Baseline IL-6 Levels Research Articles

CPAP Does Not Reduce Inflammatory Biomarkers in Patients With Coronary Artery Disease and Nonsleepy Obstructive Sleep Apnea: A Randomized Controlled Trial.

Objectives Obstructive sleep apnea (OSA) and enhanced vascular inflammation coexist in patients with coronary artery disease (CAD). Continuous positive airway pressure (CPAP) is first-line treatment for OSA with daytime sleepiness. This analysis of data from the RICCADSA (Randomized Intervention with CPAP in Coronary Artery Disease and Sleep Apnea) trial investigated the effects of CPAP on inflammatory markers in patients with CAD and nonsleepy OSA. Methods This single-center, randomized, controlled, open-label trial enrolled consecutive revascularized patients with nonsleepy OSA (apnea-hypopnea index >15/h; Epworth Sleepiness Scale score <10). Levels of high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF-α) were measured in blood samples taken at baseline (median 94 days after revascularization) and after 1 year of follow-up in patients randomized to CPAP or no-CPAP. Results A total of 220 patients with analyzable blood samples at baseline and 1 year were included. Baseline IL-6 levels were significantly lower in the CPAP versus no-CPAP group (median 3.1 pmol/L [interquartile range 1.3-5.7] vs. 4.2 pmol/L [2.0-8.9], respectively; p = .005). At 1-year follow-up, median IL-6 levels were significantly reduced in both groups (to 2.2 pmol/L [1.2-3.9] in the CPAP group and to 2.2 [1.2-4.7] in no-CPAP group; both p < .001 vs. baseline). IL-8, hs-CRP, and TNF-α did not change significantly from baseline. There was no association between CPAP adherence and changes in inflammatory marker levels. Conclusions In patients with stable CAD and nonsleepy OSA, inflammatory biomarkers did not change significantly over time except for IL-6 levels, which reduced to the same extent in the CPAP and no-CPAP groups. Clinical Trial Registration ClinicalTrials.gov, ID: NCT00519597; researchweb.org, VGSKAS-4731.

IL-8 and thrombospondin-1 as prognostic markers in patients with metastatic colorectal cancer receiving bevacizumab.

PurposeBevacizumab (B) plus chemotherapy (CT) is a common choice for first-line treatment of metastatic colorectal cancer. Molecular predictors of B efficacy have still not been identified. We analyzed the role of 22 angiogenesis-associated proteins in patient outcome.Patients and methodsSerum samples collected at baseline and at the first clinical evaluation were available for 58 patients enrolled in the randomized multicenter ITACa trial and who received CT+ B. Serum protein levels were determined using multiplex ELISA.ResultsPatients with baseline ≥145 pg/mL IL-8 showed shorter median progression-free survival and overall survival (OS) than those with lower levels (6.5 vs 6. 12.6 months; HR 7.39, P<0.0001 and 8.7 vs 28.8 months, HR 7.68, P<0.001, respectively). Moreover, patients with baseline thrombospondin-1 levels ≥12,000 ng/mL had a better median OS than those with lower levels (34.5 vs 13.1 months, HR 0.43, P=0.007). Patients with a ≥20% reduction in IL-8 levels from baseline to first clinical evaluation showed a better progression-free survival and OS than the others (HR 0.41, P=0.005 and HR 0.43, P=0.007, respectively).ConclusionBaseline IL-8 and thrombospondin-1 levels and reduced IL-8 during B treatment could represent potential prognostic markers in metastatic colorectal cancer.

BIOMARKERS OF LEAKY GUT ARE RELATED TO INFLAMMATION AND REDUCED PHYSICAL FUNCTION IN UNHEALTHY OLDER ADULTS

Age-related leaky gut is hypothesized to be causative for the inflammatory burden of older adults. A relationship between the leaky gut biomarkers and physical function has been observed in healthy older adults, however it is not known whether co-morbid conditions alters this connection. Therefore, we measured biomarkers of inflammation and leaky gut within a cohort of older patients (60–79 years of age; n=288) enrolled into a weight loss and lifestyle intervention study (CLIP-1). Circulatory lipopolysaccharide binding protein 1 (LBP-1), soluble cluster of differentiation (sCD)14, pro-inflammatory cytokines were measured along with a panel of physical function measures. LBP-1 was strongly associated with increases in inflammatory cytokines interleukin (IL)-6, IL-6 soluble receptor, and IL-8 levels in the unadjusted correlation analysis. sCD14 associations were not as strong thus we chose LBP-1 in regression analyses. LBP-1 and inflammatory outcomes remained significantly associated even after adjustment for age, gender, and body mass index (BMI). LBP-1 was also significantly related to physical functional measures after adjusting for age, gender, and BMI. Log transformed 400m walk time (p=0.003) and log transformed IL-8 levels (p<0.001) were positively associated with LBP-1 even when adjusted for baseline IL-6 levels. The lifestyle interventions resulted in improved BMI and some physical function measures, however biomarkers of leaky gut and inflammation did not change. Leaky gut remains an important factor in inflammatory burdens and physical function in older adults with comorbid conditions. Strategies other than weight loss and exercise are needed to improve gut barrier function and limit inflammation in older persons.

