Circulating TNF-RII, IP-10 and HGF are associated with severity of COVID-19 in oncologic patients.

The COVID-19 patients showed hyperinflammatory response depending on the severity of the disease but little have been reported about this response in oncologic patients that also were infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Sixty-five circulating cytokines/chemokines were quantified in 15 oncologic patients, just after SARS-CoV-2 infection and fourteen days later, and their levels were compared in patients who required hospitalisation by COVID-19 versus non-hospitalised patients. A higher median age of 72 years (range 61-83) in oncologic patients after SARS-CoV-2 infection was associated with hospitalisation requirement by COVID-19 versus a median age of 49 years (20-75) observed in the non-hospitalised oncologic patients (p = 0.008). Moreover, oncologic patients at metastatic stage or with lung cancer were significantly associated with hospitalisation by COVID-19 (p = 0.044). None of these hospitalised patients required ICU treatment. Higher basal levels of tumour necrosis factor receptor II (TNF-RII), interferon-γ (IFNγ)-induced protein 10 (IP-10) and hepatocyte growth factor (HGF) in plasma were significantly observed in oncologic patients who required hospitalisation by COVID-19. Higher TNF-RII, IP-10 and HGF levels after the SARS-CoV-2 infection in oncologic patients could be used as biomarkers of COVID-19 severity associated with hospitalisation requirements.

Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals. METHODS: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change. RESULTS: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline. CONCLUSIONS: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.

Levels of Soluble CD14 and Tumor Necrosis Factor Receptors 1 and 2 May Be Predictive of Death in Severe Coronavirus Disease 2019.

People infected with severe acute respiratory syndrome coronavirus 2 display a wide range of illness, from asymptomatic infection to severe respiratory distress resulting in death. We measured serum biomarkers in uninfected individuals and in individuals with mild, moderate, or critical coronavirus disease 2019 (COVID-19) disease. Levels of monocyte activation (soluble CD14 and fatty acid-binding protein 4) and inflammation (tumor necrosis factor receptors 1 and 2 [TNFR1 and TNFR2]) were increased in COVID-19 individuals, regardless of disease severity. Among patients with critical disease, individuals who recovered from COVID-19 had lower levels of TNFR1 and TNFR2 at hospital admission compared to these levels in patients with critical disease who ultimately died.

Effects of the SGLT2 inhibitor canagliflozin on plasma biomarkers TNFR-1, TNFR-2 and KIM-1 in the CANVAS trial.

AIMS/HYPOTHESIS: Higher plasma concentrations of tumour necrosis factor receptor (TNFR)-1, TNFR-2 and kidney injury molecule-1 (KIM-1) have been found to be associated with higher risk of kidney failure in individuals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in samples of the CANVAS study and examined the effect of the sodium-glucose cotransporter 2 inhibitor canagliflozin on these biomarkers and assessed whether the early change in these biomarkers predict cardiovascular and kidney outcomes in individuals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS). METHODS: Biomarkers were measured with immunoassays (proprietary multiplex assay performed by RenalytixAI, New York, NY, USA) at baseline and years 1, 3 and 6. Mixed-effects models for repeated measures assessed the effect of canagliflozin vs placebo on the biomarkers. Associations of baseline levels and the early change (baseline to year 1) for each biomarker with the kidney outcome were assessed using multivariable-adjusted Cox regression. RESULTS: In total, 3523/4330 (81.4%) of the CANVAS participants had available samples at baseline. Each doubling in baseline TNFR-1, TNFR-2 and KIM-1 was associated with a higher risk of kidney outcomes, with corresponding HRs of 3.7 (95% CI 2.3, 6.1; p < 0.01), 2.7 (95% CI 2.0, 3.6; p < 0.01) and 1.5 (95% CI 1.2, 1.8; p < 0.01), respectively. Canagliflozin reduced the level of the plasma biomarkers with differences in TNFR-1, TNFR-2 and KIM-1 between canagliflozin and placebo during follow-up of 2.8% (95% CI 3.4%, 1.3%; p < 0.01), 1.9% (95% CI 3.5%, 0.2%; p = 0.03) and 26.7% (95% CI 30.7%, 22.7%; p < 0.01), respectively. Within the canagliflozin treatment group, each 10% reduction in TNFR-1 and TNFR-2 at year 1 was associated with a lower risk of the kidney outcome (HR 0.8 [95% CI 0.7, 1.0; p = 0.02] and 0.9 [95% CI 0.9, 1.0; p < 0.01] respectively), independent of other patient characteristics. The baseline and 1 year change in biomarkers did not associate with cardiovascular or heart failure outcomes. CONCLUSIONS/INTERPRETATION: Canagliflozin decreased KIM-1 and modestly reduced TNFR-1 and TNFR-2 compared with placebo in individuals with type 2 diabetes in CANVAS. Early decreases in TNFR-1 and TNFR-2 during canagliflozin treatment were independently associated with a lower risk of kidney disease progression, suggesting that TNFR-1 and TNFR-2 have the potential to be pharmacodynamic markers of response to canagliflozin.

