Elevated Interleukin-6 Levels Research Articles

Elevated inflammation and decreased platelet activity is associated with poor outcomes after traumatic brain injury

The inflammatory processes following traumatic brain injury (TBI) have not been fully characterized. We hypothesize that differences in systemic cytokine/chemokine (CC) levels are associated with TBI clinical outcomes. To test this hypothesis, we examined systemic levels of CCs and their relationship with patient outcomes. Plasma from acute TBI subjects was collected at 24–48 h, and the CC levels were measured using a multiplex 41-plex-kit. Clinical outcomes were assessed using the modified Rankin scale (mRS) with good outcomes defined as mRS ≤ 3 and poor outcome as mRS ≥ 4. The differences in CC concentrations between groups were then compared using the Mann-Whitney U test. Seventy-six acute TBI subjects were included in this study. In the mRS ≥ 4 group, interleukin-6 (IL-6) and interleukin-10 (IL-10) were elevated, indicating early activation of immune reaction and modulation. Simultaneously, PDGFAA and RANTES were lower in the mRS ≥ 4 group. Poor outcomes after TBI were associated with elevated levels of IL-6 and IL-10 and lower levels of PDGFAA and RANTES within 24–48 h after injury.

Brain Region That Produces Spinal Fluid Implicated in Psychosis

Back to table of contents Previous article Next article Clinical & ResearchFull AccessBrain Region That Produces Spinal Fluid Implicated in PsychosisNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:1 Sep 2019https://doi.org/10.1176/appi.pn.2019.8a15AbstractAn analysis of over 1,300 MRI scans suggests a connection between an enlarged choroid plexus and cognitive problems among patients with a psychotic disorder.In 1921, researchers first proposed a link between psychosis and abnormalities in the choroid plexus—a cluster of cells and blood vessels at the base of the brain responsible for making cerebrospinal fluid (CSF) and maintaining a barrier between the brain and spinal column. But since then, little research has examined this link. Now a study in the July issue of The American Journal of Psychiatry has brought this brain region back into the fold.The study, which involved an analysis of over 1,300 brain scans, found that the choroid plexus is significantly larger in patients with psychosis compared with their relatives or healthy people without psychosis. This analysis included patients with multiple psychotic disorders, which suggests choroid plexus enlargement may be a common trait shared across the psychosis spectrum.Paulo Lizano, M.D., Ph.D., an instructor of psychiatry at Harvard Medical School, and colleagues analyzed MRI scans from participants in a nationwide psychosis study called B-SNIP. The sample included 223 patients with schizophrenia, 141 with schizoaffective disorder, and 190 with psychotic bipolar disorder. The researchers also analyzed the brain scans of 564 first-degree relatives without psychosis and 333 unrelated adults, also without psychosis.The comparison of scans showed that the choroid plexus was significantly enlarged in patients with a psychotic disorder relative to healthy controls, with family members falling in between. The increased choroid plexus volume was about the same regardless of whether the patients had schizophrenia, schizoaffective disorder, or bipolar disorder.What’s more, greater choroid plexus volume correlated with worse performance on cognitive tests in these patients, particularly in verbal fluency tests (in which patients have to provide as many words as possible in a certain category in a given time). Choroid plexus volume did not correlate with the severity of other psychosis symptoms like delusions or social withdrawal, however, suggesting that this abnormality specifically affects cognition.Since the analysis was based on MRI scans taken at a single point in time, Lizano cautioned that it is too early to determine whether the choroid plexus enlargement is a cause or consequence of psychosis or what mechanisms might contribute to the enlargement.However, as part of this study, the investigators also analyzed the composition of inflammatory proteins in blood samples that were available from 107 B-SNIP participants with psychosis and 52 healthy participants. This additional analysis revealed that patients with larger choroid plexuses also had elevated blood levels of the inflammatory biomarker interleukin 6 (IL-6). Several previous studies have found a connection between elevated levels of IL-6 and schizophrenia.“This suggests inflammation is part of the [disease] process [in psychosis], but we are in the early stages of this work and want to be cautious in how we interpret these findings,” Lizano told Psychiatric News. “However, the excitement in how neuroinflammation contributes to psychosis has ignited interest in [both] the choroid plexus and how it is involved in brain homeostasis.” He hopes the findings from this study will inspire a vibrant new field of choroid plexus research—only 100 years in the making.This study was supported by grants from the National Institute of Mental Health, National Center for Advancing Translational Sciences, the Commonwealth Research Center, and a Livingston Award from Harvard Medical School. ■“Association of Choroid Plexus Enlargement With Cognitive, Inflammatory, and Structural Phenotypes Across the Psychosis Spectrum” is posted here. ISSUES NewArchived

High Coping Self-Efficacy Associated With Lower Sweat Inflammatory Cytokines in Adults: A Pilot Study.