Pro-inflammatory effects of extracellular Hsp70 and cigarette smoke in primary airway epithelial cells from COPD patients

Extracellular Hsp70 (eHsp70) can activate immune cells via Toll-like receptors (TLR) 2 and 4, and induce cytokine synthesis. The aim of this study was to explore inflammation-associated effects of eHsp70 alone and in combination with cigarette smoke extract (CSE) in primary bronchial epithelial cells.We assessed IL-6 and IL-8 concentrations, TLR2, TLR4 and Hsp70 mRNA expressions, and mitogen-activated protein kinases (MAPKs) activation induced by recombinant human (rh) Hsp70, CSE or their combinations in normal human bronchial epithelial cells (NHBE) obtained commercially, and primary bronchial epithelial cells isolated from non-COPD lung donors (PBEC) or COPD patients (PBEC COPD).Baseline levels of IL-6 and IL-8 were significantly higher in PBEC COPD than in non-COPD PBECs. Upon rhHsp70 stimulation, IL-6 and IL-8 were significantly increased, with the strongest response in COPD-derived PBECs. CSE alone elevated cytokine secretion in all examined cells. rhHsp70 and CSE had antagonistic interactions on IL-8 release in PBECs from COPD patients, while the addition of rhHsp70 further increased CSE-induced IL-6 secretion in NHBE cells. rhHsp70 and CSE alone decreased TLR2 and TLR4 mRNA expression in COPD-derived PBECs. In non-COPD PBECs, combined treatments decreased only TLR2 mRNA expression. Hsp70 mRNA expression, as indicator of intracellular Hsp70, which may have anti-inflammatory effects, was reduced in COPD-derived cells upon exposure to CSE and rhHsp70 alone, but not with their combinations. Contrary to this, in PBECs from lung donors only combined treatments supressed Hsp70 gene expression. CSE activated JNK and p38 MAPKs, while rhHsp70 increased activation of c-Jun kinase in NHBE cells.Collectively, both eHsp70 and CSE induce pro-inflammatory responses in PBECs from non-COPD as well as COPD donors, but in combination antagonistic effects were observed in COPD-derived cells. These effects may be related to the regulation of TLR2/4 and might lead to modulation of inflammation with possible deleterious consequences for COPD patients.

Chronic inflammation and risk of lung cancer in older adults in the health, aging and body composition cohort study.

We examined the association between three inflammatory markers (Interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) and incident lung cancer using baseline, updated, and averaged inflammatory measures in older adults. We fitted multivariable Cox models to assess whether circulating levels of inflammation markers were associated with incident lung cancers in the Health Aging, Body and Composition (HealthABC) prospective cohort of 3075 older adults aged 70-79 years at baseline. IL-6 and CRP were measured biennially, whereas TNF-α was measured at baseline. Baseline levels of IL-6 were significantly associated with incident lung cancer risk in a model that adjusted for age, gender, race, and site (Model 1) (Hazard RatioT3 vs. T1: 3.34, 95% Confidence Interval: 1.91, 5.85) and in a model adjusted for health factors linked to chronic inflammation (Model 2) (HR T3 vs. T1: 2.57, 95% CI: 1.41, 4.65). The associations observed in time-updated IL-6 (HR T3 vs. T1: 2.47, 95% CI: 1.43, 4.28), cumulatively averaged IL-6 (HR T3 vs. T1: 2.47, 95% CI: 1.43, 4.35), and baseline CRP levels (HR T3 vs. T1: 1.85, 95% CI: 1.11, 3.08) with incident lung cancer in Model 1 were not statistically significant in Model 2. Baseline CRP and IL-6 levels were associated with increased risk of lung cancer in Model 1 and both models, respectively. Chronic IL-6 inflammation, as quantified by repeated measures was associated with incident lung cancer in Model 1, but not Model 2. Further research is needed to understand the role of CRP and IL-6 in lung carcinogenesis.

Increased IL-6 Levels Correlate with Severity of Lung Damage and Early Death in Tanzanian Patients with Pulmonary Tuberculosis