Systemic inflammation and symptomatology in patients with prostate cancer treated with androgen deprivation therapy: Preliminary findings.

BACKGROUND: Increases in fatigue, depressive symptomatology, and cognitive impairment are common after the initiation of androgen deprivation therapy (ADT) for prostate cancer. To date, no studies have examined the potential role of inflammation in the development of these symptoms in ADT recipients. The goal of the current study was to examine circulating markers of inflammation as potential mediators of change in fatigue, depressive symptomatology, and cognitive impairment related to the receipt of ADT. METHODS: Patients treated with ADT for prostate cancer (ADT+; n = 47) were assessed around the time of the initiation of ADT and 6 and 12 months later. An age- and education-matched group of men without a history of cancer (CA-; n = 82) was assessed at comparable time points. Fatigue, depressive symptomatology, and cognitive impairment were assessed with the Fatigue Symptom Inventory, the Center for Epidemiological Studies Depression Scale, and a battery of neuropsychological tests, respectively. Circulating markers of inflammation included interleukin 1 receptor antagonist (IL-1RA), interleukin 6 (IL-6), soluble tumor necrosis factor receptor II (sTNF-RII), and C-reactive protein (CRP). RESULTS: Fatigue, depressive symptomatology, and serum IL-6 increased significantly over time in the ADT+ group versus the CA- group; rates of cognitive impairment also changed significantly between the groups. No significant changes in IL-1RA, sTNF-RII, or CRP over time were detected. Treatment-related increases in IL-6 were associated with worsening fatigue but not depressive symptomatology or cognitive impairment. CONCLUSIONS: Results of this preliminary study suggest that increases in circulating IL-6, perhaps due to testosterone inhibition, may play a role in fatigue secondary to receipt of ADT. Additional research is needed to determine whether interventions to reduce circulating inflammation improve fatigue in this population.

Biomarker profiles of endothelial activation and dysfunction in rare systemic autoimmune diseases: implications for cardiovascular risk.

