Management of Febrile Neutropenia - a German Prospective Hospital Cost Analysis in Lymphoproliferative Disorders, Non-Small Cell Lung Cancer, and Primary Breast Cancer

Background: Febrile neutropenia/leukopenia (FN/FL) is the most frequent dose-limiting toxicity of myelosuppressive chemotherapy, but German data on economic consequences are limited. Patients and Methods: A prospective, multicentre, longitudinal, observational study was carried out to evaluate the occurrence of FN/FL and its impact on health resource utilization and costs in non-small cell lung cancer (NSCLC), lymphoproliferative disorder (LPD), and primary breast cancer (PBC) patients. Costs are presented from a hospital perspective. Results: A total of 325 consecutive patients (47% LPD, 37% NSCLC, 16% PBC; 46% women; 38% age >= 65 years) with 68 FN/FL episodes were evaluated. FN/FL occurred in 22% of the LPD patients, 8% of the NSCLC patients, and 27% of the PBC patients. 55 FN/FL episodes were associated with at least 1 hospital stay (LPD n = 34, NSCLC n = 10, PBC n = 11). Mean (median) cost per FN/FL episode requiring hospital care amounted to (sic) 3,950 ((sic) 2,355) and varied between (sic) 4,808 ((sic) 3,056) for LPD, (sic) 3,627 ((sic) 2,255) for NSCLC, and (sic) 1,827 ((sic) 1,969) for PBC patients. 12 FN/FL episodes (LPD n = 9, NSCLC n = 3) accounted for 60% of the total expenses. Main cost drivers were hospitalization and drugs (60 and 19% of the total costs). Conclusions: FN/FL treatment has economic relevance for hospitals. Costs vary between tumour types, being significantly higher for LPD compared to PBC patients. The impact of clinical characteristics on asymmetrically distributed costs needs further evaluation

Mycobacterium tuberculosis nuoG Is a Virulence Gene That Inhibits Apoptosis of Infected Host Cells

The survival and persistence of Mycobacterium tuberculosis depends on its capacity to manipulate multiple host defense pathways, including the ability to actively inhibit the death by apoptosis of infected host cells. The genetic basis for this anti-apoptotic activity and its implication for mycobacterial virulence have not been demonstrated or elucidated. Using a novel gain-of-function genetic screen, we demonstrated that inhibition of infection-induced apoptosis of macrophages is controlled by multiple genetic loci in M. tuberculosis. Characterization of one of these loci in detail revealed that the anti-apoptosis activity was attributable to the type I NADH-dehydrogenase of M. tuberculosis, and was mainly due to the subunit of this multicomponent complex encoded by the nuoG gene. Expression of M. tuberculosis nuoG in nonpathogenic mycobacteria endowed them with the ability to inhibit apoptosis of infected human or mouse macrophages, and increased their virulence in a SCID mouse model. Conversely, deletion of nuoG in M. tuberculosis ablated its ability to inhibit macrophage apoptosis and significantly reduced its virulence in mice. These results identify a key component of the genetic basis for an important virulence trait of M. tuberculosis and support a direct causal relationship between virulence of pathogenic mycobacteria and their ability to inhibit macrophage apoptosis

Mycobacterium tuberculosis pks12 Produces a Novel Polyketide Presented by CD1c to T Cells

CD1c-mediated T cells are activated by a mycobacterial phospholipid antigen whose carbohydrate structure precisely corresponds to mammalian mannosyl β-1-phosphodolichol (MPD), but contains an unusual lipid moiety. Here, we show that this T cell antigen is a member of a family of branched, alkane lipids that vary in length (C30-34) and are produced by medically important mycobacteria such as M. tuberculosis and M. bovis Bacille-Calmette-Guerin. The alkane moiety distinguished these mycobacterial lipid antigens from mammalian MPDs and was necessary for activation of CD1c-restricted T cells, but could not be accounted for by any known lipid biosynthetic pathway. Metabolic labeling and mass spectrometric analyses suggested a mechanism for elongating lipids using alternating C2 and C3 units, rather than C5 isopentenyl pyrophosphate. Inspection of the M. tuberculosis genome identified one candidate gene, pks12, which was predicted to encode the largest protein in M. tuberculosis, consisting of 12 catalytic domains that correspond to key steps in the proposed pathway. Genetic deletion and complementation showed that Pks12 was necessary for antigen production, but did not affect synthesis of true isoprenols. These studies establish the genetic and enzymatic basis for a previously unknown type of polyketide, designated mycoketide, which contains a lipidic pathogen-associated molecular pattern