Background: There is an urgent need for clinically relevant host biomarkers of protection, disease activity, response to treatment and predicting long term tissue damage for patients with pulmonary tuberculosis (TB). We studied cytokine biomarkers in a longitudinal cohort of patients with pulmonary TB in order to predict pulmonary tissue damage or death. Methods: Two hundred and thirtyfour (234) Tanzanian adult patients (96 HIV-positive) with newly diagnosed pulmonary TB and seven healthy controls were enrolled. Serum concentrations of IFN-gamma, TNF-α, IL-2, IL-6, IL-10. IL-17A and IL-21 were determined using enzyme-linked immunosorbent assay (ELISA) kits on day 1, two and five months after anti-TB treatment initiation. Postero-anterior chest X-rays (CXR) were scored for lung injury. Correlations between cytokine concentrations, mortality and lung injury were determined using multivariate logistic regression. Findings: Patients with TB had significantly higher median levels of IL-6 (3863pg/ml) at diagnosis compared to healthy controls (11 pg/ml). Increased IL-6 levels significantly correlated with survival (RR = 0.95; 95% CI 0.91 - 0.98; P < 0.01) and were associated with severe lung injury (RR 1.03; 95% 1.01 - 1.05; P = 0.02). Among patients with severe lung injury at diagnosis, every 100pg/ml increase in baseline IL-6 levels was accompanied with 6% increased risk for residual lung damage post-TB treatment (RR = 1.06; 95%CI 1.01 - 1.13). Anti-TB therapy was associated with reduction in serum cytokine levels except for IL-6, which did not decrease with treatment (P = 0.003). Interpretation: Increased IL-6 levels correlate with severity of lung damage in patients with pulmonary TB regardless of HIV status. IL-6 may serve as a target for host-directed therapy in patients with pulmonary TB. Funding: This study was supported by grants from the Swedish International Development Cooperation Agency (SIDA); Vinnova and Swedish Heart and Lung Foundation (Hjartlungfonden) to MM. AZ and MM acknowledge support from the European and Developing Countries Clinical Trials Partnership (EDCTP). Declaration of Interest: The authors declare no conflicts of interest Ethical Approval: Ethical clearance was granted by the Muhimbili University of Health and Allied Health sciences (MUHAS) Senate Research and Publications committee (Ref. No. RP/AEC/VOL.XII dated November 23rd2011). Written informed consent was obtained from all study participants prior to inclusion.

Plasma Biomarkers of Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy

To evaluate plasma brain specific proteins and cytokines as biomarkers of brain injury in newborns with hypoxic-ischemic encephalopathy (HIE) and, secondarily, to assess the effect of erythropoietin (Epo) treatment on the relationship between biomarkers and outcomes. A study of candidate brain injury biomarkers was conducted in the context of a phase II multicenter randomized trial evaluating Epo for neuroprotection in HIE. Plasma was collected at baseline (<24 hours) and on day 5. Brain injury was assessed by magnetic resonance imaging (MRI) and neurodevelopmental assessments at 1 year. The relationships between Epo, brain-specific proteins (S100B, ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1], total Tau, neuron specific enolase), cytokines (interleukin [IL]-1β, IL-6, IL-8, IL-10, IL-12P70, IL-13, interferon-gamma [IFN-γ], tumor necrosis factor alpha [TNF-α], brain-derived neurotrophic factor [BDNF], monocyte chemoattractant protein-1), and brain injury were assessed. In 50 newborns with encephalopathy, elevated baseline S100B, Tau, UCH-L1, IL-1β, IL-6, IL-8, IL-10, IL-13, TNF-α, and IFN-γ levels were associated with increasing brain injury severity by MRI. Higher baseline Tau and lower day 5 BDNF were associated with worse 1 year outcomes. No statistically significant evidence of Epo treatment modification on biomarkers was detected in this small cohort. Elevated plasma brain-specific proteins and cytokine levels in the first 24 hours of life are associated with worse brain injury by MRI in newborns with HIE. Only Tau and BDNF levels were found to be related to neurodevelopmental outcomes. The effect of Epo treatment on the relationships between biomarkers and brain injury in HIE requires further study. ClinicalTrials.gov: 01913340.

Long-Term Protective Effect of N-Acetylcysteine against Amikacin-Induced Ototoxicity in End-Stage Renal Disease: A Randomized Trial.

The aim of the study is to evaluate the long-term protective effect of N-acetylcysteine (NAC), an antioxidant agent, against aminoglycoside (AG)-induced ototoxicity. A total of 40 patients receiving continuous ambulatory peritoneal dialysis (CAPD) and having their first peritonitis attacks and planned to be treated with AGs were enrolled in the study. They were randomized into 2 groups: 1 group received additional NAC and the other did not. All patients underwent hearing tests with pure tone audiometry (PTA) after the diagnosis, at 1 month and 12 months and at the same time the tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels were measured. Patients taking NAC had better hearing test results in both ears at 1 month except 2,000 Hz for the left ear, which wasn't significantly different between the 2 groups. Although patients taking NAC had generally better PTA results at 12 months, differences between the 2 groups were not statistically significant. Baseline IL-6 level was significantly higher in the NAC group than the control group. Both TNF-α and IL-6 levels at 1 month were significantly lower in the NAC group than in the control group. On the other hand, there was no significant difference between the 2 groups in terms of TNF-α and IL-6 levels at 12 months. The results of the current study showed that NAC, a potent anti-inflamatory drug, may be otoprotective, but that the effect is not long-lasting.