OBJECTIVES: Vasculopathy is an important hallmark of systemic chronic inflammatory connective tissue diseases (CICTD) and is associated with increased cardiovascular risk. We investigated disease-specific biomarker profiles associated with endothelial dysfunction, angiogenic homeostasis and (tissue) inflammation, and their relation to disease activity in rare CICTD. METHODS: A total of 38 serum proteins associated with endothelial (dys)function and inflammation were measured by multiplex-immunoassay in treatment-naive patients with localized scleroderma (LoS, 30), eosinophilic fasciitis (EF, 8) or (juvenile) dermatomyositis (34), 119 (follow-up) samples during treatment, and 65 controls. Data were analysed by unsupervised clustering, Spearman correlations, non-parametric t test and ANOVA. RESULTS: The systemic CICTD, EF and dermatomyositis, had distinct biomarker profiles, with 'signature' markers galectin-9 (dermatomyositis) and CCL4, CCL18, CXCL9, fetuin, fibronectin, galectin-1 and TSP-1 (EF). In LoS, CCL18, CXCL9 and CXCL10 were subtly increased. Furthermore, dermatomyositis and EF shared upregulation of markers related to interferon (CCL2, CXCL10), endothelial activation (VCAM-1), inhibition of angiogenesis (angiopoietin-2, sVEGFR-1) and inflammation/leucocyte chemo-attraction (CCL19, CXCL13, IL-18, YKL-40), as well as disturbance of the Angiopoietin-Tie receptor system and VEGF-VEGFR system. These profiles were related to disease activity, and largely normalized during treatment. However, a subgroup of CICTD patients showed continued elevation of CXCL10, CXCL13, galectin-9, IL-18, TNFR2, VCAM-1, and/or YKL-40 during clinically inactive disease, possibly indicating subclinical interferon-driven inflammation and/or endothelial dysfunction. CONCLUSION: CICTD-specific biomarker profiles revealed an anti-angiogenic, interferon-driven environment during active disease, with incomplete normalization under treatment. This warrants further investigation into monitoring of vascular biomarkers during clinical follow-up, or targeted interventions to minimize cardiovascular risk in the long term.

Comparison of serum cytokine profiles in macrophage activation syndrome complicating different background rheumatic diseases in children.

OBJECTIVES: To compare the cytokines involved in the development of macrophage activation syndrome (MAS) in different background rheumatic diseases and to identify serum biomarkers for MAS diagnosis. METHODS: Serum neopterin, IL-6, IL-18 and soluble TNF receptor (sTNFR) type I (sTNFR-I) and type II (sTNFR-II) levels were determined using ELISA in 12 patients with SLE, including five with MAS; 12 patients with JDM, including four with MAS; 75 patients with Kawasaki disease (KD), including six with MAS; and 179 patients with systemic JIA (s-JIA), including 43 with MAS. These results were compared with the clinical features of MAS. RESULTS: Serum neopterin, IL-18 and sTNFR-II levels were significantly higher during the MAS phase than during the active phase in patients with all diseases. Furthermore, serum sTNFR-I levels were significantly higher during the MAS phase than during the active phase in patients with SLE, KD and s-JIA. Receiver operating characteristic (ROC) curve analysis revealed that serum sTNFR-I levels for SLE, serum IL-18 levels for JDM, and serum sTNFR-II levels for KD and s-JIA had the highest areas under the ROC curve. Serum levels of these cytokines were significantly and positively correlated with serum ferritin levels. CONCLUSIONS: Overproduction of IFN-γ, IL-18 and TNF-α might be closely related to the development of MAS. Serum levels of sTNFR-I for SLE, IL-18 for JDM, and sTNFR-II for KD and s-JIA might be useful diagnostic markers for the transition from active phase to MAS.

Cross-sectional study of plasma Axl, ferritin, IGFBP4 and sTNFR2 as biomarkers of disease activity in childhood-onset SLE: A study of the Pediatric Nephrology Research Consortium.