Chronic diseases, like diabetes and heart disease, are considered inflammatory conditions with elevated levels of the proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) and the anti-inflammatory cytokine interleukin-10 (IL-10). Disease progression is not consistent from person to person. Psychosocial factors are hypothesized to play a modifying role. Self-efficacy, the confidence in one's ability to perform well in a specific life domain or at a specific task, is associated with better health outcomes. Coping self-efficacy is confidence in one's ability to handle life's problems through emotional regulation, problem-solving, and social support. Little is known about associations between coping self-efficacy and inflammation. The purpose of this pilot study was to examine associations between coping self-efficacy and IL-6, IL-10, and TNF-α levels. This was a cross-sectional study conducted over two visits. Sociodemographic variables, chronic disease count, body mass index (BMI), and coping self-efficacy were collected. Inflammatory markers were collected via sweat using the sweat patch, a noninvasive collection device. Higher TNF-α and IL-10 levels were significantly associated with low coping self-efficacy (β = -.03, p = .028; β = -.017, p = .007, respectively) after adjustment for age, sex, race, BMI, and chronic disease count. IL-6 trended toward significance after adjustment as well (β = -.22, p = .054). This pilot study showed that high coping self-efficacy was associated with lower IL-6, IL-10, and TNF-α levels, indicating a potential buffering effect of high coping self-efficacy. Further longitudinal research with larger sample sizes is needed.

Increased interferon-1α, interleukin-10 and BLyS concentrations as clinical activity biomarkers in systemic lupus erythematosus

Background and objectiveTo analyse the association between interferon-1α (INF1α), interleukin-10 (IL-10) and BLyS concentrations and clinical activity in systemic lupus erythematosus (SLE). Patients and methodsA cross-sectional, observational study of 142 SLE patients and 34 healthy controls was performed, through a complete blood and urine test and review of their medical history. Serum concentration of INF1α, IL-10 and BLyS was determined by colorimetric methods. A biostatistical analysis was performed with R (3.3.2). Results69% of our SLE patients showed at least one cytokine increased. INF1α, IL-10 and BLyS are higher in SLE patients than in healthy controls (p<0.001, p=0.005 and p=.043, respectively), being INF1α the most frequent. Patients were categorised according to low or high concentrations of the three cytokines. We found a significant association between increased IL-10/INF1α concentrations and a higher clinical activity measured by SELENA-SLEDAI (p<0.0001) and, to a lesser extent, an association with increased INF1α/IL-10/BLyS concentrations. Elevated levels of IL-10/INF1α and INF1α/IL-10/BLyS related to increased C3-C4 consumption (p<0.001 and p=0.001, respectively) and anti-dsDNA titres (p=0.001 and p=0.002, respectively). Elevated INF1α/BLyS related to higher anti-dsDNA titres (p=0.004) and ENA positivity (p<0.001). Increased levels of INF1α/IL-10/BLyS related to positivity of ANAs (p<0.001) and APL (p=0.004). ConclusionsINF1α, IL-10 and BLyS are higher in SLE patients than in healthy controls. Increased IL-10 levels, regardless of whether or not there were also increased levels of BLyS and/or INF1α, was the cytokine that best fit with clinical activity in SLE measured with classic methods.

Inflammatory Cytokines Associated With Failure of Lower-Extremity Endovascular Revascularization (LER): A Prospective Study of a Population With Diabetes.

Peripheral artery disease (PAD) is one of the most relevant complications of diabetes. Although several pharmacological and revascularization approaches are available for treating patients with diabetes and PAD, an endovascular approach is often associated with postprocedural complications that can increase the risk for acute limb ischemia or amputation. However, no definitive molecular associations have been described that could explain the difference in outcomes after endovascular treatment in patients with diabetes, PAD, and chronic limb-threatening ischemia (CLTI). We evaluated the relationship between the levels of the main cytokines associated with diabetic atherosclerosis and the outcomes after endovascular procedures in patients with diabetes, PAD, and CLTI. A total of 299 patients with below-the-knee occlusive disease who were undergoing an angioplasty procedure were enrolled. The levels of key cytokines-osteoprotegerin (OPG), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP)-were measured, and major adverse limb events (MALE) and major adverse cardiovascular events (MACE) were assessed 1, 3, 6, and 12 months after the procedure. There was a linear trend from the lowest to the highest quartile for each cytokine at baseline and incident MALE. A linear association was also observed between increasing levels of each cytokine and incident MACE. Receiver operating characteristics models were constructed using clinical and laboratory risk factors, and the inclusion of cytokines significantly improved the prediction of incident events. We demonstrated that elevated OPG, TNF-α, IL-6, and CRP levels at baseline correlate with worse vascular outcomes in patients with diabetes, PAD, and CLTI undergoing an endovascular procedure.

Role of Interleukin-10 and Abdominopelvic Ultrasound as a Potential Predictor of Disease Severity in Dengue Hemorrhagic Fever.