The production of IL-6 in acute epileptic seizure: A video-EEG study

Experimental and clinical reports highlight the role of cytokines in pathophysiological processes in underpinning epilepsy, but the clinical data remains somewhat limited. The levels of Interleukin (IL)-6 were measured in serum from 49 patients with refractory epilepsy [temporal lobe epilepsy (TLE, n=23), extratemporal lobe epilepsy (XLE, n=22), and idiopathic generalized epilepsy (IGE, n=4)] before and after the first verified seizure (IS; index seizure) during inpatient video-electroencephalographic (VEEG) monitoring. The levels of IL-6 increased significantly at all time points between 3h and 24h after the IS compared to the baseline. IL-6 concentrations were significantly higher at the 3h and 6h time point after tonic-clonic seizures (TCS) compared to the situation with simple partial and complex partial seizures. An IS duration longer than 100s, low baseline IL-6 level and <10 seizures/month in patients with TLE were associated with an increase in IL-6 concentrations during the 24h after the IS. In patients with TLE, the maximum change in IL-6 levels after IS was significantly higher than in XLE. If the baseline level of IL-6 was low (under 5pg/ml), seizures induced a significant elevation in both absolute and relative values in TLE patients but not in XLE. In patients with ≤10 seizures per month during the last year, the maximum change was higher than in patients with >10 seizures. If the total seizure burden during registration was ≥100s, the IL-6 increase was significantly higher than if it were under 100s. The results of this study highlight the complexity of factors involved in the seizure induced production of the inflammatory cytokine, IL-6. The major factor is the epilepsy type i.e. increased production of IL-6 in TLE compared to XLE. The response to a single seizure in TLE is dependent on the previous seizure frequency and the baseline IL-6 concentration.

Baseline and postoperative levels of C-reactive protein and interleukins as inflammatory predictors of atrial fibrillation following cardiac surgery: a systematic review and meta-analysis.

Postoperative atrial fibrillation (POAF) is a leading arrhythmia with high incidence and serious clinical implications after cardiac surgery. Cardiac surgery is associated with systemic inflammatory response including increase in cytokines and activation of endothelial and leukocyte responses. This systematic review and meta-analysis aimed to determine the strength of evidence for evaluating the association of inflammatory markers, such as C-reactive protein (CRP) and interleukins (IL), with POAF following isolated coronary artery bypass grafting (CABG), isolated valvular surgery, or a combination of these procedures. We conducted a meta-analysis of studies evaluating measured baseline (from one week before surgical procedures) and postoperative levels (until one week after surgical procedures) of inflammatory markers in patients with POAF. A compre-hensive search was performed in electronic medical databases (Medline/PubMed, Web of Science, Embase, Science Direct, and Google Scholar) from their inception through May 2017 to identify relevant studies. A comprehensive subgroup analysis was performed to explore potential sources of heterogeneity. A literature search of all major databases retrieved 1014 studies. After screening, 42 studies were analysed including a total of 8398 patients. Pooled analysis showed baseline levels of CRP (standard mean difference [SMD] 0.457 mg/L, p < 0.001), baseline levels of IL-6 (SMD 0.398 pg/mL, p < 0.001), postoperative levels of CRP (SMD 0.576 mg/L, p < 0.001), postoperative levels of IL-6 (SMD 1.66 pg/mL, p < 0.001), postoperative levels of IL-8 (SMD 0.839 pg/mL, p < 0.001), and postoperative levels of IL-10 (SMD 0.590 pg/mL, p < 0.001) to be relevant inflammatory parameters significantly associated with POAF. Perioperative inflammation is proposed to be involved in the pathogenesis of POAF. Therefore, perioperative assessment of CRP, IL-6, IL-8, and IL-10 can help clinicians in terms of predicting and monitoring for POAF.

Plasma levels of alarmin HNPs 1\u20133 associate with lung dysfunction after cardiac surgery in children

BackgroundEarly onset of lung injury is considerable common after cardiac surgery and is associated with increasing in morbidity and mortality, but current clinical predictors for the occurrence of this complication always have limited positive warning value. This study aimed to evaluate whether elevated plasma levels of human neutrophil peptides (HNPs) 1–3 herald impaired lung function in infants and young children after cardiac surgery necessitating cardiopulmonary bypass (CPB).MethodsConsecutive children younger than 3 years old who underwent cardiac surgery were prospectively enrolled. Plasma concentrations of HNPs 1–3 and inflammatory cytokines were measured before, and immediately after CPB, as well as at 1 h, 12 h, and 24 h after CPB.ResultsThirty patients were enrolled, 18 (60%) of whom were infants. Plasma levels of HNPs 1–3 and the pro-inflammatory cytokine interleukin-6 (IL-6) significantly increased immediately after CPB (P < 0.001), while IL-8 increased 1 h after the CPB operation (P = 0.002). The anti-inflammatory cytokine IL-10 levels were also significantly elevated immediately after CPB compared with the baseline (P < 0.001). The stepwise multiple linear regression analysis showed that the plasma HNPs 1–3 levels immediately after CPB was independent correlated with the declined lung function, as reflected by the PaO2/FiO2 ratio on the first 2 days after operation (for the first day: OR, −1.067, 95% CI, −0.548 to −1.574; P < 0.001; for the second day: OR, −0.667, 95% CI, −0.183 to −1.148; P = 0.009) and prolonged mechanical ventilation time (OR, 0.039, 95% CI, 0.005 to 0.056; P = 0.011). Plasma levels of HNPs 1–3 and IL-10 returned to the baseline values, while IL-6 and IL-8 levels remained significantly higher than baseline 24 h after CPB (P ≤ 0.01).ConclusionsElevated HNPs 1–3 levels immediately after CPB correlate with impaired lung function, and HNPs 1–3 could serve as a quantifiable early alarmin biomarker for onset of lung injury in infants and young children undergoing cardiac surgery with CPB.