OBJECTIVE: To evaluate the performance of 4 plasma protein markers for detecting disease activity in childhood-onset systemic lupus erythematosus (SLE) patients. METHODS: Eighty-three consecutive pediatric patients fulfilling ≥4 ACR criteria for SLE and twenty-five healthy controls were prospectively recruited for serological testing of 4 protein markers identified by antibody-coated microarray screen, namely Axl, ferritin, IGFBP4 and sTNFR2. SLE disease activity was assessed using SLEDAI-2000 score. Fifty-seven patients had clinically active SLE (SLEDAI score ≥4, or having a flare). RESULTS: The plasma concentrations of Axl and ferritin were significantly higher in patients with active SLE than inactive SLE. Plasma Axl levels were significantly higher in active renal versus active non-renal SLE patients. Levels of Axl, ferritin and IGFBP4 correlated significantly with SLEDAI scores. Levels of Axl, IFGBP4 and sTNFR2 inversely correlated with plasma complement C3 levels. Only plasma Axl and ferritin levels correlated with degree of proteinuria. These markers were more specific, but less sensitive, in detecting concurrent SLE activity than elevated anti-dsDNA antibody titer or decreased C3. Ferritin and IGFBP4 levels were more specific for concurrent active lupus nephritis than anti-dsDNA or C3. Plasma ferritin was the best monitor of global SLE activity, followed by C3 then Axl, while both Axl and C3 were best monitors of clinical lupus nephritis activity. CONCLUSION: In childhood-onset SLE patients, plasma ferritin and Axl perform better than traditional yardsticks in identifying disease activity, either global or renal. The performance of these plasma markers should be explored further in longitudinal cohorts of SLE patients.

Association between circulating tumor necrosis factor receptors and oral bacterium in patients receiving hemodialysis: a cross-sectional study.

BACKGROUND: High levels of tumor necrosis factor (TNF) receptors (TNFRs; TNFR1 and TNFR2), markers of inflammation, have been reported as significant predictors of mortality in hemodialysis patients. Porphyromonas gingivalis is a major pathogenic bacterium involved in periodontitis, which induces systemic inflammation. We investigated the association between the abundance of P. gingivalis in saliva and serum TNFR levels in hemodialysis patients. METHODS: A cross-sectional study was conducted on 121 hemodialysis patients visiting a clinic in the Tokyo metropolitan area. Medical interviews and examinations, comprehensive dental examinations, bacterial examinations for P. gingivalis in saliva, and measurements of circulating TNFR levels were conducted. Multiple linear regression analysis was performed to evaluate the association between the number of P. gingivalis and circulating TNFR levels. RESULTS: TNFR1 and TNFR2 were positively correlated with high-sensitivity C-reactive protein (hsCRP). Severe periodontitis was significantly associated with the number of P. gingivalis in saliva but not serum TNFR levels. The number of P. gingivalis was significantly associated with both TNFR1 and TNFR2 levels in sera after adjusting for age, sex, body mass index, smoking status, history of diabetes, prior cardiovascular disease events, serum levels of hsCRP and albumin, and severity of periodontitis [for TNFR1: coefficient 0.76, 95% confidence interval (CI) 0.14-1.37, p = 0.02; for TNFR2: coefficient 0.95, 95% CI 0.09-1.80, p = 0.03]. CONCLUSION: Circulating TNFR levels are associated with the number of P. gingivalis in saliva after adjusting for relevant clinical factors.

Patients with obstructive sleep apnea have suppressed levels of soluble cytokine receptors involved in neurodegenerative disease, but normal levels with airways therapy.

PURPOSE: Obstructive sleep apnea (OSA) results in systemic intermittent hypoxia. By one model, hypoxic stress signaling in OSA patients alters the levels of inflammatory soluble cytokines TNF and IL6, damages the blood brain barrier, and activates microglial targeting of neuronal cell death to increase the risk of neurodegenerative disorders and other diseases. However, it is not yet clear if OSA significantly alters the levels of the soluble isoforms of TNF receptors TNFR1 and TNFR2 and IL6 receptor (IL6R) and co-receptor gp130, which have the potential to modulate TNF and IL6 signaling. METHODS: Picogram per milliliter levels of the soluble isoforms of these four cytokine receptors were estimated in OSA patients, in OSA patients receiving airways therapy, and in healthy control subjects. Triplicate samples were examined using Bio-Plex fluorescent bead microfluidic technology. The statistical significance of cytokine data was estimated using the nonparametric Wilcoxon rank-sum test. The clustering of these high-dimensional data was visualized using t-distributed stochastic neighbor embedding (t-SNE). RESULTS: OSA patients had significant twofold to sevenfold reductions in the soluble serum isoforms of all four cytokine receptors, gp130, IL6R, TNFR1, and TNFR2, as compared with control individuals (p = 1.8 × 10-13 to 4 × 10-8). Relative to untreated OSA patients, airways therapy of OSA patients had significantly higher levels of gp130 (p = 2.8 × 10-13), IL6R (p = 1.1 × 10-9), TNFR1 (p = 2.5 × 10-10), and TNFR2 (p = 5.7 × 10-9), levels indistinguishable from controls (p = 0.29 to 0.95). The data for most airway-treated patients clustered with healthy controls, but the data for a few airway-treated patients clustered with apneic patients. CONCLUSIONS: Patients with OSA have aberrantly low levels of four soluble cytokine receptors associated with neurodegenerative disease, gp130, IL6R, TNFR1, and TNFR2. Most OSA patients receiving airways therapy have receptor levels indistinguishable from healthy controls, suggesting a chronic intermittent hypoxia may be one of the factors contributing to low receptor levels in untreated OSA patients.

