Serum sIL-2R Levels Research Articles

Increased serum level of soluble interleukin-2 receptor is associated with a worse response of metastatic clear cell renal cell carcinoma to interferon alpha and sequential VEGF-targeting therapy

BackgroundRenal cell carcinoma (RCC) is a tumor with immunogenic properties. Soluble interleukin-2 receptor (sIL-2R) has a role in T cell activation and may be important for immune regulation in various conditions, including infections, transplantation rejection, autoimmune inflammatory states, and cancer. We investigated the prognostic value of the serum sIL-2R level in patients with metastatic RCC receiving IFN-alpha and vascular endothelial growth factor (VEGF)-targeting therapy.MethodsWe monitored the serum level of sIL-2R over time and examined phosphorylated Akt expression by the primary tumor in 47 patients with metastatic clear cell RCC (ccRCC) undergoing cytoreductive nephrectomy followed by first-line adjuvant therapy with IFN-alpha plus sequential VEGF-targeting therapy as second- or third-line adjuvant therapy.ResultsA preoperative increase of the serum level of sIL-2R was correlated with a higher preoperative serum level of programmed cell death 1 (PD-1)-ligand 1 (PD-L1), increased expression of phosphorylated Akt by the primary tumor, and a worse response to IFN-alpha/sequential VEGF-targeting therapy, as well as being an independent prognostic factor for a shorter overall survival time by multivariate analysis. Over time, the serum sIL-2R level largely reflected the tumor response to therapy.ConclusionsMonitoring the serum level of sIL-2R may help to predict the biological behavior of ccRCC, its response to IFN-alpha/sequential VEGF-targeting therapy, and the prognosis.

High serum levels of soluble interleukin-2 receptor (sIL2-R), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF) are associated with adverse clinical features and predict poor outcome in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with heterogeneous outcomes. To improve accuracy of the international prognostic index score, new biological variables are being investigated. The aim of this study was to determine the prognostic significance of serum levels of different cytokines, namely soluble interleukin-2 receptor (sIL2-R), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF). We analyzed 197 de novo DLBCL patients (91 M/106 F; median age 66 years) treated with immunochemotherapy in a single institution. Serum cytokine determination was performed with ELISA, using the upper normal values as cut-offs. sIL-2R, IL-6 and TNF were elevated in 133, 130 and 144 cases, respectively. Elevation of each of these cytokines correlated with worse performance status, presence of B symptoms, advanced stage, elevated LDH and β2-microglobulin (P<0.03) and lower complete remission rate (P<0.001). Elevated levels of serum sIL-2R and TNF were significantly associated with shorter progression-free (PFS) and overall survival (OS), while elevated IL-6 only with shorter PFS. Early death (<4months from diagnosis) strongly correlated with elevated cytokines. Determination of serum cytokines levels is simple and adds information regarding risk of early death, response to therapy, and outcome.

Structural and functional correlates of serum soluble IL-6 receptor level in patients with bipolar disorder

ObjectivesInflammation is reported to play a crucial role in the pathogenesis of bipolar disorder (BD). Higher serum levels of soluble interleukin-6 receptor (sIL-6R), which forms a ligand–receptor complex with the potent proinflammatory cytokine IL-6, have been consistently observed in patients with BD. However, the effect of sIL-6R on neural structure and function remains unclear. This study investigated the association between serum sIL-6R levels and the structural and functional connectivity (FC) of the brain in patients with BD. MethodsSeventy-four stable patients with BD-I or BD-II were enrolled from the outpatient clinic. Structural and resting functional MRI and clinical evaluations were performed in all participants, and serum sIL-6R levels were measured. We used an automated surface-based method (FreeSurfer) to measure cortical thickness and a seed-based FC analysis to derive the FC map of the medial prefrontal cortex (mPFC), a key region implicated in the fronto–limbic disconnection hypothesis of BD. Brain-wise regression analyses of cortical thickness and FC mapping on IL-6 levels were performed using a general linear model. ResultsHigher sIL-6R levels were associated with a thinner cortex in the right middle temporal gyrus. Furthermore, higher sIL-6R levels were associated with increased FC between the mPFC and amygdala, pallidum, putamen, and insula and decreased FC between the mPFC and subgenual anterior cingulate cortex and frontal pole. ConclusionThe results evidence that higher serum inflammatory marker levels are associated with a severer deficit in structural and connectivity abnormalities implicated in BD.