IntroductionDengue viral infections are a major cause of morbidity and mortality in tropical/subtropical countries. Early and prompt detection of dengue hemorrhagic fever (DHF), though challenging, is helpful to identify an individual that would benefit from intensive therapy.ObjectiveThe goal of this study was to determine the plasma interleukin-10 (IL-10) levels in DHF patients at four to seven days of disease onset and 24 hours after the first sample. We also aimed to determine the association of plasma IL-10 levels and abdominopelvic ultrasound findings.MethodsA total of 50 registered DHF patients aged 15 to 50 years were recruited. Plasma IL-10 concentration measurements and abdominopelvic ultrasounds were performed. Patients were also categorized based on ultrasound grading I to IV (based on severity). Outcomes were described as recovery and shock. Platelet count and hematocrit percentages were also recorded.ResultsPlasma IL-10 levels were elevated in DHF patients and associated with fatal outcomes (p = 0.00). Binary regression-coefficient showed the direct effect of high levels of plasma IL-10 on the fatal outcome of patients 24 hours after the first sample (p = 0.04). Disease severity was predicted by a positive correlation between ultrasound grades and outcomes (p = 0.00). Spearman’s correlation coefficient found a highly significant inverse relationship between plasma IL-10 levels and platelet count after 24 hours (p = 0.01). However, a significant positive relationship was observed between elevated plasma IL-10 levels and hematocrit percentage after 24 hours (p = 0.01).ConclusionElevated plasma IL-10 levels and abdominopelvic ultrasonography are promising potential predictors of disease progression and fatal outcome in DHF patients.

MiR-182-5p contributes to intestinal injury in a murine model of Staphylococcus aureus pneumonia-induced sepsis via targeting surfactant protein D.

Sepsis is a severe clinical disease, which is resulted from the excessive host inflammation response to the infection. Growing evidence indicates that Staphylococcus aureus pneumonia is a significant cause of sepsis, which can lead to intestinal injury, inflammation, and apoptosis. Studies have shown that miR-182-5p can serve as a tumor oncogene or a tumor suppressive microRNA in various cancers, however, its biological role in sepsis is still uninvestigated. Here, we reported that miR-182-5p was obviously increased in S. aureus pneumonia mice models. Loss of miR-182-5p inhibited intestinal damage and intestinal apoptosis as indicated by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. In addition, we observed the lack of miR-182-5p altered the local inflammatory response to pneumonia in the intestine. Elevated tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were observed in intestinal tissue of pneumonia groups compared with the shams. Furthermore, miR-182-5p knockout (KO) pneumonia group demonstrated decreased levels of intestinal TNF-α and IL-6. Primary murine intestinal epithelial cells were isolated and cultured in our investigation. We exhibited downregulation of miR-182-5p repressed intestinal epithelial cells apoptosis and rescued the cell viability. Meanwhile, miR-182-5p caused elevated cell apoptosis and reduced cell proliferation. Moreover, the surfactant protein D (SP-D) binds with the bacterial pathogens and remove the pathogens and apoptotic bodies, which exhibits important roles in modulating immune responses. It was displayed in our study that SP-D was greatly decreased in pneumonia mice models. SP-D was predicted as a downstream target of miR-182-5p. These data concluded that miR-182-5p promoted intestinal injury in S. aureus pneumonia-induced sepsis via targeting SP-D.

Alopecia areata is characterized by dysregulation in systemic type 17 and type 2 cytokines, which may contribute to disease-associated psychological morbidity.

Alopecia areata (AA) is a common autoimmune disease, causing patchy hair loss that can progress to involve the entire scalp (totalis) or body (universalis). CD8+ NKG2D+ T cells dominate hair follicle pathogenesis, but the specific mechanisms driving hair loss are not fully understood. To provide a detailed insight into the systemic cytokine signature associated with AA, and to assess the association between cytokines and depression. We conducted multiplex analysis of plasma cytokines from patients with AA, patients with psoriatic arthritis (PsA) and healthy controls. We used the Hospital Anxiety and Depression Scale (HADS) to assess the occurrence of depression and anxiety in our cohort. Our analysis identified a systemic inflammatory signature associated with AA, characterized by elevated levels of interleukin (IL)-17A, IL-17F, IL-21 and IL-23 indicative of a type 17 immune response. Circulating levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25) were also significantly increased in AA. In comparison with PsA, AA was associated with higher levels of IL-17F, IL-17E and IL-23. We hypothesized that circulating inflammatory cytokines may contribute to wider comorbidities associated with AA. Our assessment of psychiatric comorbidity in AA using HADS scores showed that 18% and 51% of people with AA experienced symptoms of depression and anxiety, respectively. Using linear regression modelling, we identified that levels of IL-22 and IL-17E are positively and significantly associated with depression. Our data highlight changes in both type 17 and type 2 cytokines among people with AA, suggesting that complex systemic cytokine profiles may contribute both to the pathogenesis of AA and to the associated depression. What's already known about this topic? NKG2D+ CD8+ T cells cause hair loss in alopecia areata (AA) but the immunological mechanisms underlying the disease are not fully understood. AA is associated with changes in levels of interleukin (IL)-6, tumour necrosis factor-α, IL-1β and type 17 cytokines. Psychiatric comorbidity is common among people with AA. What does this study add? People with AA have increased plasma levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25), in addition to the type 17 cytokines IL-17A, IL-21, IL-23 and IL-17F. Levels of IL-17E and IL-22 positively predict depression score. What is the translational message? AA is associated with increased levels of multiple inflammatory cytokines, implicating both type 17- and type 2 immune pathways. Our data indicate that therapeutic strategies for treating AA may need to address the underlying type 17- and type 2 immune dysregulation, rather than focusing narrowly on the CD8+ T-cell response. An immunological mechanism might contribute directly to the depression observed in people with AA.

