Citations

Objective To identify the clinical and laboratory predictors of clinical improvement in a cohort of myositis patients treated with rituximab. Methods We analyzed data for 195 patients with myositis (75 with adult polymyositis [PM], 72 with adult dermatomyositis [DM], and 48 with juvenile DM) in the Rituximab in Myositis trial. Clinical improvement was defined as 20% improvement in at least 3 of the following 6 core set measures of disease activity: physician's and patient's/parent's global assessment of disease activity, manual muscle testing, physical function, muscle enzymes, and extramuscular disease activity. We analyzed the association of the following baseline variables with improvement: myositis clinical subgroup, demographics, myositis damage, clinical and laboratory parameters, core set measures, rituximab treatment, and myositis autoantibodies (antisynthetase, anti–Mi‐2, anti–signal recognition particle, anti–transcription intermediary factor 1γ [TIF‐1γ], anti‐MJ, other autoantibodies, and no autoantibodies). All measures were univariately assessed for association with improvement using time‐to‐event analyses. A multivariable time‐dependent proportional hazards model was used to evaluate the association of individual predictive factors with improvement. Results In the final multivariable model, the presence of an antisynthetase, primarily anti–Jo‐1 (hazard ratio [HR] 3.08, P < 0.01), anti–Mi‐2 (HR 2.5, P < 0.01), or other autoantibody (HR 1.4, P = 0.14) predicted a shorter time to improvement compared to the absence of autoantibodies. A lower physician's global assessment of damage (HR 2.32, P = 0.02) and juvenile DM (versus adult myositis) (HR 2.45, P = 0.01) also predicted improvement. Unlike autoantibody status, the predictive effect of physician's global assessment of damage and juvenile DM diminished by week 20. Rituximab treatment did not affect these associations. Conclusion Our findings indicate that the presence of antisynthetase and anti–Mi‐2 autoantibodies, juvenile DM subset, and lower disease damage strongly predict clinical improvement in patients with refractory myositis.

Abstract Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P &lt; 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P &lt; 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P &lt; 10−8. Results from the second analytic approach were consistent with those from the first (P &gt; 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.

Objective To evaluate the association of perioperative blood transfusion ( PBT ) with survival after nephrectomy. Patients and Methods We identified 2318 patients who underwent partial or radical nephrectomy at M ayo C linic between 1990 and 2006. PBT was defined as transfusion of allogenic red blood cells during surgery or postoperative hospitalisation. Survival was estimated using the K aplan– M eier method and compared with the log‐rank test. Cox proportional hazards regression models were used to evaluate the association of PBT with outcome. Results In all, 498 patients (21%) received a PBT . The median (interquartile range) number of units transfused was 3 (2, 5). Patients receiving a PBT were significantly older at surgery ( P < 0.001), more likely to be female ( P < 0.001), with more frequent symptomatic presentation ( P < 0.001), worse E astern C ooperative O ncology G roup performance status ( P < 0.001), and more frequent adverse pathological features, such as high nuclear grade ( P < 0.001), locally‐advanced tumour stage ( P < 0.001) and lymph node invasion ( P < 0.001). The median follow‐up was 9.1 years. Receipt of a PBT was associated with adverse 5‐year cancer‐specific (68% vs 92%; P < 0.001) and overall (56% vs 82%; P < 0.001) survival. On multivariate analyses, PBT remained associated with higher risk of death from any cause (hazard ratio [ HR ] 1.23; P = 0.02). Among patients who received a PBT , an increasing number of units transfused was independently associated with increased all‐cause mortality ( HR 1.08; P = 0.001). Conclusion PBT is associated with a significantly increased risk of mortality after nephrectomy. While external validation is needed, continued efforts to minimise the use of blood products in these patients are warranted.

Abstract Purpose: Although the International Prognostic Score (IPS) is the gold standard for risk-stratifying patients with classical Hodgkin lymphoma (cHL), these criteria do not accurately predict outcome. As cytokines are critically involved in driving cHL, we tested whether pretreatment serum cytokine levels could provide additional prognostic information. Experimental Design: Thirty cytokines were measured in pretreatment serum from 140 patients with cHL and compared with 50 nonlymphoma controls. Patients were followed for event-free survival (EFS) and overall survival (OS), and Cox proportional hazards regression models were used to assess the association of individual cytokines and the cytokine profiles with outcome via unadjusted and IPS-adjusted HR. Results: Twelve cytokines (EGF, bFGF, G-CSF, HGF, IL-6, IL-8, IL-12, IL-2R, IP-10, MIG, TNF-α, and VEGF) were significantly (P &lt; 0.05) higher in patients with cHL than controls; elevated levels of HGF, IL-6, IL-2R, IP-10, and MIG were all associated with poorer EFS. Only interleukin-2 receptor (IL-2R; P = 0.002) and interleukin (IL)-6 (P &lt; 0.001) were independently prognostic. Patients with increased IL-6 and IL-2R had a significantly higher risk of early relapse and death, a finding that remained significant even after IPS-based risk stratification. Although elevated IL-6 and IL-2R correlated with the IPS, soluble CD30 (sCD30), and thymus and activation-related chemokine (TARC) levels, the two-cytokine model remained independently predictive of prognosis. Conclusions: Elevated pretreatment serum cytokines are associated with increased disease relapse and inferior survival in cHL. Thus, the pretreatment cytokine profile, particularly serum levels of IL-6 and IL-2R, may be used to identify patients with cHL at high risk for early-disease relapse. Clin Cancer Res; 19(24); 6812–9. ©2013 AACR.