Seventy FDG-PET/CT Cases in Which Nuclear Medicine Physicians Suspected Lymphoma: How Reliable Are We?

Objective(s):To validate the reliability of nuclear medicine physicians in diagnosing lymphoma using positron emission tomography/computed tomography using 2-deoxy-2-[18F]fluoro-D-glucose (FDG-PET/CT) and to determine findings that reliably suggest lymphoma.Methods:Seventy patients suspected of having lymphoma using FDG-PET/CT were enrolled in this retrospective study. Two nuclear medicine physicians read all the interpretation reports and graded the degree of suspicion by consensus (3: definitely suspicious, 2: probably suspicious, and 1: possibly suspicious). The following factors were also investigated for each patient: maximum standardized uptake value (SUVmax) of the lesions, serum level of soluble interleukin-2 receptor (sIL-2R), and the presence of splenic FDG uptake higher than that of the liver.Results:The study group consisted of 34 lymphomas, 18 other malignancies, and 18 benign lesions according to histopathological diagnosis. No patient with a Grade 1 degree of suspicion was diagnosed as lymphoma. SUVmax and the serum level of sIL-2R could not distinguish lymphoma from other diseases. Of the 11 patients who presented with elevated splenic FDG uptake, 10 were diagnosed as having lymphoma.Conclusion:When the degree of suspicion by nuclear medicine physicians is low, the possibility of lymphoma is also low. On the other hand, elevated splenic FDG uptake may suggest lymphoma.

Soluble Interleukin-2 Receptor and C-Reactive Protein Levels Are Associated with the Efficacy of Bendamustine As a Salvage Treatment for Indolent Lymphoma

Background:Bendamustine has demonstrated a favorable efficacy and toxicity profile in relapsed or refractory indolent lymphoma. Limited information is available regarding the prognostic factors (particularly laboratory parameters) of bendamustine treatment, although studies have shown a relationship between the hampered effect of bendamustine and an increase in lactate dehydrogenase (LDH) levels. Therefore, we retrospectively evaluated clinical and laboratory factors immediately prior to initiating bendamustine treatment and analyzed its correlation with the clinical outcome among patients with relapsed or refractory indolent lymphoma.Patients and methods:We analyzed 55 relapsed or refractory indolent lymphoma patients who had been treated with bendamustine alone (n = 19) or rituximab plus bendamustine (n = 36) at our hospital from 2000 to 2015. The median age at diagnosis was 65 years and the median follow-up period was 552.5 days. Histological analysis revealed follicular lymphoma (n = 21), mantle cell lymphoma (n = 10), MALT lymphoma (n = 7), lymphoplasmacytoid lymphoma (n = 5), and other low-grade B cell lymphomas (n = 4). We further analyzed the relationships between the clinical outcome [overall response rate (ORR), complete response (CR), progression-free survival (PFS), and overall survival (OS)] and clinical data, including sex, patient age (≥65 years), performance status (≥2), IPI (≥HI), FLIPI (≥HI), no. of previous therapies (≥2), prior purine analogue treatment, response to last treatment, and laboratory parameters [white blood cell count (≥5000/µl), lymphocyte count (≥1000/µl), platelet count (≥10000/µl), LDH (elevated or normal), sIL-2R (elevated or normal), and CRP (elevated or normal)], before starting bendamustine treatment.Results:The median number of cycles of bendamustine was 4 (range: 1-8). The ORR was 80.3% with a CR of 39.2%. Moreover, the CR rate was significantly worse in patients who had elevated sIL-2R and CRP, high or high-intermediate IPI scores, and a high WBC count (P = 0.002, P < 0.001, P = 0.072, and P < 0.046, respectively). Among follicular lymphoma patients, elevated CRP was only associated with a low CR rate (P = 0.028). In multivariate analysis, sIL-2R, CRP, and a high WBC count were all significantly associated with a worse CR rate (P = 0.044, P = 0.002, and P = 0.032, respectively). The 1- and 2- year OS rates were 80.3% and 76.1%, respectively. The OS was significantly higher in a group of the patients who obtained CR after bendamustine, were treated with rituximab plus bendamustine, and did not receive prior purine analogue treatment (P = 0.007, P = 0.008, and P < 0.001, respectively). An elevated CRP was associated with worse OS (P = 0.055). In multivariate analysis, only CR after bendamustine was significantly associated with improved OS (P = 0.023).The 1- and 2-year PFS rates were 69.2% and 60.5%, respectively. PFS was significantly better in patients who obtained CR after bendamustine treatment, had a normal CRP, had not received more than 2 previous therapies, and had a good performance status (P < 0.001, P = 0.007, P = 0.031, and P = 0.033, respectively). In multivariate analysis, any prognosis factors were significantly associated with PFS.Conclusion:This is the first study to demonstrate a correlation between laboratory parameters (i.e., CRP and sIL-2R) and the clinical outcome in patients with relapsed or refractory indolent lymphoma who were treated with bendamustine. In this study, CRP and sIL-2R levels as well as the WBC count were associated with the CR rate. In addition, the CRP levels were associated with OS and PFS, but LDH levels were not associated with any clinical outcomes. Previous studies have reported that the elevation of serum CRP and sIL-2R levels were associated with poor OS or PFS in patients who were treated with rituximab combined with CHOP in diffuse large B-cell lymphoma or follicular lymphoma. Our study indicates that serum CRP and sIL-2R levels are also important laboratory parameters for patients with indolent lymphoma who underwent bendamustine treatment. DisclosuresNo relevant conflicts of interest to declare.