Successful application of CytoSorb®hemadsorption in an immunocompromised teenager with collapsing glomerulopathy, acute respiratory distress syndrome, and sepsis

CytoSorb® hemadsorption is an adjunctive therapy in order to reduce elevated cytokine levels of interleukin-6, interleukin-1, and tumor necrosis factor alpha. Here we present a successful administration of CytoSorb® hemadsorption in an immunocompromised pediatric patient with collapsing glomerulopathy, acute respiratory distress syndrome, and sepsis. Clinical observations of one patient. Case report. Data sources are clinical observation during patient management and patient's medical records if needed. The patient's consent was obtained prior to the study. A 17-year-old male with diarrhea was admitted to the hospital and was later found to have elevated creatinine levels and proteinuria. The renal biopsy was consistent with collapsing glomerulopathy and treatment with multi immunosuppressive agents including corticosteroids, mycophenolate mofetil, and rituximab coupled with several courses of hemodialysis and plasmapheresis were administered. During the hospital stay, Stenotrophomonas maltophilia bacteremia from the blood and the catheter cultures were identified. No clinical response was achieved, and patient developed severe sepsis despite antibiotics, intravenous immunoglobulin, and supportive management including albumin, platelet and erythrocyte concentrations, and fresh frozen plasma. CytoSorb® hemadsorption was then added to the ongoing treatment for three consecutive days. Subsequent to CytoSorb® hemadsorption, immediate laboratory and clinical response were observed. This is the successful clinical report of an immunocompromised teenager with collapsing nephropathy, sepsis, and multi-organ dysfunction syndrome treated with a combination of renal replacement therapy and CytoSorb® hemadsorption. The usage of CytoSorb® hemadsorption represents a novel approach to improve survival of the patients with multiple organ dysfunction and sepsis.

Interleukin-18 as a drug repositioning opportunity for inflammatory bowel disease: A Mendelian randomization study

Support from human genetics increases the probability of success in drug development. However, few examples exist of successful genomically-driven drug repositioning. Given that a Mendelian form of severe enterocolitis is due to up-regulation of the interleukin-18 (IL18) signaling pathway, and pharmacologic inhibition of IL18 has been shown to reverse this enterocolitis, we undertook a Mendelian randomization study to test the causal effect of elevated IL18 levels on inflammatory bowel disease susceptibility (IBD) in 12,882 cases and 21,770 controls. Mendelian randomization is an established method to assess the role of biomarkers in disease etiology in a manner that minimizes confounding and prevents reverse causation. Using three SNPs that explained almost 7% of the variance in IL18 level, we found that each genetically predicted standard deviation increase in IL18 was associated with an increase in IBD susceptibility (odds ratio = 1.22, 95% CI = 1.11–1.34, P-value = 6 × 10−5). This association was further validated in 25,042 IBD cases and 34,915 controls (odds ratio = 1.13, 95% CI = 1.05–1.20). Recently, an anti-IL18 monoclonal antibody, which decreased free IL18 levels, was found to be safe, yet ineffective in a phase II trial for type 2 diabetes. Taken together, these genomic findings implicated IBD as an alternative indication for anti-IL18 therapy, which should be tested in randomized controlled trials.

Elevated serum levels of interleukin-10 in adult-onset Still's disease are associated with disease activity.

To evaluate the serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) in patients with adult-onset Still's disease (AOSD), a rare, systemic, and multigenic inflammatory disease. The serum levels of IL-10, IL-1β, IL-6, IL-18, and TNF-α were examined by electrochemiluminescence assay. The serum levels of IL-10 were higher in AOSD patients than in healthy controls and positively correlated with systemic score, erythrocyte sedimentation rate (ESR), C-reactive protein level (CRP), ferritin, and inflammatory cytokine (IL-1β, IL-6, IL-18, and TNF-α) levels. Moreover, the levels of IL-10 were significantly higher in AOSD patients who had fever, sore throat, rash, lymphadenopathy, splenomegaly, pneumonia, and arthralgia than in patients who did not. IL-10 was increased in AOSD patients and correlated with disease activity. KEY POINTS: • In this manuscript, we confirmed the elevated serum levels of the anti-inflammatory cytokine IL-10 in AOSD patients, which was previously poorly defined. • We revealed for the first time that the levels of IL-10 were correlated with disease activity and inflammatory cytokine levels in AOSD.