Use of autologous radiolabelled neutrophils to quantify lung neutrophil retention in healthy volunteers, experimental LPS-induced lung inflammation, and COPD

Background: There is a need for non-invasive imaging protocols to support early-phase studies in man that test the efficacy of drugs targeting neutrophilic inflammation. We aimed to quantify lung neutrophil accumulation and circulating biomarkers in healthy volunteers after saline or inhaled lipopolysaccharide (LPS) administration and in COPD patients with the use of radiolabelled neutrophils and single-photon-emission computed tomography (SPECT/CT). Methods: This was an exploratory study conducted at the Clinical Unit Cambridge (GSK) and Cambridge University Hospitals. 20 stable COPD patients (stage 2/3) and 18 healthy volunteers were studied. Healthy volunteers received either inhaled saline (n=6) or LPS (50 μg; n=12) 90 minutes or 180 minutes before injection of radiolabelled cells. Neutrophils were isolated using hetastarch red cell sedimentation and percoll-plasma gradients and labelled with 99mTechnetium-hexamethylpropyleneamine oxime. SPECT was performed over the thorax/upper abdomen at 45 minutes, 2 hours, 4 hours, and 6 hours post-injection of cells. Circulating IL-6 levels were measured. Pulmonary neutrophil clearance was determined using Patlak-Rutland analysis based on whole-lung volumes of interest drawn separately at each time-point. Parametric tests were applied. Ethics approval was received (14/EE/1273). Study registration number NCT02551614. Findings: We observed an increased rate (mean±1 SD) of accumulation of labelled neutrophils into the lungs of COPD patients (0.0022±0.00097 mL/min/mL lung-blood-distribution volume) and LPS-challenged subjects (0.0025±0.0008 mL/min/mL lung-blood-distribution volume) compared with saline-challenged subjects (0.0006±0.00025 mL/min/mL lung-blood-distribution volume; p=0.0003 and p<0.0001, respectively). Mean baseline IL-6 levels were elevated in COPD patients compared with healthy volunteers (1.453±1.058 pg/mL versus 0.48±0.24 pg/mL). LPS challenge had induced increased circulating IL-6 levels (7.54±2.72 pg/mL) 9 hours post-challenge. Interpretation: These data verify the use of inhaled LPS as a reliable, in vivo, model of lung neutrophilia and support the use of SPECT/CT and autologous radiolabelled neutrophils to quantify 'whole-lung' neutrophil clearance. This platform can be used to assess the efficacy of drugs that target lung neutrophil retention in COPD or after LPS challenge. Funding: GSK funded this study (number 201463). Conflicts of interest: We declare that we have no conflicts of interest.

CPAP Does Not Reduce Inflammatory Biomarkers in Patients With Coronary Artery Disease and Nonsleepy Obstructive Sleep Apnea: A Randomized Controlled Trial

Obstructive sleep apnea (OSA) and enhanced vascular inflammation coexist in patients with coronary artery disease (CAD). Continuous positive airway pressure (CPAP) is first-line treatment for OSA with daytime sleepiness. This analysis of data from the RICCADSA (Randomized Intervention with CPAP in Coronary Artery Disease and Sleep Apnea) trial investigated the effects of CPAP on inflammatory markers in patients with CAD and nonsleepy OSA. This single-center, randomized, controlled, open-label trial enrolled consecutive revascularized patients with nonsleepy OSA (apnea-hypopnea index >15/h; Epworth Sleepiness Scale score <10). Levels of high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF-α) were measured in blood samples taken at baseline (median 94 days after revascularization) and after 1 year of follow-up in patients randomized to CPAP or no-CPAP. A total of 220 patients with analyzable blood samples at baseline and 1 year were included. Baseline IL-6 levels were significantly lower in the CPAP versus no-CPAP group (median 3.1 pmol/L [interquartile range 1.3-5.7] vs. 4.2 pmol/L [2.0-8.9], respectively; p = .005). At 1-year follow-up, median IL-6 levels were significantly reduced in both groups (to 2.2 pmol/L [1.2-3.9] in the CPAP group and to 2.2 [1.2-4.7] in no-CPAP group; both p < .001 vs. baseline). IL-8, hs-CRP, and TNF-α did not change significantly from baseline. There was no association between CPAP adherence and changes in inflammatory marker levels. In patients with stable CAD and nonsleepy OSA, inflammatory biomarkers did not change significantly over time except for IL-6 levels, which reduced to the same extent in the CPAP and no-CPAP groups. ClinicalTrials.gov, ID: NCT00519597; researchweb.org, VGSKAS-4731.