Retrospective Analysis of NK/T Cell Lymphoma Prognostic Index (NKPI), EBV-DNA and Soluble IL-2 Receptor (sIL2R) for Extranodal NK/T-Cell Lymphoma, Nasal Type

IntroductionExtranodal NK/T cell lymphoma (ENKTL) is a rare aggressive lymphoma, and more prevalent in Asians, Mexico, Central America, and South America. ENKTL relates to Epstein-Barr Virus (EBV) reactivation, and occurs most often in adults.The prognosis of ENKTL relates to NK/T Cell Lymphoma Prognostic Index (NKPI), which includes presence of B symptom, elevated serum lactate dehydrogenase (LDH), stage III or IV, and regional lymph node involvement. Recently, EBV-DNA level is known to be an important prognosis factor of ENKTL.We retrospectively analyzed relationship among NKPI, EBV-DNA level and other factors in patients with ENKTL.Patients and methodsWe analyzed the data of ENKTL patients who were diagnosed and treated at our hospital from April 2007 to July 2016, retrospectively. Data of the blood test and EBV-DNA level, when we diagnosed were also analyzed. PET-CT examination was performed for staging of ENKTL before treatment.The event-free survival (EFS) and overall survival (OS) were estimated using Kaplan-Meier method.ResultsA total of 26 ENKTL patients (14 male, 12 female) were analyzed. All patients were treated with radiation therapy (RT) and 2/3DeVIC (dexamethasone 40mg/body days 1 through 3, ifosfamide 1000mg/m² days 1 through 3, carboplatin 200mg/m² day 1, etoposide 67mg/m² days 1 through 3).Median age was 58 years old (range; 18-77 years old). Median OS was 17 months (range; 1-105 months), and EFS was 12 months (range 1-105 months).Seven patients had B symptoms, and serum LDH level (median 192.5 U/L, range 153-540 U/L) was elevated in 10 patients at diagnosis. The patients with stage I, IIand IV were 19, 5, and 2 patients, respectively. The patients with stage IV were treated with RT and 2/3DeVIC, because patient’s performance status, age or other factor is not good.According to the NKPI, the patients were stratified into low score (10 patients), low intermediate (13 patients), and high intermediate (3 patients).In our analysis, 2 year-EFS (p=0.125) was not changed among all score groups o However, low score group was associated with better 2 year-OS (p=0.0734) than intermediate and high score groups.Twenty patients were tested EBV-DNA level at diagnosis. Median EBV-DNA at diagnosis was 113.5 copies/106 WBC (range; 0-38000 copies/106 WBC). We analyzed relationship between the prognosis and EBV-DNA level. However, EBV-DNA level (EBV-DNA cut-off; 140 copies/106 WBC ) was not related to 2 year-OS (p=0.838) and 2 year-EFS (p=0.686).Twenty-six patients were tested serumβ2-microglobulin (β2MG) and soluble IL-2 receptor (sIL2R). Serum β2MG level (median; 2.035 mg/l , range; 1.10-4.95 mg/l) was increased in 13 patients, and serum sIL2R level (median; 543 U/ml, range; 264-2490 U/ml) was increased in 14 patients.β2MG level was not related to 2 year-OS (p=0.152) and 2 year-EFS (p=0.181). Low sIL2R level was associated with better OS (p=0.0445) and EFS (p=0.0793) than high level.Discussion NKPI score and serum sIL2R were related to the prognosis of patients with ENKTL with early stage, although EBV-DNA copies were not related to the prognosis. DisclosuresNishimura:Chugai: Consultancy. Mishima:Chugai: Consultancy. Yokoyama:Chugai: Consultancy. Terui:Yanssen: Honoraria. Hatake:Chugai: Research Funding; Meiji-Seika: Consultancy; Otsuka: Consultancy; Kyowa Kirin: Honoraria, Research Funding.

