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.     

Vascular endothelial growth factor in bacterial meningitis: detection in cerebrospinal fluid and localization in postmortem brain

Vascular endothelial growth factor (VEGF) is a potent vascular permeability factor and a mediator of brain edema. To assess the role of VEGF during bacterial meningitis, VEGF was measured in cerebrospinal fluid (CSF) and blood of 37 patients with bacterial meningitis and 51 control patients, including 16 patients with viral meningitis. Circulating VEGF levels were similar in bacterial meningitis patients and control patients. VEGF(CSF) was detected in 11 (30%) of 37 of bacterial meningitis patients (range, <25-633 pg/mL) but in none of the control patients. The median VEGF index was 6.2 (range, 0.6-42), indicating intrathecal production. Median CSF cell counts, protein levels, and CSF: serum albumin ratios were higher for patients with detectable VEGF(CSF), although the difference was not statistically significant. VEGF immunoreactivity in autopsy brain specimens was found in the inflammatory infiltrate of patients with bacterial meningitis. These results indicate that inflammatory cells secrete VEGF during bacterial meningitis and that VEGF may contribute to blood-brain barrier disruption.     

Hematopoietic stem cells in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a malignant myeloproliferative disorder originating from a pluripotent hematopoietic stem cell that acquires a Philadelphia (Ph) chromosome encoding the BCR-ABL oncogenic fusion protein. This molecular abnormality that is thought to be causative in CML was the first acquired chromosome translocation associated with a human malignancy. This chromosomal translocation also makes it possible to precisely distinguish between residual normal (i.e., Ph-, BCR-ABL-) progenitor or stem cells and their leukemic counterpart, Ph+ or BCR-ABL+ progenitor/stem cells in every given sample of a patient with CML. This has provided seminal insights into the molecular and cellular biology of leukemia and also of the process of normal hematopoiesis. CML has become a fascinating model disease for malignancy in general.     

Candida ciferrii, a new fluconazole-resistant yeast causing systemic mycosis in immunocompromised patients

Systemic infections related to fluconazole-resistant yeasts are increasingly observed in immunocompromised patients receiving fluconazole as a prophylactic antifungal treatment. Here, we report a case of invasive candidiasis caused by Candida ciferrii in a patient with acute myeloid leukemia and who suffered a relapse after autologous peripheral blood progenitor cell transplantation. Erythematous skin papulae and spotted pulmonary infiltrations were present. A skin biopsy led to the diagnosis of invasive candidiasis, emphasizing the diagnostic usefulness of this procedure. The yeast was identified as Candida ciferrii and in vitro susceptibility testing revealed its resistance to fluconazole. Until now, Candida ciferrii has not been known to cause invasive fungal infections in humans. Thus, we add another fungus to the list of flucanozole-resistant yeasts and suggest that in vitro susceptibility testing of isolated fungi should be performed for the selection of appropriate antimycotic drugs.     

RNAi-mediated knockdown of P-glycoprotein using a transposon-based vector system durably restores imatinib sensitivity in imatinib-resistant CML cell lines

OBJECTIVE: Resistance to therapeutic drugs is a frequent phenomenon in hematologic malignancies, causing treatment failure in patients with leukemias and lymphomas. Overexpression of the multidrug-resistance gene (MDR-1) and its translational product P-glycoprotein (PgP) represents one mechanism of fatal drug resistance. METHODS: We constructed a nonviral, transposon-based vector system for the stable knockdown of PgP in chronic myeloid leukemia cell lines resistant to imatinib and doxorubicin. RESULTS: Using this strategy, PgP expression was completely knocked down 72 hours after vector inoculation and lasted for several months. Cellular efflux of the PgP substates rhodamine and doxorubicin was abolished. Vector-treated cells were resensitized to imatinib- and doxorubicin-induced cell death. CONCLUSION: Using chronic myeloid leukemia as a model, we show that PgP-mediated resistance to imatinib and anthracyclines can be durably reversed by nonviral, transposon-based knockdown of PgP in malignant cells.