Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by pathologic immune activation in which prompt recognition and initiation of immune suppression is essential for survival. Children with HLH have many overlapping clinical features with critically ill children with sepsis and systemic inflammatory response syndrome (SIRS) in whom alternative therapies are indicated. To determine if plasma biomarkers could differentiate HLH from other inflammatory conditions and to better define a 'core inflammatory signature' of HLH, concentrations of inflammatory plasma proteins were compared in 40 patients with HLH to 47 pediatric patients with severe sepsis or SIRS. Fifteen of 135 analytes were significantly different in HLH plasma compared to SIRS/sepsis, including increased interferon-γ (IFN-γ)-regulated chemokines CXCL9, CXCL10 and CXCL11. Further, a two-analyte plasma protein classifier including CXCL9 and IL-6 was able to differentiate HLH from SIRS/sepsis. Gene expression in CD8+ T cells and activated monocytes from blood were also enriched for IFN-γ pathway signatures in peripheral blood cells from patients with HLH compared to SIRS/sepsis. This study identifies differential expression of inflammatory proteins as a diagnostic strategy to identify critically ill children with HLH, and comprehensive unbiased analysis of inflammatory plasma proteins and global gene expression demonstrates that IFN-γ signaling is uniquely elevated in HLH. In addition to demonstrating the ability of diagnostic criteria for HLH and sepsis or SIRS to identify groups with distinct inflammatory patterns, results from this study support the potential for prospective evaluation of inflammatory biomarkers to aid in diagnosis of and optimizing therapeutic strategies for children with distinctive hyperinflammatory syndromes.
BACKGROUND: Curative therapy places childhood cancer survivors at increased risk for second primary malignancies (SPMs). However, there have been few population-based attempts to characterize differences between outcomes of SPMs in childhood cancer survivors and outcomes of first primary malignancies (FPMs). METHODS: Clinical and demographic information about childhood cancer survivors who developed SPMs and individuals with comparable FPMs was extracted from the Surveillance, Epidemiology, and End Results program. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards models comparing the overall survival (OS) of individuals with and without a history of childhood cancer. OS was evaluated both overall and for specific cancers diagnosed in 50 or more childhood cancer survivors. Models accounted for potential confounders, including sex, race, age, treatment decade, histology, and disease stage. RESULTS: Compared with individuals with FPMs (n = 1,332,203), childhood cancer survivors (n = 1409) with an SPM experienced poorer OS (HR, 1.86; 95% CI, 1.72-2.02) after the study had accounted for cancer type, age, sex, race, and decade of diagnosis. A history of childhood cancer remained a poor prognostic factor for all specific cancers evaluated, including breast cancer (HR, 2.07; 95% CI, 1.63-2.62), thyroid cancer (HR, 3.59; 95% CI, 2.08-6.19), acute myeloid leukemia (HR, 2.38; 95% CI, 1.87-3.05), brain cancer (HR, 2.09; 95% CI, 1.72-2.55), melanoma (HR, 2.57; 95% CI,, bone cancer (HR, 1.88; 95% CI, 1.37-2.57), and soft-tissue sarcoma (HR, 2.44; 95% CI, 1.78-3.33). CONCLUSIONS: Compared with individuals without a prior cancer diagnosis, survivors of childhood cancer with an SPM experienced inferior outcomes. Survival disparities were observed for the most frequent SPMs diagnosed in childhood cancer survivors. Cancer 2019;125:3623-3630.
Hodgkin lymphoma (HL) histopathology is characterized by rare malignant Reed–Sternberg cells among an inflammatory infiltrate. We hypothesized that characteristics of inflammation in pediatric HL lesions would be reflected by the levels of inflammatory cytokines or chemokines in pre-therapy plasma of children with HL. The study objectives were to better define the inflammatory pre-therapy plasma proteome and identify plasma biomarkers associated with extent of disease and clinical outcomes in pediatric HL. Pre-therapy plasma samples were obtained from pediatric subjects with newly diagnosed HL and healthy pediatric controls. Plasma concentrations of 135 cytokines/chemokines were measured with the Luminex platform. Associations between protein concentration and disease characteristics were determined using multivariate permutation tests with false discovery control. Fifty-six subjects with HL (mean age: 13 years, range 3–18) and 47 controls were analyzed. The cytokine/chemokine profiles of subjects with HL were distinct from controls, and unique cytokines/chemokines were associated with high-risk disease (IL-10, TNF-α, IFN-γ, IL-8) and slow early response (CCL13, IFN-λ1, IL-8). TNFSF10 was significantly elevated among those who ultimately relapsed and was significantly associated with worse event-free survival. These biomarkers could be incorporated into biologically based risk stratification to optimize outcomes and minimize toxicities in pediatric HL.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.