The relation between clinical features of adult T-cell leukemia/lymphoma and the serum levels of soluble CD25 and CD30.

Adult T-cell leukemia (ATL) is an aggressive neoplasm of mature T cells. We aimed to ascertain the relationships between soluble CD25 (sIL-2R) and CD30 (sCD30) levels and nodal or extra-nodal involvement of ATL. Our study subjects were ATL patients whose sIL-2R and sCD30 levels were measured before initial therapy (n=32). Their sCD30 levels correlated significantly with the number of ATL cells in peripheral blood (PB) (ρ=0.456; P=0.009), while sIL-2R levels correlated significantly with the number of nodal lesions (ρ=0.660; P=0.001). We then also assessed the relationships of pulmonary lesions with the number of ATL cells in PB, lactate dehydrogenase levels, sIL-2R levels, and sCD30 levels in 24 patients whose pleural effusions and hilar lymphadenopathy were investigated before initial therapy. The results suggested that a high number of ATL cells in PB may be associated with pulmonary lesions. It is known that metalloproteinases shed and cleave cytokine receptors such as CD25 and CD30 from the cell surface as well as E-cadherin and extracellular matrix. It seems that serum levels of sIL-2R and sCD30 indicate the activation of metalloproteinases associated with ATL involvement in vivo.

Associations Between Delirium and Preoperative Cerebrospinal Fluid C-Reactive Protein, Interleukin-6, and Interleukin-6 Receptor in Individuals with Acute Hip Fracture.

To examine whether delirium in individuals with hip fracture is associated with high C-reactive protein (CRP), interleukin-6 (IL-6), and soluble IL-6 receptor (sIL-6R) levels in the cerebrospinal fluid (CSF). Prospective cohort study. Two university hospitals in Oslo, Norway, and Edinburgh, United Kingdom. Individuals admitted with acute hip fracture (N = 151). Participants were assessed for delirium pre- and postoperatively using the Confusion Assessment Method. Prefracture cognitive impairment was detected using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Serum was collected preoperatively and CSF just before the onset of spinal anesthesia. Cytokine levels in serum and CSF samples were determined using an enzyme-linked immunosorbent assay. Student t-tests or Mann-Whitney U-tests were used for between-group comparisons. Spearman rho was used for correlations. Sixty participants had prior cognitive impairment (IQCODE score ≥3.44). Delirium was diagnosed in 46 participants (77%) with prior cognitive impairment and 25 (29%) without. In participants without prior cognitive impairment, CSF CRP levels were higher in participants with delirium (median 0.05 μg/mL, interquartile range (IQR) 0.02-0.12 μg/mL) than in those without delirium (median 0.01 μg/mL, IQR 0.00-0.06 μg/mL) (P = .01); there were no differences in participants with prior cognitive impairment. In secondary analyses, in participants with prior cognitive impairment, the concentration of CSF sIL-6R was higher in those participants who developed delirium than in the other subgroups, but this difference was not statistically significant. Serum levels of CRP, IL-6, and sIL-6R were not different according to delirium in participants with or without prefracture cognitive impairment. High CSF levels of CRP and sIL-6R may be associated with delirium. Different pathophysiological mechanisms may operate in different subgroups, notably in relation to the presence of prior cognitive impairment.