Plasma Biomarkers of Tubular Injury and Inflammation Are Associated with CKD Progression in Children.

BACKGROUND: After accounting for known risk factors for CKD progression in children, clinical outcomes among children with CKD still vary substantially. Biomarkers of tubular injury (such as KIM-1), repair (such as YKL-40), or inflammation (such as MCP-1, suPAR, TNF receptor-1 [TNFR-1], and TNFR-2) may identify children with CKD at risk for GFR decline. METHODS: We investigated whether plasma KIM-1, YKL-40, MCP-1, suPAR, TNFR-1, and TNFR-2 are associated with GFR decline in children with CKD and in subgroups defined by glomerular versus nonglomerular cause of CKD. We studied participants of the prospective CKiD Cohort Study which enrolled children with an eGFR of 30-90 ml/min per 1.73 m2 and then assessed eGFR annually. Biomarkers were measured in plasma collected 5 months after study enrollment. The primary endpoint was CKD progression, defined as a composite of a 50% decline in eGFR or incident ESKD. RESULTS: Of the 651 children evaluated (median age 11 years; median baseline eGFR of 53 ml/min per 1.73 m2), 195 (30%) had a glomerular cause of CKD. Over a median follow-up of 5.7 years, 223 children (34%) experienced CKD progression to the composite endpoint. After multivariable adjustment, children with a plasma KIM-1, TNFR-1, or TNFR-2 concentration in the highest quartile were at significantly higher risk of CKD progression compared with children with a concentration for the respective biomarker in the lowest quartile (a 4-fold higher risk for KIM-1 and TNFR-1 and a 2-fold higher risk for TNFR-2). Plasma MCP-1, suPAR, and YKL-40 were not independently associated with progression. When stratified by glomerular versus nonglomerular etiology of CKD, effect estimates did not differ significantly. CONCLUSIONS: Higher plasma KIM-1, TNFR-1, and TNFR-2 are independently associated with CKD progression in children.

Serum TNFRII: A promising biomarker for predicting the risk of subcentimetre lung adenocarcinoma.

Early diagnosis of lung adenocarcinoma requires effective risk predictors. TNFRII was reported to be related to tumorigenesis, but remained unclear in lung cancer. This research set out to investigate the relationship between the sTNFRII (serum TNFRII) level and the risk of lung adenocarcinoma less than 1 cm in diameter. Seventy-one pairs of subcentimetre lung adenocarcinoma patients and healthy controls were analysed through multiplex bead-based Luminex assay and found a significantly lower expression of sTNFRII in patients with subcentimetre lung adenocarcinoma than that in the healthy controls (P < .001), which was further verified through ONCOMINE database analysis. Increased levels of sTNFRII reduced the risk of subcentimetre lung adenocarcinoma by 89% (P < .001). Patients with a higher level of BLC had a 2.70-fold (P < .01) higher risk of subcentimetre adenocarcinoma. Furthermore, a higher BLC/TNFRII ratio was related to a 35-fold higher risk of subcentimetre adenocarcinoma. TNFRII showed good specificity, sensitivity and accuracy (0.72, 0.75 and 0.73, respectively), with an AUC of 0.73 (P < .001). In conclusion, the present study assessed the value of sTNFRII as a potential biomarker to predict the risk of subcentimetre lung adenocarcinoma and provided evidence for the further use of TNFRII as an auxiliary marker in the diagnosis of subcentimetre lung adenocarcinoma.