Different inflammatory cytokines release after open and endovascular reconstructions influences wound healing.

Prodromal signs of a non-healing wound after revascularisation, which might be strictly linked with impending failure of vascular reconstructions, are associated with an inflammatory response mediated by several circulating adhesion molecules, extracellular endopeptidases, and cytokines. The aim of our study was to investigate the role of selected plasma biomarkers in the prediction of both wound healing and failure of infrapopliteal vein graft or percutaneous trans-luminal angioplasty (PTA) with selective stent positioning of the superficial femoral artery (SFA) in a population affected with critical limb ischaemia. A total of 68 patients who underwent either surgical or endovascular revascularisation of the inferior limb with autologous saphenous vein infrapopliteal bypass or PTA and selective stenting of the SFA were enrolled in our study. Patients were divided into two groups according to treatment: 41 patients were included in Group 1 (open surgery) and 27 in Group 2 (endovascular procedure). Plasma and blood samples were collected on the morning of surgery and every 6 months thereafter for up to 2 years of follow-up or until an occlusion occurred of either the vein bypass graft or the vessel treated endovascularly. Fifteen age-matched healthy male volunteers were considered a reference for biological parameters. Vascular cell adhesion molecule 1 [VCAM-1]/CD106, inter-cellular adhesion molecule-1 [ICAM-1]/CD54), interleukin-1 (IL-1), interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), and metalloproteinases (MMP)-2 and -9 plasma levels were measured with enzyme-linked immunosorbent assay (ELISA) kits. The mean observed time to heal of 54 wounds was 13 ± 4 months, with no statistically significant differences among the groups. The healing failure of the remaining wounds was strictly related to an unsuccessful open (n = 12) or endovascular (n = 8) treatment. The 2-year primary patency rate was 65% (SE = .09) in Group 1 and 52% (SE = .1) in Group 2. When compared with mean concentration values of Group 1, VCAM-1 and ICAM-1 were always significantly higher during follow-up in patients of Group 2 (P < .05). Furthermore, in the same group, IL-6 and tumour necrosis factor alpha (TNF-α) were found to be significantly higher at 6- and 12-month (P < .05) when compared with surgically treated patients. Cox regression analysis showed that elevated plasma levels of VCAM-1, ICAM-1, IL-6, and TNF-α during follow up were strongly related to impaired wound healing and/or revascularisation failure (P < .05). Elevated plasma levels of inflammatory markers VCAM-1, ICAM-1, IL-6, and TNF-α may be related to the failure of wound healing and revascularisation procedures. Interestingly, we have observed that endovascular treatments cause a higher level of these inflammation biomarkers when compared with a vein graft, although wound-healing and patency and limb salvage rates are not influenced.

Interleukin-6 as a biomarker in patients with hepatobiliary cancers.

The role of inflammation has been well established in many cancers, including hepatobiliary cancers. Elevated levels of interleukin-6 (IL-6), a pro-inflammatory marker, are associated with poor overall survival (OS) in hepatocellular carcinoma (HCC) patients. We performed a study to establish the role of IL-6 as a prognostic biomarker in both HCC and biliary cancer patients and further assessed the impact of IL-6 on pain score and performance status, two parameters that affect the quality of life. We evaluated 91 patients with newly diagnosed unresectable hepatobiliary cancer and compared them with age, gender and BMI matched healthy controls. We found that IL-6 levels were elevated in hepatobiliary cancer patients compared to healthy controls. Higher levels of IL-6 were associated with poor prognosis, elevated pain scores and poor performance status in patients. Interestingly, we found an association between elevated IL-6 levels and the presence of portal vein thrombosis (PVT) at the time of cancer diagnosis. This study suggests that IL-6 is an important prognostic biomarker in hepatobiliary cancers, where elevated levels are not only associated with a worse survival but also linked to an inferior quality of life.