Prospective translational study investigating circulating predictors of outcome to first-line pazopanib in patients with metastatic renal cell carcinoma (mRCC)

Background: We investigated plasma levels of circulating angiogenic factors (CAFs) involved in angiogenesis in patients (pts) with mRCC treated with first-line pazopanib to assess potential biomarkers of clinical outcome. Patients and Methods: Pts (n = 25) with mRCC receiving first-line pazopanib at Istituto Nazionale Tumori of Milan between July 2015 and February 2017 were prospectively enrolled in the study. Plasma samples were obtained at different time-points: before treatment and every 4 weeks until radiographic disease progression (PD) as per RECIST 1.1. assessed by CT scan every 12 weeks. Levels of 7 CAFs of interest including: IL-6, IL-8, SDF-1, VEGF-A, HGF, Osteopontin and E-selectin were quantified by Luminex® technology. Baseline levels and changes during treatment were analyzed for association with efficacy (progression-free survival [PFS] and objective response). Results: 21 out of 25 pts enrolled were evaluated. The median follow up was 8 months (IQR 5.1 months). Overall plasma levels of SDF-1 (p<.0001), VEGF-A (p=.0052) and IL-8 (p=.0275) showed the highest modulation during treatment. At the end of first pazopanib cycle (week 4) plasma VEGF-A levels were significantly higher in pts with partial response (PR) than in pts with PD. IL-8 levels were significantly higher in pts with PD vs pts with PR at the time of response (p=.0481). Moreover baseline IL-8 levels were significantly higher in pts with PD vs pts with stable disease (SD) (p=.0181). Mean levels of SDF-1 (p=.0022), HGF (p=.0002), osteopontin (p<.0001) and E-selectin (p<.0001) were significantly associated with best response (PR vs SD vs PD) while IL-6 levels were significantly associated with PFS (p=.0082). The 6 months and one year estimated PFS rate was 73% and 63% respectively. Conclusions: Treatment with first-line pazopanib is associated with variation of CAFs levels. Week 4 levels of VEGF-A as well as pretreatment levels of IL-8 showed the strongest correlation with PD suggesting that monitoring these CAFs during treatment may be useful for identifying patients likely to respond. These findings warrant further investigation in larger trials.

THE EFFECT OF ABATACEPT ON BLOOD BIOMARKERS IN PATIENTS WITH RHEUMATOID ARTHRITIS

Objective:to estimate changes in the cytokine profile in patients receiving abatacept (ABC).Subjects and methods.The investigation enrolled 44 patients with rheumatoid arthritis (RA) who had been unsuccessfully treated with disease-modifying antirheumatic drugs and biological agents. A control group included 16 healthy donors. The majority of patients were women who were positive for rheumatoid factor (RF) (80%) and antibodies to cyclic citrullinated peptide (ACCP) (79.5%); the mean age was 49.6±13.9 years; the median disease duration was 2 [1.4; 3] years with high RA activity (mean DAS28, 5.2±0.8). The serum concentrations of interleukin (IL) 1β, IL-6, IL-17AF, tumor necrosis factor-α (TNF-α), VEGF-A, IP-10, and YKL-40 were measured by enzyme immunoassay before and 6 months after ABC therapy. Disease activity was assessed using DAS28 every 3 months. ABC was infused intravenously according to the standard regimen.Results and discussion. The patients with RA as compared with the control group had significantly elevated levels of IL-6 (2.4 [1.1; 6.4] and 0.7 [0.62; 1.0] pg/ml; p=0.0002), YKL-40 (97 [68.4; 97.9] and 64 [52.4; 107.5] pg/ml; p=0.03), IP-10 (21 [12.9; 49.8] and 14 [9.2; 15.2] pg/ml, respectively; p=0.005). ABC caused a significant decrease in RA activity after 3 months of therapy (p&lt;0.05). Following 6 months, 86% of the patients achieved good and moderate EULAR responses; low RA activity according to DAS28 was recorded in 52%. ABC induced significant decreases in the concentrations of IL-6 to 1.29 [0.9; 2.2] pg/ml (p=0.0006) and IP-10 to 14 [7.5; 28] pg/ml (p=0.007) after 6 months of therapy. A similar trend was observed when assessing changes in the concentration of matrix metalloproteinase 3 (MMP-3), which reduced from 30.1 [13; 82] to 10 [7.4; 55] pg/ml (p=0.0003), and in that of RF, which declined from 218 [9.6; 187] to 159 [9.7; 155] pg/ml (p=0.02). The lower levels of IL-6 (r=0.5) and IP-10 (r=0.32) significantly correlated with a decrease in DAS28 (p&lt;0.05). There was a trend towards a more pronounced reduction in disease activity in patients positive for ACCP and antibodies to modified citrullinated vimentine (AMCV). The percentage of non-responders to therapy in the ACCP- and AMCV-negative groups was nearly twice as high as in those who were positive for these antibodies (27.2 and 16%; 26.7 and 14.8%, respectively), but these differences failed to reach significance. However, after 6-month of follow-up, the percentage of non-respondents in the AMCV-negative group was significantly higher than in the AMCV-positive group (20% and 0%, respectively; p=0.03). The patients who did not respond to ABC therapy had higher baseline levels of IL-6 (p=0.03) and YKL-40 (p=0.02). Conclusion.ABC therapy results in a substantial reduction in the concentration of the proinflammatory cytokines IL-6 and IP-10, as well as MMP-3 and RF. The lower levels of IL-6 and IP-10 significantly correlated with a decrease in RA activity. There was a tendency towards a more pronounced reduction of disease activity in ACCP- and AMCV-positive patients. The high baseline levels of IL-6 and YKL-40 and the absence of AMCV may suggest that ABC therapy can be ineffective.