Interplay of TNF-α, soluble TNF receptors and oxidative stress in coronary chronic total occlusion of the oldest patients with coronary heart disease.

BACKGROUND: The interplay of tumour necrosis factor-α (TNF-α) and oxidative stress was related to severities of coronary atherosclerosis and congestive heart failure. We tried to identify TNF-α, soluble tumour necrosis factor-α receptor-1 (sTNFR-1), soluble tumour necrosis factor-α receptor-2 (sTNFR-2) and oxidative stress as potential non-invasive diagnostic and therapeutic biomarkers for coronary chronic total occlusion (CCTO) in the oldest patients with coronary heart disease (CHD). METHODS: We determined the expression levels of TNF-α, sTNFR-1, sTNFR-2, oxidative stress biomarkers (malondialdehyde [MDA], aldosterone [ALD], angiotensin II [Ang II], and high sensitivity C-reactive protein [hs-CRP]) in oldest patients with CCTO. RESULTS: The levels of TNF-α, sTNFR-1, sTNFR-2, MDA, ALD, Ang II and hs-CRP were increased in oldest patients with CCTO (P < 0.001). The CCTO of oldest patients with CHD may involve the interplay of TNF-α, sTNFR-1, sTNFR-2 and oxidative stress. CONCLUSIONS: The TNF-α, sTNFR-1, sTNFR-2 and oxidative stress could be considered as potential non-invasive diagnostic and therapeutic biomarkers for CCTO in the oldest patients with CHD.

Comparison of serum biomarkers for the diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis during tocilizumab therapy.

BACKGROUND: To compare the accuracy of serum biomarkers for the diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA) during tocilizumab therapy. METHODS: Serum cytokine levels of neopterin, IL-18, C-X-C motif chemokine ligand 9, soluble tumor necrosis factor receptor (sTNFR)-I, and sTNFR-II were determined by enzyme-linked immunosorbent assay in 36 patients with MAS complicating s-JIA including 12 patients receiving tocilizumab. Furthermore, the serum sTNFR-II/I ratio was compared with the clinical features of MAS. RESULTS: The levels of all serum cytokines at MAS diagnosis were significantly lower in the tocilizumab-treated group than in the tocilizumab-untreated group. In contrast, the serum sTNFR-II/I ratio at MAS diagnosis was comparable between the tocilizumab-treated and the tocilizumab-untreated groups. The receiver operating characteristic curve analysis revealed that the area under the curve and cut-off values of sTNFR-II/I ratio were 0.9722 and 4.71, respectively. The serum sTNFR-II/I ratio, which was significantly elevated in patients with MAS complicating s-JIA, was correlated positively with disease activity. CONCLUSIONS: These findings suggest that the serum sTNFR-II/I ratio might be a useful indicator to evaluate disease activity in MAS complicating s-JIA and a useful diagnostic marker for the transition from active-phase s-JIA to MAS even in tocilizumab-treated patients. IMPACT: This is the first study to analyze the role of tocilizumab in modifying the serum levels of biomarkers used for the diagnosis of MAS complicating s-JIA. We found the biomarker for the diagnosis of MAS complicating s-JIA during tocilizumab therapy. We hope our results might be useful for the development of a new criteria for the diagnosis of MAS complicating s-JIA in patients treated with tocilizumab in future.

Analysis of Serum Markers with Regard to Treatment Procedures in Advanced Stage Prostate Cancer Patients.