PS1324 GENETIC SIMILARITY BETWEEN WALDENSTRÖM MACROGLOBULINEMIA AND IGG-TYPE LYMPHOPLASMACYTIC LYMPHOMA. TARGETED NEXT-GENERATION SEQUENCING RESULTS OF FORMALIN-FIXED PARAFFIN EMBEDDED SAMPLES

Background: Follicular lymphoma (FL), the most frequent type of indolent non Hodgkin lymphoma, exhibits a heterogeneous clinical behavior. Predictive biological variables are eagerly sought, in an effort to better anticipate outcomes for each individual patient. Cytokines are small proteins involved in cell signaling and immune regulation. The levels of soluble interleukin 2 receptor (sIL-2R), interleukin 6 (IL-6), and tumor necrosis factor (TNF) have been correlated with tumor burden and prognosis in solid tumors and some lymphomas. High sIL-2R has been associated with shorter progression-free survival (PFS) in FL, but the impact of the levels of IL-6 and TNF is not known in this disease specifically. Aims: To determine the prognostic significance of the serum levels of sIL-2R, IL-6 and TNF in patients with newly diagnosed FL. Methods: We identified 300 patients (132 males/168 females; median age: 60 years) diagnosed with FL at our institution between January 2002 and December 2017 who had available information about serum cytokine levels (sIL-2R, IL-6 and TNF), determined by ELISA, before the initiation of frontline treatment. Baseline patient and disease characteristics, type of frontline treatment, PFS and overall survival (OS) were assessed retrospectively and compared between patients with normal vs. elevated levels (above the upper normal limit) of each one of the three evaluated cytokines. Results: Baseline characteristics, treatment, response, PFS and OS data are detailed in the table. Patients with elevated IL-6 or TNF levels were older and those with elevated IL-6 had a worse performance status and higher rate of B symptoms. An advanced stage was more frequently seen in patients with any elevated cytokine, while secondary extranodal involvement, and specifically, bone marrow involvement, was more frequent if either sIL-2R or TNF were raised. Patients with any elevated cytokine were more likely to have elevated LDH or β2-microglobulin (β2m) levels or a high-risk FLIPI score. A Ki67 index >30% was more frequently seen among patients with high TNF levels. Patients requiring frontline treatment with R-CHOP showed higher levels of any one of the 3 evaluated cytokines, while those who were not treated or received single-agent rituximab were more likely to have normal levels. The complete response (CR) rate was higher for patients with normal levels of sIL-2R and TNF. Median PFS was 10 years for treated patients in the entire series. 10-year PFS was significantly lower for patients with high levels of either sIL-2R, IL-6 or TNF. Similarly, patients who had elevated levels of any one of the 3 evaluated cytokines had a lower 10-year OS. However, in a multivariate analysis including FLIPI score, β2m and cytokine levels, only FLIPI and β2m retained statistical significance for PFS and OS.Summary/Conclusion: FL patients with elevated levels of cytokines are more symptomatic and have a higher tumor burden. Despite being treated more aggressively, they are less likely to achieve a CR after treatment or to maintain it after 2 years. PFS and OS are also significantly shorter in patients with elevated cytokine levels compared to those with normal levels. Determination of serum cytokine levels is simple and could become an additional factor informing about response to treatment, early progression, and survival.

Combination of metformin and gefitinib as first-line therapy for nondiabetic advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations: A multicenter, randomized, double-blind, placebo-controlled phase II trial.

9035 Background: Several lines of evidence suggested a role for metformin in sensitizing diabetic NSCLC patients to EGFR tyrosine kinase inhibitors (TKIs). However, data regarding its effects on non-diabetic populations remained scarce. We hereby examined metformin’s first-line use alongside gefitinib in EGFR mutation positive (EGFRm) patients without diabetes. Methods: In this trial (NCT01864681), 224 non-diabetic patients with treatment naïve stage IIIB-IV EGFRm NSCLC were randomly assigned at 1:1 to receive gefitinib plus metformin or placebo. Gefitinib was administered at 250 mg once daily, while metformin/placebo was initiated at 500 mg once daily and then escalated to 1000 mg twice daily over 2 weeks. Dose reduction was permitted for metformin/placebo in case of intolerable toxicity. The primary endpoint was progression-free survival (PFS) rate at 1 year. Secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and safety. Serum levels of interleukin-6 were also subjected to exploratory analysis. Results: Baseline characteristics were well balanced between treatment groups. The median duration of follow-up was 19.15 (IQR 12.99-28.44) months. The estimated 1-year PFS rate was 41.2% (95% confidence interval [CI] 30.0-52.2) in the metformin group versus 42.9% (95% CI 32.6-52.7) in the placebo group (p = 0.6268). Metformin did not increase median PFS (10.3 months vs. 11.4 months), median OS (22.0 months vs. 27.5 months), or ORR (66.0% vs. 66.7%) over placebo. No significant treatment group differences in terms of PFS were detected across subgroups either, including those with elevated levels of interleukin-6. Metformin plus gefitinib shared a similar safety profile with the control group, except for a remarkably higher incidence of diarrhea (78.38% vs. 43.24%). Conclusions: Our study did not show enhanced gefitinib efficacy upon addition of metformin and hence does not support its concurrent use with first-line EGFR-TKI therapy in non-diabetic EGFRm NSCLC patients. Clinical trial information: NCT01864681.