Prospective, Controlled Study of Invasiveness and Post-Aggression Metabolism in Patients Undergoing Robotic-Assisted Radical Prostatectomy

Objectives: To evaluate in a prospective, controlled, nonrandomized study the surgical stress and acute-phase systemic response in robotic-assisted laparoscopic prostatectomy (RALP) compared to open radical retro-pubic prostatectomy (ORRP) by measuring humoral mediators. Methods: Forty consecutive patients undergoing either RALP or ORRP were prospectively included to assess the extent of systemic response. Blood samples were collected before surgery (T1), at the time of prostatectomy (T2), at the time of wound closure (T3), and 12 h (T4), 24 h (T5), and 48 h (T6) after surgery, and assayed for interleukins (IL-6 and IL-10), C-reactive protein (CRP), and hemoglobin. A 2-sided p < 0.05 was considered to indicate significance. Results: Baseline levels of IL-6, IL-10, and CRP were comparable in both arms of the study. IL-6 and IL-10 increased in both groups during surgery and reached maximum levels at 12 and 24 h after surgery. The RALP and RRP groups differed significantly at T2 (p = 0.009), T3 (p = 0.046), T5 (p = 0.05) and T6 (p = 0.0007) for IL-6, and at T3 (p = 0.05) and T4 (p = 0.05) for IL-10. CRP levels differed significantly at 48 h postoperative (p = 0.0053). The maximum levels of all 3 mediators in the RALP group were significantly lower than those in the open surgery group. Patients in the RALP group experienced less pain from day 2 to 4 according to the Visual Analog Scale (p < 0.05). Conclusions: The study suggests that IL-6 and IL-10 are useful objective markers for surgical stress and that tissue trauma and activation of post-aggression metabolism seem to be less in RALP compared to ORRP.

Pre-treatment interleukin-6 levels strongly affect bone erosion progression and repair detected by magnetic resonance imaging in rheumatoid arthritis patients.

To examine the relationship between MRI structural damage and repair and plasma inflammatory cytokines in patients with RA. A total of 88 newly diagnosed, untreated RA patients were enrolled. Contrast MRI of the dominant hand and X-rays of the hands and feet were performed at baseline and 1 year later. MR images were evaluated using RA MRI scoring, and X-ray. Progression of bone erosion and repair were observed more frequently in MRI than in X-rays (erosion, 52% vs 26%, P < 0.001; repair, 26% vs 15%, P = 0.003, respectively). Baseline IL-6 levels and seropositivity were independent relevant factors for MRI erosion progression, with IL-6 having stronger effect than seropositivity. A receiver operating characteristic curve identified the baseline IL-6 level of 7.6 pg/ml for predicting erosion progression during 1 year, with an area under the curve of 0.82; higher IL-6 levels resulted in more erosion progression. Baseline low IL-6 was also an independent predictor for MRI erosion repair. In newly diagnosed, untreated RA patients, baseline plasma IL-6 levels are responsible for 1-year MRI bone erosion progression and repair.

