramatically downregulated by ultraviolet B treatment. Moreover, in the presence of phosphoramidon, a stable inhibitor of neprilysin, we observed an increased efficiency of alpha-melanocyte-stimulating hormone and adrenocorticotropic hormone to stimulate both tyrosinase activity and microphthalmia expression. Taken together, these data indicate that neprilysin expressed by melanocytes has a physiologic role in the regulation of melanogenesis by proopiomelanocortin peptide. Further, its downregulation by ultraviolet B irradiation shed light on a new and appealing mechanism of ultraviolet B induced melanogenesis via the control of melanocortins degradation.     

Involvement of mast cells in gastritis caused by Helicobacter pylori: a potential role in epithelial cell apoptosis

BACKGROUND: The role(s) of mast cells (MC) in gastric mucosal inflammation caused by Helicobacterpylori is (are) still debated. AIM: To determine whether there is an association between MC density and epithelial cell apoptosis in antral gastric mucosa infected by H pylori. Patients and methods: Biopsy specimens from 122 H pylori-positive subjects with chronic active gastritis, 84 patients with non-steroidal anti-inflammatory drug-induced gastritis and 48 volunteers were included. H pylori genotypes were determined by PCR amplification of bacterial cultures. Immunohistochemical analysis was performed on tissue microarrays with anti-CD117, anti-chymase, anti-tryptase, anti-myeloperoxidase, anti-Bcl-2, anti-Bcl-x, anti-Bax and anti-caspase 3 antibodies. RESULTS: Of the 122 patients infected with H pylori, 76 (62.3%) harboured cagA positive strains. H pylori isolates belonged to the vacAs1/m1 genotype in 82 (67%) cases, to the vacAs2/m2 genotype in 23 (18.8%) cases and to the vacAs1/m2 genotype in 17 (13.9%) cases. 61 (50%) H pylori isolates were babA2+. In patients infected with H pylori, the density of MC, and in particular the number of MC-associated epithelial cells, was correlated with a high number of apoptotic epithelial cells. Moreover, the density of MC was correlated with the number of neutrophils infiltrating the antral gastric mucosa, and was strongly increased in patients infected with cagA, vacAs1/m1 and babA2 positive strains. CONCLUSIONS: Taken together, these data show that the density of MC can be considered as a histopathological criterion of gastritis activity in patients infected with H pylori.     

Significant alterations in the epidemiology and treatment outcome of invasive fungal infections in patients with hematological malignancies

Invasive fungal infections (IFI) remain a leading cause of morbidity and mortality in immunocompromised patients. This retrospective single-center study analyzed incidence, treatment and outcome of invasive fungal infections in 1,095 patients with hematological malignancies receiving either cytoreductive chemotherapy or autologous or allogeneic hematopoietic stem cell transplantation at our institution between 1995 and 2004. IFI occurred in 167/1,095 (15%) patients with a significant increase over time (12.7% between 1995 and 2000 vs. 18.1% in the later IFI cohort, P = 0.0134). Fifty-four (32%) patients had proven, 70 (42%) patients had probable, and 43 (26%) patients suffered from possible IFI according to EORTC/MSG criteria. In 108/124 (87%) cases with proven or probable IFI, moulds were the causative pathogens. Both, Aspergillus fumigatus (n = 46) and Aspergillus terreus (n = 41) were predominant. Yeast infections (Candida spp.) were documented in 16/124 (10%) cases with proven or probable IFI. Median overall survival of the entire IFI cohort was 7 (3–17) months. Overall survival was significantly better in patients with probable or possible IFI (37 and 38%, respectively) compared with patients with proven IFI (28%, P = 0.019). In 35% of patients, IFI was the principal cause of death with a significant decrease over time (44% in time cohort 1995–2000 vs. 28% in the later IFI cohort, P = 0.018) accompanied by an increased use of novel antifungals. By multivariate analysis, only proven IFI was significantly predictive for death (HR 1.7, P = 0.018). A significant decrease in fungus-related deaths was observed despite a significant increase of IFI over time, probably due to improved diagnostic and therapeutic approaches.     