Atopic Patients Show Increased Interleukin 4 Plasma Levels but the Degree of Elevation Is Not Sufficient to Upregulate Interleukin-4-Sensitive Genes

Background: Atopic diseases constitute a major health challenge for industrialized countries, and elevated levels of interleukin 4 (IL-4) frequently characterize these disorders. Previous in vitroanalyses have indicated that IL-4 strongly upregulates the expression of IL-4-sensitive genes in human monocytes. Objective: To explore whether similar expression alterations may contribute to the pathomechanisms of atopic diseases in vivo we carried out a small-scale case-control clinical study (n = 43), in which we quantified the plasma levels of IgE and IL-4 as well as the expression of selected IL-4-sensitive genes in blood leukocytes. Methods: 34 allergic patients suffering from allergic rhinitis (n = 11), atopic eczema (n = 11) and allergic asthma (n = 12) as well as 9 healthy control individuals were recruited. IgE and IL-4 plasma levels were determined by ELISA, and the expression of selected IL-4-sensitive gene products in blood leukocytes was quantified by qRT-PCR. In addition, the fatty acid oxygenase activity of isolated monocytes was measured by RP-HPLC analysis of the arachidonic acid oxygenation products (ex vivo activity assays). Results: We found that plasma levels of IgE and IL-4 were significantly elevated in atopic patients but the degree of elevation was not sufficient to upregulate the expression of the selected IL-4-sensitive genes in circulating leukocytes. Moreover, the arachidonic acid oxygenase activity of blood monocytes was not significantly altered in atopic patients. Conclusion: Our data suggest that the IL-4 plasma levels of atopic patients are not high enough to impact the expression of IL-4-sensitive genes.

Elevated Serum Ferritin and Interleukin-6 Level as the Risk Factor in Preterm Labor

&#x0D; Objective : To investigate the association ofserum ferritin and Interleukin-6 (IL-6) elevation as the risk factors for preterm labor.&#x0D; Method : This study was a case-control study conducted at the Obstetrics and Gynecology Outpatient and Emergency Department at Sanglah General Hospital Denpasar, Bali in November 2014 until June 2015. The sample selection was done by consecutive sampling with total sample as many as 20 case samples (women with preterm labor) and 20 control samples (women with normal preterm pregnancy).&#x0D; Results : Based on the analysis, there was no significant difference of patient demografic such as age, gestational age, and parity among the two groups. Chi-square analysis showed that the increased serum ferritin level had 5 fold increased risk of developing preterm labor (OR = 4.89, 95% CI = 1.20-19.94; p = 0.022), and increased serum IL-6 level had 9 fold increased risk of developing preterm labor (OR = 9.33, 95% CI = 2.18-39.96; p = 0.001) compared to normal preterm pregnancy.&#x0D; Conclusion : It can be concluded that level of IL-6 and serum ferritin was the risk factor for preterm labor.&#x0D; Keywords: Interleukin-6, preterm labor, serum ferritin&#x0D; &#x0D; Abstrak &#x0D; Tujuan :Untuk membuktikan hubungan kadar ferritin dan Interleukin-6 (IL-6) serum yang tinggi sebagai faktor risiko terjadinya persalinan preterm. &#x0D; Metode :Penelitian ini bersifat observasional dengan studi case-control yang dilakukan di Poliklinik dan IRD Kebidanan dan Penyakit Kandungan RSUP Sanglah Denpasar, yang dilakukan mulai bulan November 2014 hingga Juni 2015. Pemilihan sampel dilakukan dengan cara berurutan dengan sampel penelitian sebanyak 20 sampel kasus (ibu dengan persalinan preterm) dan 20 sampel kontrol (ibu hamil preterm normal). &#x0D; Hasil :Tidak didapatkan perbedaan bermakna dari demografik pasien yaitu usia, umur kehamilan, dan paritas pada kedua kelompok. Analisa chi-square menunjukkan peningkatan kadar ferritin serum memiliki peningkatan risiko 5 kali terjadinya persalinan preterm (OR = 4,90, IK 95% = 1,20-19,94; p = 0,022), dan peningkatan kadar IL-6 serum memiliki peningkatan risiko 9 kali terjadinya persalinan preterm (OR = 9,33, IK 95% = 2,18-39,96; p = 0,001) dibandingkan dengan kelompok ibu hamil preterm normal. &#x0D; Kesimpulan : Kadar feritin dan IL-6 serum adalah faktor risiko terjadinya persalinan preterm. &#x0D; Kata kunci: Interleukin-6, persalinan preterm, ferritin serum&#x0D;

Serum levels of TARC, MDC, IL-10, and soluble CD163 in Hodgkin lymphoma: a SWOG S0816 correlative study

