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Tumour necrosis factor (TNF) is primarily secreted by monocytes/macrophages and activated T lymphocytes in response to fungal infections. TNF acts through TNF receptor 1 (TNFR1) triggering a pro-inflammatory response, and therefore plays a pivotal role in immune regulation and host immune responses. We hypothesized that single nucleotide polymorphisms (SNPs) in TNFR1 gene may influence the innate immune response against Aspergillus. Three SNPs were genotyped in 275 individuals (144 immunocompromised haematological patients with high-risk of developing IPA and 131 healthy controls): TNFR1(-383(A/C)) (rs2234649) and TNFR1(-609(G/T)) (rs4149570) in the 5 prime UTR region, and TNFR1(+36(A/G)) SNP (rs767455) in the first exon of the gene. Of the 144 haematological patients, 77 patients developed Invasive Pulmonary Aspergillosis (IPA) infection and the remaining 67 patients were not infected. TNFR1(+36(A/G)) and TNFR1(-609(G/T)) were associated with IPA susceptibility (p=0.033 and p=0.018, respectively). A role of TNFR1 genetic variants in the susceptibility of patients to develop IPA was also supported by the significantly lower TNFR1 mRNA expression level in IPA than in IPA-resistant patients and the strong correlation between the TNFR1(-609) genetic variant and the expression levels of TNFR1. There was also a tendency for a higher frequency of galactomannan (GM) positivity in patients with TNFR1(-609G/G) genotype than in patients with TNFR1(-609G/T) (p=0.0909) or TNFR1(-609T/T) (p=0.0913) genotype. Predictive sequence analysis of the effects of TNFR1(-609) promoter polymorphism revealed that this SNP might play a critical role in modifying the affinity of ICSBP/IRF-8, a transcription factor that is involved in the TNFR1-mediated activation of NFkappaB signalling pathway. Taken together, these data suggest that TNFR1 polymorphisms influence the risk of IPA disease and might be useful for risk stratification strategies. These findings need to be confirmed in validation studies with larger samples of haematological patients.

Multiple myeloma is a heterogeneous disease with variable survival; this variability cannot be fully explained by the current systems of risk stratification. Early mortality remains a serious obstacle to further improve the trend toward increased survival demonstrated in recent years. However, the definition of early mortality is not standardized yet. Importantly, no study has focused on the impact of comorbidity on early mortality in multiple myeloma to date. Therefore, we analyzed the role of baseline comorbidity in a large populationbased cohort of 621 real-life myeloma patients over a 31-year period. To evaluate early mortality, a sequential multivariate regression model at 2, 6, and 12 months from diagnosis was performed. It was demonstrated that comorbidity had an independent impact on early mortality, which is differential and time-dependent. Besides renal failure, respiratory disease at 2 months, liver disease at 6 months, and hepatitis virus C infection at 12 months, were, respectively, associated with early mortality, adjusting for other well-established prognostic factors. On the other hand, the long-term monitoring in our study points out a modest downward trend in early mortality over time. This is the first single institution population-based study aiming to assess the impact of comorbidity on early mortality in multiple myeloma. It is suggested that early mortality should be analyzed at three key time points (2, 6, and 12 months), in order to allow comparisons between studies. Comorbidity plays a critical role in the outcome of myeloma patients in terms of early mortality.Am. J. Hematol. 91:700-704,

pRecent studies suggest that immune-modulating single-nucleotide polymorphisms (SNPs) influence the risk of developing cancer-related infections. Here, we evaluated whether 36 SNPs within 14 immune-related genes are associated with the risk of invasive aspergillosis (IA) and whether genotyping of these variants might improve disease risk prediction. We conducted a case-control association study of 781 immunocompromised patients, 149 of whom were diagnosed with IA. Association analysis showed that the IL4R rs2107356 and IL8 rs2227307 SNPs (using dbSNP numbering) were associated with an increased risk of IA (IL4R rs2107356 odds ؊4 and P 50.000 permutation test ‫؍‬ 9.34 · 10 ؊5 ). These findings suggest that the IFN␥ rs2069705 SNP influences the risk of IA and that predictive models built with IFN␥, IL8, IL12p70, and VEGFA variants can used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies.

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Prompt identification and good management of TA-TMA, with better control of GVHD, may contribute to a decrease in patient mortality that would result from this complication.

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