Comparative Treatment Planning on Localized Prostate Carcinoma

Purpose: To assess the potential benefit of proton–beam therapy in comparison to 3–D conformal photon therapy and photon– based intensity–modulated radiotherapy (IMRT) in prostate carcinoma for various stages of disease.Material and Methods: In five patients a 3–D conformal proton–based (two lateral beams) irradiation technique was compared with 3–D conformal photon–beam radiotherapy (four–field box) and IMRT (seven beams). For each patient different target volumes (CTVs) were defined according to early, intermediate and advanced stages of disease: CTV I consisted of the prostate gland, CTV II encompassed prostate and basis of seminal vesicles, and CTV III the prostate and seminal vesicles. Corresponding planning target volumes PTV I–III were defined by uniformly adding a margin of 5 mm to CTV I–III. Dose–volume histograms (DVHs) were analyzed for the different PTVs and various organs at risk (OARs), i.e., rectal wall, bladder, both femoral heads. In addition, maximum and mean doses were derived for the various structures and irradiated non–target tissue volumes were compared for PTV I–III and the different irradiation techniques. Finally, dose conformity and target dose homogeneity were assessed.Results: With photon– and proton–based radiotherapy techniques similar dose distributions were determined for PTV I–III: mean and maximum PTV dose values were between 99–104% and 102–107% of the normalized total doses (70 Gy), respectively. Conformity indices varied from 1.4 to 1.5 for the photon techniques, whereas for proton–beam radiotherapy values ranged from 1.1 to 1.4. Both the 3–D conformal and the IMRT photon treatment technique resulted in increased mean doses (~ 40–80%) for OARs when compared to protons. With both photon techniques non–target tissue volumes were irradiated to higher doses (mean dose difference ≥ 70%) compared to proton–beam radiotherapy. Differences occurred mainly at the low and medium dose levels, whereas in high dose levels similar values were obtained. In comparison to conformal 3–D treatments IMRT reduced doses to OARs in the medium dose range, especially for the rectal wall.Conclusion: IMRT enabled dose reductions to OARs in the medium dose range compared to 3–D conformal radiotherapy. A rather simple two–field proton–based treatment technique further reduced doses to OARs compared to photon–beam radiotherapy. The advantageous dose distribution of proton–beam therapy for prostate cancer may result in reduced side effects, which needs to be confirmed in clinical studies.     

Leukemic cell xenograft in zebrafish embryo for investigating drug efficacy

Zebrafish were proposed as an alternative to mammalian models to assess the efficacy and toxicity of antileukemic drugs. Due to the limited number of transgenic zebrafish leukemia models, we explored human leukemic cell xenograft in zebrafish embryos. Human leukemic cell lines and blast cells sorted from patients with acute myelogenous leukemia were injected 48 hours post-fertilization and remained in the circulation of zebrafish embryos for several days without affecting their development. Imatinib and oxaphorines did not demonstrate any toxicity on normal zebrafish embryos and decreased the leukemic burden in animals xenografted with sensitive leukemic cell lines. Two other molecules, all-trans retinoic acid and the translation inhibitor 4EGI-1, demonstrated teratogenic effects at concentrations shown to be efficient in vitro, which precluded investigation of their antileukemic activity in such models. Altogether, xenografted leukemic cells in zebrafish embryos are a pharmacologically relevant model for screening non-teratogenic drugs.     

A survey of the signaling pathways involved in megakaryocytic differentiation of the human K562 leukemia cell line by molecular and c-DNA array analysis

The K562 cell line serves as a model to study the molecular mechanisms associated with leukemia differentiation. We show here that cotreatment of K562 cells with PMA and low doses of SB202190 (SB), an inhibitor of the p38 MAPK pathway, induced a majority of cells to differentiate towards the megakaryocytic lineage. Electronic microscopy analysis showed that K562 cells treated with PMA+SB exhibited characteristic features of physiological megakaryocytic differentiation including the presence of vacuoles and demarcation membranes. Differentiation was also accompanied by a net increase in megakaryocytic markers and a reduction of erythroid markers, especially when both effectors were present. PMA effect was selectively mediated by new PKC isoforms. Differentiation of K562 cells by the combination of PMA and SB required Erk1/2 activation, a threshold of JNK activation and p38 MAPK inhibition. Interestingly, higher concentrations of SB, which drastically activated JNK, blocked megakaryocytic differentiation, and considerably increased cell death in the presence of PMA. c-DNA microarray membranes and PCR analysis allow us to identify a set of genes modulated during PMA-induced K562 cell differentiation. Several gene families identified in our screening, including ephrins receptors and some angiogenic factors, had never been reported so far to be regulated during megakaryocytic differentiation.     

Targeted therapies in non-small cell lung cancer: proven concepts and unfulfilled promises

Targeted therapies focus on signaling pathways in cancer cells and other molecular processes involved in oncogenesis. Recent approaches affect the following major groups: the epidermal growth factor receptor (EGFR)-family, angiogenesis, the eicosanoid pathway, the PKC/ Ras/ MAPK pathway, the proteasome and inducers of apoptosis. Numerous phase I and II trials have provided promising results and recently, anti-EGFR and anti-VEGF treatments have proven their efficacy in phase III trials. However, others failed in phase III settings (e.g. PKC- and matrix metalloproteinase inhibitors) and it is a moot point, whether patients have been selected properly. The huge amount of new medications raises questions like when to use which strategy in which sequence. The successful implementation of targeted agents into clinical routine will depend on the verification of sufficient predictive markers, allowing their economically reasonable usage. In the current review the up-to-date knowledge concerning targeted therapies in NSCLC is summarized and their therapeutical potential is discussed.     

Tiapride: effects on tardive dyskinesia and on prolactin plasma concentrations

In a placebo-controlled double-blind crossover study of 21 patients chronically treated with neuroleptics and suffering from tardive dyskinesia, tiapride (600 mg/day, mean plasma level: 682 ng/ml) exhibited a transient efficacy during 12 weeks of treatment, most distinct in the 6th week (p less than 0.01). Tiapride induced an increase of prolactin plasma levels, on the average, from 1,195 to 2,179 microIU/ml (p less than 0.01). Tiapride was well tolerated. Increase of parkinsonism was only mild and not significant. The results underline the difficulty in treating tardive dyskinesia and, thus, confirm the importance of prevention.