High baseline levels of interleukin-8 in leukocytes and urine predict tumor recurrence in non-muscle invasive bladder cancer patients receiving bacillus Calmette–Guerin therapy: A long-term survival analysis

ABSTRACTBacillus Calmette–Guerin (BCG) therapy for non-muscle invasive bladder cancer (NMIBC) can significantly reduce the risk of recurrence and progression. However, BCG therapy may fail in up to a half of treated patients and may also cause toxicities. Biomarkers to predict the effectiveness of BCG therapy are desired to pre-select patients for BCG therapy to maximize efficacy while avoid unnecessary toxicity. Twelve cytokines were measured in 100 blood and 112 urine samples using cytokine antibody array and correlated with recurrence-free survival in overall and BCG-treated NMIBC patients. Of the 12 cytokines, interleukin (IL) -2, IL-8, IL-10, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon (IFN)-γ were measurable in more than 30% of peripheral blood leukocyte (PBL) samples. Only IL-8 in PBL was found to be significantly associated with tumor recurrence, especially in those who receiving BCG therapy (hazard ratio [HR] = 4.24; 95% confidence interval [95%CI] = 1.65–10.88; p = 0.003). The median recurrence-free survival time for BCG-treated patients with high baseline IL-8 levels were much shorter than those with low IL-8 levels (7.9 vs. >78.4 mo, p = 0.004). Furthermore, consistent associations between urinary IL-8 levels and tumor recurrence in patients receiving BCG therapy were observed in 58 pre-BCG and 54 long-term post-BCG-treated urine samples (both p ≤ 0.005). High urinary baseline IL-8 level also predicted shorter time to tumor recurrence in NMIBC patients (both p ≤ 0.004). By using antibody array-based technology in two separate cohorts of NMIBC patients, we found that PBL and urinary baseline IL-8 levels were significantly associated with tumor recurrence after BCG therapy.

The Effect of Probiotics on Interleukin-8 and Intestinal Flora in Irritable Bowel Syndrome in Hospital of Zagazig University

Background: Irritable Bowel Syndrome (IBS) is a common functional Gastrointestinal disorder, characterized by recurrent abdominal pain or discomfort in association with change in stool form or stool frequency . These symptoms have a relapsing and remitting course. The pathophysiology of IBS is not yet well understood. A probiotic is a live organism that when ingested in enough amounts, causes a health benefit to the host. While probiotics have been used on an empiric basis to manage IBS symptoms, several recent researches provide a more logical basis for probiotics use in this field. Objectives: This study was performed to assess the effect of daily use of probiotic on IBS symptoms, pro-inflammatory cytokine (IL-8 level) and intestinal flora. Methodology: This study included total number of 90 patients complaining of IBS symptoms. These patients comprised 22 men and 68 women. They were divided into two groups: Group I included 45 patients complaining of IBS symptoms and treated with probiotics and group II included 45 patients complaining of IBS symptoms and treated with symptomatic treatment. All patients in the study were subjected to blood sampling for measurement of interleukin- 8 and stool sampling for stool culture. Patients of group1 were treated with probotic daily for 4 weeks (Lactobacillus delbruekii and Lactobacillus fermentum 10 billions twice daily). Results: There were statistical significance difference between Group I and Group II in abdominal pain improvement with increase number of improved cases among group1. Regarding improvement time it was statisticaly significant shorter in Group I comparing to group II. There was no statistical significance difference between Group I and Group II in base line IL-8 level. While there was statistical significance differences between them in its level after 1 month. Regarding comparison within the same group there was highly statistical significance differences between base line IL-8 levels and after 1 month results in group I. While there were statistical significance differences between Group I and Group II in IL-8 level after 1 month. There were no statistical significance difference between Group I and Group II regarding base line and after 1 month stool culture results. Regarding comparison within the same group there were highly statistical significance differences between base line stool culture results and after 1 month results in both groups with higher significance difference in group I . Conclusion: Probiotics are an effective treatment option for IBS patients. Daily use of probiotic will improve IBS symptoms, decrease IL-8 level and restore normal intestinal flora.

Multi-analyte analysis of cytokines that predict outcomes in patients with hepatocellular carcinoma treated with radiotherapy.

AIMTo analyze cytokine levels and to identify their association with outcome in patients with hepatocellular carcinoma (HCC) treated with radiotherapy (RT).METHODSPatients with HCC who were treated with RT were eligible for this prospective study. Blood samples were collected before and after RT, and serum cytokine levels including interleukin (IL)-1, IL-6, IL-8, IL-10, IL-12, and tumor necrosis factor-α were analyzed.RESULTSBetween 2008 and 2009, 51 patients were enrolled in this study. Baseline IL-6 level was high in patients with a history of pre-RT treatment. Median survival was 13.9 mo with alpha-fetoprotein (AFP) as a significant factor (P = 0.020). Median failure-free survival (FFS) for infield, outfield-intrahepatic and extrahepatic failures were 23.3, 11.5 and 12.0 mo, respectively. Sex and baseline IL-6 level were associated with infield FFS, and baseline IL-10 level was correlated with outfield-intrahepatic FFS. For extrahepatic FFS, AFP was significant (P = 0.034). Patients with a baseline IL-6 level of ≥ 9.7 pg/mL showed worse infield FFS (P = 0.005), and this significance was observed only in treatment-non-naïve patients (P = 0.022).CONCLUSIONIn addition to AFP, cytokines seem useful in predicting infield and outfield-intrahepatic failure. Serum cytokines could be useful biomarkers for predicting RT outcome in HCC.