AbstractSerum soluble chemokines/cytokines produced by Hodgkin cells and the tumor microenvironment might be of value as biomarkers in classic Hodgkin lymphoma (cHL). We assessed serum thymus and activation-related chemokine (TARC), macrophage-derived chemokine (MDC), interleukin-10 (IL-10), and soluble CD163 (sCD163) levels at baseline, time of interim fluorodeoxyglucose positron emission tomography (PET), and after therapy in cHL patients treated on S0816, an intergroup phase 2 response-adapted study evaluating escalated therapy for interim PET (PET2)–positive patients (www.clinicaltrials.gov #NCT00822120). Epstein-Barr virus (EBV) status was assessed, and 559 serum samples were evaluated for TARC, MDC, IL-10, and sCD163 by immunoassay. EBV positivity correlated with higher sCD163 and IL-10 levels but lower TARC levels. While baseline biomarker levels were not associated with outcome, sCD163 levels at the time of PET2 were associated with favorable progression-free survival (PFS), adjusting for PET2 status. After therapy TARC, MDC, and IL-10 correlated with PFS and overall survival (OS) on univariable analysis, which remained significant adjusting for international prognostic score. When also adjusting for end-of-therapy PET results, TARC and IL-10 remained significantly associated with shorter PFS and OS. Exploratory analysis in PET2-negative patients showed that elevated posttherapy TARC and IL-10 levels were associated with PFS. Serum cytokine levels correlate with outcome in cHL and should be investigated further in risk-adapted cHL trials.

Gut microbiota in obstructive sleep apnea-hypopnea syndrome: disease-related dysbiosis and metabolic comorbidities.

Gut microbiota alterations manifest as intermittent hypoxia and fragmented sleep, thereby mimicking obstructive sleep apnea–hypopnea syndrome (OSAHS). Here, we sought to perform the first direct survey of gut microbial dysbiosis over a range of apnea–hypopnea indices (AHI) among patients with OSAHS. We obtained fecal samples from 93 patients with OSAHS [5 < AHI ≤ 15 (n=40), 15 < AHI ≤ 30 (n=23), and AHI ≥ 30 (n=30)] and 20 controls (AHI ≤ 5) and determined the microbiome composition via 16S rRNA pyrosequencing and bioinformatics analysis of variable regions 3–4. We measured fasting levels of homocysteine (HCY), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). Results revealed gut microbial dysbiosis in several patients with varying severities of OSAHS, reliably separating them from controls with a receiver operating characteristic-area under the curve (ROC-AUC) of 0.789. Functional analysis in the microbiomes of patients revealed alterations; additionally, decreased in short-chain fatty acid (SCFA)-producing bacteria and increased pathogens, accompanied by elevated levels of IL-6. Lactobacillus levels correlated with HCY levels. Stratification analysis revealed that the Ruminococcus enterotype posed the highest risk for patients with OSAHS. Our results show that the presence of an altered microbiome is associated with HCY among OSAHS patients. These changes in the levels of SCFA affect the levels of pathogens that play a pathophysiological role in OSAHS and related metabolic comorbidities.

MCC950 blocks enhanced interleukin-1β production in patients with NLRP3 low penetrance variants

ObjectiveTo determine the role of the NLRP3 inflammasome by using the selective NLRP3 inhibitor MCC950 in patients with NLRP3 low penetrance variants and clinical symptoms suggestive for an autoinflammatory syndrome including central nervous system (CNS) involvement. MethodsNineteen symptomatic patients with low penetrance NLRP3 variants (Q703K n = 17, V198M n = 2) recruited between 2011 and 2017 were included in this monocentric study. A functional inflammasome activation assay was performed in patients in comparison to healthy controls (HC), including the determination of interleukin-1beta (IL-1β), interleukin-6 (IL-6) and tumor-necrosis factor alpha (TNF-α) secretion in the presence of the NLRP3 selective small-molecule inhibitor MCC950. Detailed clinical features were assessed and anti-IL-1 treatment response was determined. ResultsPeripheral blood mononuclear cells (PBMC) from patients with low penetrance NLRP3 variants displayed enhanced IL-1β levels following inflammasome activation compared to HC. Furthermore, IL-1β release was NLRP3-dependent as it was blocked by MCC950. The production of IL-6 and TNF-α was also increased in patients with low penetrance NLRP3 variants. Clinically, they presented with a heterogenous spectrum of neurological manifestations, while cranial nerve inflammation was the most common feature. Overall inflammasome activation did not correlate with disease severity. Eight of ten treated patients responded to anti IL-1 treatment, however a complete response was only documented in four patients. ConclusionPBMC of several patients with NLRP3 low penetrance variants and CNS manifestation showed increased NLRP3-specific IL-1β release upon stimulation and elevated NLRP3-independent IL-6 and TNF-α levels as those were not suppressed by MCC950. Our data suggest that beside the possible causal involvement of the NLRP3 inflammasome additional, yet unidentified genetic or environmental factors may contribute to the multi-organ inflammation in our patients and explain the partial response to IL-1 targeting therapies.