Quantitative Features of serum sIL-2R level in Patients with Mature B-Cell Lymphoma– Involvement of LDH

Title Quantitative Features of serum sIL-2R level in Patients with Mature B-Cell Lymphoma‒ Involvement of LDH Author(s) Matsumoto, Reiko; Kamihira, Shimeru; Matsubara, Takashi; Yamada, Shouichi; Matsuda, Kazuyuki; Kinoshita, Kazuhisa; Takahashi, Youichi; Kanematsu, Takashi; Nakashima, Kazuhisa; De Kerckhove, Charles Citation Acta medica Nagasakiensia, 60(2), pp.33-37; 2016 Issue Date 2016-01 URL http://hdl.handle.net/10069/36166 Right NAOSITE: Nagasaki University's Academic Output SITE

Soluble interleukin-2 receptor index predicts the development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation from unrelated donors.

Acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with significant morbidity and mortality. In the present study, we retrospectively evaluated whether soluble interleukin-2 receptor (sIL-2R) index, defined as the ratio of serum sIL-2R levels at neutrophil engraftment to those at the pre-conditioning regimen, was predictive of acute GVHD among 51 patients who underwent allogeneic HSCT as their first transplantation and achieved engraftment. The median sIL-2R index was 3.6, and the sIL-2R values were positively associated with acute GVHD severity (grade 0-I: 3.8 ± 2.0 vs. grade II-IV: 7.1 ± 5.7; P = 0.05). Grade II-IV acute GVHD had a cumulative incidence of 31.4 %, and was significantly more frequent among patients with an sIL-2R index of ≥4.5 (≥4.5: 50.0 % vs. <4.5: 21.2 %; P = 0.03). Multivariate analysis revealed that an sIL-2R index of ≥4.5 [hazard ratio (HR) 3.5, P < 0.01] and donor age of >35 years (HR 3.8, P = 0.02) were significant risk factors for grade II-IV acute GVHD. Therefore, increased sIL-2R levels from baseline to engraftment might predict the risk of moderate-to-severe acute GVHD after allogeneic HSCT from an unrelated donor.

IL-6 promotes an increase in human mast cell numbers and reactivity through suppression of suppressor of cytokine signaling 3

IL-6, levels of which are reported to be increased in association with mastocytosis, asthma, and urticaria, is used in conjunction with stem cell factor to generate CD34(+) cell-derived primary human mast cell (HuMC) cultures. Despite these associations, the effects on and mechanisms by which prolonged exposure to IL-6 alters HuMC numbers and function are not well understood. We sought to study the effect of IL-6 on HuMC function, the mechanisms by which IL-6 exerts its effects, and the relationship of these findings to mastocytosis. HuMCs were cultured in stem cell factor with or without IL-6. Responses to FcεRI aggregation and expression of proteases and receptors, including the soluble IL-6 receptor (sIL-6R), were then quantitated. Epigenetic changes in suppressor of cytokine signaling 3 (SOCS3) were determined by using methylation-specific PCR. Serum samples from healthy control subjects and patients with mastocytosis were assayed for IL-6, tryptase, and sIL-6R. IL-6 enhanced mast cell (MC) proliferation, maturation, and reactivity after FcεRI aggregation. IL-6 reduced expression of SOCS3, which correlated with methylation of the SOCS3 promoter and increased expression and activation of signal transducer and activator of transcription 3. IL-6 also suppressed constitutive production of sIL-6R, and serum levels of sIL-6R were similarly reduced in patients with mastocytosis. IL-6 increases MC proliferation and formation of a more reactive phenotype enabled by suppressing proteolytic cleavage of sIL-6R from IL-6R and downregulation of the SOCS3 autoinhibitory pathway. We suggest IL-6 blockade might ameliorate MC-related symptoms and pathology in patients with MC-related diseases associated with increased IL-6 levels, including mastocytosis.

Plasma Levels of Presepsin (Soluble CD14-subtype) as a Novel Prognostic Marker for Hemophagocytic Syndrome in Hematological Malignancies

