Risk factors for central nervous system involvement in diffuse large B-cell lymphoma

Several factors hinder the identification of risk factors for central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL), including the retrospective nature of most studies, the relatively low frequency of CNS relapse in DLBCL, and the heterogeneity of CNS prophylaxis methods used in these studies. Moreover, the impact of newly developed diagnostic tools (such as multiparameter flow cytometry [FCM]) and new treatments introduced in the last decade, in particular rituximab, has still not been fully clarified. Several studies 2 Early diagnosis of central nervous system events is critical for successful treatment and improved prognosis. Identification of patients at risk of central nervous system disease is critical to accurately identify candidates for central nervous system prophylaxis vs. therapy. 12 In addition to the involvement of >1 extranodal site and increased LDH, International Prognostic Index (IPI) score was also identified as an independent predictor for CNS relapse in other studies. 13,16 A post-rituximab era study of 399 DLBCL patients, randomized to R-CHOP or CHOP chemotherapy, 3 identified an age-adjusted IPI (aaIPI) >1 as the only risk factor for CNS involvement, although a high aaIPI score was recorded for more than 60% of the patients. When aaIPI was excluded from the analysis, elevated LDH and a poor performance status (PS >1) were identified as independent predictive factors for CNS relapse. Similarly, in the randomized RICOVER-60 trial, 4 the combination of increased LDH levels, the involvement of >1 extranodal site, and PS >1 (recorded for 4.8% of patients) was associated with a probability of CNS relapse of 33.5% as compared with 2.8% in the remaining patients. Elevated LDH levels, the involvement of >1 extranodal site, and an intermediate-high or high IPI score have also been cited as risk factors in other retrospective studies, reviews, and meta-analyses of the postrituximab era The influence of the biology of DLBCL on CNS relapse remains a matter of debate. There is still insufficient evidence to demonstrate an influence of B-cell origin (germinal center vs. non-germinal center DLBCL) on CNS disease. However, many retrospective and recent studies have described a high percentage of CNS involvement in DLBCL cases with MYC rearrangement, particularly when associated with either additional BCL-2 or BCL-6 gene rearrangements: in these patients, the frequency of CNS disease ranges from 9% to 45%. Based on these results Fletcher and Kahl 2 recommended that patients with DLBCL and MYC rearrangements be considered at high risk of CNS relapse. In another recent study, Savage et al. 29 reported that DLBCL patients and dual expression of MYC (≥40% positivity) and BCL2 (≥50% positivity) determined by immunohistochemistry, had higher risk of CNS relapse (2-year risk of 9.7% vs. 2.2%, P=0.001). This study also showed increased risk for those patients with activated B-cell or non-germinal center B-cell origin, but significance was not retained in the multivariate analysis. Summary and recommendations for CNS prophylaxis in DLBCL based on the presence of risk factors The authors recommend screening patients for CNS involvement by lumbar puncture and cerebrospinal fluid (CSF) analysis by conventional cytology (CC) and FCM in order to provide prophylaxis in the following situations: • Increased serum LDH and involvement of >1 extranodal site (recommendation 1, level of evidence B

ARTICLE A score of low-grade inflammation and risk of mortality: prospective findings from the Moli-sani study

L ow-grade inflammation is associated with an increased risk of chronic degenerative disease, but its relationship with mortality is less well explored. We aimed at evaluating, at a large epidemiological level, the possible association of low-grade inflammation, as measured by a composite score, with overall mortality risk. We conducted a population-based prospective investigation on 20,337 adult subjects free from major hematological disease and acute inflammatory status, randomly recruited from the general population of the Moli-sani study. A low-grade inflammation score was obtained from the sum of 10-tiles of plasmatic (C-reactive protein) and cellular (leukocyte and platelet counts, granulocyte/lymphocyte ratio) biomarkers of low-grade inflammation; higher levels indicated increased low-grade inflammation. Hazard ratios were calculated using multivariable Cox proportional hazard models with 95% confidence intervals. At the end of follow-up (median 7.6 years), 837 all-cause deaths were recorded. As compared to subjects in the lowest quartile of the low-grade inflammation score, those in the highest category had a significantly increased risk in overall mortality (HR=1.44; 1.17-1.77), independently of possible confounders, including the presence of chronic diseases and a number of health-related behaviors. The magnitude of the association of low-grade inflammation with mortality was relatively higher in type 2 diabetic patients (HR=2.90; 1.74-4.84) and in individuals with a history of cardiovascular disease (HR=2.48; 1.50-4.11) as compared to their counterparts who were free from the disease. In conclusion, an elevated degree of lowgrade inflammation, as measured by a composite score of inflammatory biomarkers, is an independent risk factor for total mortality in an apparently healthy adult general population