BACKGROUND Biomarkers predicting the efficacy of treatment for locally limited prostate cancer are greatly needed. This knowledge could improve the classification of patients for different methods of treatment and enable better recognition of groups with higher risk of biological recurrence. We prospectively assessed serial blood levels of apoptotic biomarkers and correlated them with response to treatment and clinical factors. MATERIAL AND METHODS Blood was collected from 25 patients with prostate cancer before and after surgery, 16 healthy volunteers with benign prostatic hyperplasia (BPH), and 14 patients with metastasized disease. Immunoenzymatic methods were used to determine circulating apoptotic and inflammatory mediators, including tumor necrosis factor alpha (TNF-alpha), type I receptor (TNFRI), and type II receptor (TNFRII); FAS ligand (FasL); TNF-related apoptosis-inducing ligand (TRIAL); caspase 8 (Cas8); caspase 9 (Cas9); DNA methylation (metDNA); P-selectin; and high-sensitivity C-reactive protein. The total circulating fragments of cell-free DNA (cfDNA) were measured directly in serum. RESULTS Peripheral serum prostate-specific antigen increased rapidly together with cfDNA. A negative correlation was noted between tumor volume and TNFRI and TNFRII. Postsurgery P-selectin level was decreased, and metDNA and TNFRII levels were increased. Three comparisons were made between patient groups: surgical vs. BPH; surgical vs. palliative; and palliative vs. BPH. TNFRI, TNFRII, metDNA, P-selectin, Cas8, and FasL were shown to have significant roles. CONCLUSIONS The study indicated significant roles for cfDNA, both TNF receptors, metDNA, and P-selectin as serum biomarkers in patients with prostate cancer.

Association of type and intensity of physical activity with plasma biomarkers of inflammation and insulin response.

Several biological mechanisms linking physical activity with cancer have been proposed. However, the influence of specific components of physical activity (volume, type and intensity), and their interaction with adiposity and diet, on cancer-related biomarkers remain unclear. We used cross-sectional data on 7,219 men in the Health Professionals Follow-up Study (1992-1994) with C-reactive protein (CRP), interleukin-6 (IL6), tumor necrosis factor alpha receptor 2 (TNFαR2), adiponectin, C-peptide and triglycerides/high-density lipoprotein cholesterol ratio (TG/HDL). Details on physical activity, diet and adiposity were assessed by questionnaires. We used multivariable-adjusted linear regression analyses to estimate relative concentrations of biomarkers by physical activity. Total physical activity was favorably associated with all biomarkers in a fairly linear manner. Comparing the highest (63+ metabolic equivalent (MET)-hr/week) to the lowest (0-8.9 MET-hr/week) physical activity groups, the percent relative difference in concentration of biomarkers was -31% for CRP, -22% for IL6, -8% for TNFαR2, +9% for adiponectin, -22% for C-peptide, and -20% for TG/HDL. These differences were modestly attenuated after adjustment for adiposity. For the same total MET-hours of physical activity, the association was stronger for men engaging in both aerobic and resistance exercises compared to those engaging in aerobic only. However, no difference was found between those engaging in vigorous activities (≥20% of total MET-hours) compared to those who did smaller amount of vigorous activities. Physical activity showed similar associations for these biomarkers regardless of adiposity and dietary pattern. In conclusion, high physical activity, preferably aerobic plus resistance training, was associated with favorable cancer-related biomarkers.

Exploration of potential prognostic biomarkers in aflibercept plus FOLFIRI in Japanese patients with metastatic colorectal cancer.

Aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second-line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty-two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy-eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and at pre-dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end-products binding protein, insulin-like growth factor-binding protein 1, interleukin-8, kallikrein 5, pulmonary surfactant-associated protein D, tissue inhibitor of metalloproteinases 1, tenascin-C, and tumor necrosis factor receptor 2. None correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.