Objective Recent studies suggest that presepsin (soluble CD14-subtype) is a useful diagnostic and prognostic marker for sepsis, with secretion by activated macrophages potentially dependent on phagocytosis of microorganisms. As "hemophagocytosis" is one of the major characteristics in patients with hemophagocytic syndrome (HPS), we hypothesized that presepsin may reflect the phagocytic activity and be a useful prognostic marker for HPS. Therefore, we aimed to assess the prognostic potential of presepsin in secondary HPS in adult patients with hematological malignancies. Methods Between April 2006 and August 2014, we retrospectively examined consecutive patients with HPS whose blood samples were available at our institution and compared the prognostic value of the following in HPS, singly and in combination: plasma presepsin, serum soluble interleukin (IL)-2 receptor (sIL-2R), ferritin, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-6 and IL-10. Results A total of 14 patients were enrolled. The median age of the patients was 46.5 years (range, 22-65). In univariable Cox models, there were no significant variables associated with the prognosis. However, in 12 evaluable patients, only the combination of higher median values of presepsin (>1,935 pg/mL) and sIL-2R (>4,585 U/mL) at the onset of HPS was significantly associated with the 90-day mortality (hazard ratio 14.5; 95% CI, 1.47-143.36; p=0.02). Conclusion These results suggest that a composite model of plasma presepsin and serum sIL-2R levels at the onset of HPS might be a novel predictor of the prognosis of patients with hematological malignancies and secondary HPS.

Evaluation of serum concentrations of the selected cytokines in patients with localized scleroderma.

IntroductionLocalized scleroderma is an autoimmune disease primarily affecting the skin. The cause of disease remains unexplained although environmental factors are implicated, which are likely to be responsible for activation of the endothelium and subsequent inflammation leading to excessive synthesis of collagen and extracellular matrix components.AimTo determine concentrations of interleukin (IL)-27, transforming growth factor (TGF)-β1, TGF-β2, IL-6, and sIL-6R in patients with localized scleroderma compared to controls and to assess the relations between their levels and laboratory markers.Material and methodsThe study encompassed 17 females with localized scleroderma (aged 25–67). The control group consisted of 30 age-matched healthy women. The blood was sampled from the basilic vein. Serum levels of cytokines were determined using ELISA.ResultsThe TGF-β2 levels were found to be significantly lower in patients with localized scleroderma compared to controls. Concentrations of TGF-β1 were decreased in scleroderma patients when compared to controls but without statistical significance. There were no significant differences in serum IL-6, sIL-6R and IL-27 levels between patients and the control group; however, we found a significant positive correlation between the level of sIL-6 and ESR among subjects with localized scleroderma.ConclusionsThe findings of decreased serum levels of TGF-β1 and TGF-β2 in patients with localized scleroderma demonstrate a possible association of these cytokines with pathogenesis of the disease. The results suggest also that sIL-6R is likely to be involved in inflammation in patients with localized scleroderma.

High Level of Soluble Interleukin-2 Receptor in Serum Predicts Treatment Resistance and Poor Progression Free Survival in Multiple Myeloma

Background: The IL-2/IL-2 receptor (IL-2R) system plays a central role in maintaining normal T cell immunity, and its disturbance is associated with several hematologic disorders. Studies have found in several types of lymphoma that abnormal amounts of soluble IL-2R (sIL-2R) may result in imbalance of the IL-2/IL-2R system and hence of the T cell immunoregulation. Whether the level of sIL-2R in blood could predict treatment response and survival outcomes or not needs to be investigated in multiple myeloma (MM) patients.Methods: The level of sIL-2R in serum was measured using enzyme-linked immunosorbent assay (ELISA) in 81 patients with newly diagnosed MM. 26 patients (32.1%) were treated with bortezomib-based regimens and 55 patients (67.9%) received old drugs-based regimens.Results: The mean concentration of sIL-2R for myeloma patients was 8.51ng/ml, significantly higher than that of healthy controls (0.56ng/ml, p<0.0001). The best cutoff value for sIL-2R in predicting high risk for disease progression is 6.049ng/ml with an area under curve (AUC) of 0.665 (p = 0.013). 36 patients (44.4%) were classified as higher sIL-2R level group (>6.049ng/ml), and 45 patients (55.6%) as lower group (=<6.049ng/ml). The overall response rate (ORR) was 60.0% in lower sIL-2R level group, higher than that in higher level group (41.7%, p=0.156). The 3-year progression free survival (PFS) and overall survival (OS) rate was 16% and 64%, respectively. In a multivariate survival analysis including ECOG performance status score, treatment response, and sIL-2R level, it was found that all these three parameters were significantly independent prognostic factors for PFS (p=0.032, 0.016, and 0.043, respectively), but none factors maintained their value in predicting OS. Subgroup analysis revealed that high level of sIL-2R correlated with significantly inferior PFS in patients treated with bortezomib-based regimens (p=0.004).Conclusions: Serum sIL-2R level is a valuable biomarker for predicting treatment response and an independent prognostic factor for PFS, indicating novel drugs targeting the imbalance of IL-2/IL-2R system may be a promising strategy in MM. DisclosuresNo relevant conflicts of interest to declare.