Cognitive performance in survivors of breast cancer and markers of biological aging.

BACKGROUND: Biological aging pathways accelerated by cancer treatments may be a mechanism for cognitive impairment in cancer survivors. The goal of the current study was to examine whether indicators of biological aging, namely elevated levels of DNA damage, reduced telomerase enzymatic activity, and shorter peripheral blood mononuclear cell (PBMC) telomere length (TL) would be related to cognitive function in a cohort of survivors of breast cancer. METHODS: The authors evaluated a cross-sectional sample of 94 women aged 36 to 69 years who were treated for early-stage breast cancer 3 to 6 years previously. Leukocyte DNA damage, PBMC telomerase enzymatic activity, PBMC TL, and the inflammatory marker soluble tumor necrosis factor receptor II (sTNF-RII) were determined from blood samples. Cognitive function was assessed using a neuropsychological test battery and self-report. Linear regression models examined the relationship between biological aging predictors and cognitive outcomes. RESULTS: Both higher DNA damage and lower telomerase were found to be statistically significantly related to lower executive function scores adjusting for age, body mass index, race, years from treatment, and intelligence score (standardized coefficients [B], -0.23 and 0.30; all P values <.05). In addition, lower telomerase activity was associated with worse attention and motor speed scores (B values, 0.30 and 0.24; P <.05). sTNF-RII and TL were found to be unrelated to any of the neurocognitive domains. CONCLUSIONS: The results of the current study suggest a significant association between measures of biological aging and objective measures of cognitive performance in survivors of breast cancer. Future prospective studies are needed to confirm a causal role of biological aging as a driver of declines in cognitive function after cancer treatment.

Extensive serum biomarker analysis in patients with macrophage activation syndrome associated with systemic lupus erythematosus.

The present study employed an antibody array that simultaneously detects 174 cytokines to identify cytokines involved in the development of macrophage activation syndrome (MAS) associated with systemic lupus erythematosus (SLE) with a view to elucidating potential predictive markers. Eight SLE patients, including four with MAS, were analyzed. Levels of 31 cytokines were significantly elevated in the MAS phase compared with those in the active phase of SLE. Among these cytokines, the MAS/active phase ratios of CXCL9 and soluble tumor necrosis factor receptor II (sTNFR-II) were highest. Elevated serum CXCL9 and sTNFR-II levels during the MAS phase were confirmed by ELISA and were strongly correlated with other inflammatory markers, reflecting the disease activity of MAS associated with SLE. These results highlight the clinical significance of serum CXCL-9 and sTNFR-II levels, and indicate they may be useful biomarkers for the diagnosis of MAS associated with SLE.

Inflammation and breast density among female Chinese immigrants: exploring variations across neighborhoods.

PURPOSE: We examined associations of inflammation with breast density, a marker of breast cancer risk, among female Chinese immigrants and explored whether associations varied by neighborhood environment. METHODS: Assessments of serum C-reactive protein (CRP), soluble tumor necrosis factor receptor 2 (sTNFR2), and breast density were performed among 401 Chinese immigrants across the Philadelphia region. Participant addresses were geocoded, with the majority residing in areas representing traditional urban enclaves (i.e., Chinatown and South Philadelphia) or an emerging enclave with a smaller, but rapidly growing Chinese immigrant population (i.e., the Near Northeast). The remainder was classified as residing in non-enclaves. RESULTS: In multivariable adjusted regression models, CRP was inversely associated with dense breast area (p = 0.01). Levels of sTNFR2 were also inversely associated with dense breast area, but these associations varied by neighborhood (interaction p = 0.01); specifically, inverse associations were observed among women residing in the emerging enclave (p = 0.03), but not other neighborhoods. CONCLUSIONS: Among Chinese immigrant women, aggregate analyses that do not take neighborhood context into consideration can mask potential variations in association of inflammatory markers with breast density. Future studies should consider how neighborhood contextual factors may contribute to differential risk pathways.