The effect of vitamin D deficiency on serum sIL-2R, IL-6 and TNF-alpha levels in adults with Type 1 diabetes

Objective : The aim of this study was to investigate the role of vitamin D deficiency in DMT1 pathogenesis by examining the effects of vitamin D levels on immune modulatory cytokines in patients with DMT1. Methods: Thirty adults with DMT1 from the endocrine clinic and 30 healthy controls were included in the study. Measurements for 25-hydroxyvitamin D (25OHD), soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels were obtained from serum samples from each study participant. Measurements were compared between the control group and the patient group. Correlations between 25OHD levels and the levels of sIL-2R, IL-6, and TNF-α cytokines were investigated in patients with DMT1. Results: The mean 25OHD value for the DMT1 patients was significantly lower than for the control group (14.9±9.8 ng/ml versus 24.8±9.4 ng/ml, respectively; p<0.01). The mean sIL-2R and TNF-α scores for patients with DMT1 were significantly higher than for the control group (707.3 ± 265 U/mL versus 403.1 ± 128 U/mL, respectively; p<0.01; and 10.2±3.0 pg/mL versus 3.8 ± 1.6 pg/mL, respectively; p<0.01). There was no significant difference between the mean IL-6 scores of the DMT1 patients and the controls (3.7±1.5 pg/mL versus 4.6±1.3 pg/mL, respectively; p=0,202). Negative correlations with varying levels of significance were observed between 25OHD and sIL-2R, IL-6, and TNF-α cytokine levels in patients with DMT1. Conclusion: Vitamin D deficiency in DMT1 patients may contribute to disease pathogenesis by increasing sIL-2R, IL-6, and TNF-α cytokines. Key words: Diabetes mellitus type 1, vitamin D deficiency, soluble interleukin-2 receptor, interleukin-6, tumor necrosis factor-α

ID: 196: Proteolysis of the human Interleukin-6 Receptor in vivo

Interleukin-6 (IL-6) has been linked to numerous inflammatory diseases and is therefore an attractive therapeutic target in the clinic. Soluble and membrane-bound forms of the Interleukin-6 Receptor (IL-6R) are responsible for its pro- and anti-inflammatory properties via the membrane-bound β -receptor gp130. Formation of the signaling complex results in activation of the JAK/STAT signaling pathway. In addition, soluble forms of the IL-6R (sIL-6R) have been identified in several body fluids. Interestingly, a coding nonsynonymous single nucleotide polymorphism (SNP) within the IL-6R (rs2228145, Asp358Ala) results in a 2-fold increase in soluble IL-6R (sIL-6R) serum levels and a reduced risk for coronary heart disease. In vitro data show that the sIL-6R is generated either via limited proteolysis of the membrane-bound precursor or via alternative splicing of the IL-6R mRNA, and the latter has been shown to occur also in vivo . In order to identify and analyze sIL-6R that was generated by proteolysis we combined a “bottom-up” proteomics approach with LC-MS. We could determine the cleavage site used in vitro and in vivo , identify novel glycan motifs, and show for the first time that proteolysis contributes to sIL-6R serum levels in humans. Further analysis of N- and O-linked glycosylation revealed different functions in terms of signaling and proteolysis. Mutation of the identified cleavage site resulted in an IL-6R that was resistant towards shedding by ADAM10 and ADAM17. In summary, our data show that limited proteolysis contributes to sIL-6R serum levels in humans, and that glycosylation is an important regulatory modification of the IL-6R.

Influence of CRBN, IKZF1, and IKZF3 expression on outcome in lenalidomide treated newly diagnosed multiple myeloma patients

RB1,TP53, t(4;14), t(11;14), t(14;16) and a centromeric probes for chromosomes 7, 9, 11, 15 and 17 (Abbott-Vysis Inc., Downers Grove, IL, USA; Dako, Glostrup, Denmark; Kreatech, Amsterdam, The Netherlands; MetaSystems, Altlusheim, Germany). Some complex chromosomal rearrangements were analyzed by using mFISH and arrayCGH methods (MetaSystems;Agilent, Santa Clara,CA,USA). Results: Patients with the absence of delRB1 had significantly increased levels of sOPG (p 1⁄4 0.025) and sVEGF (p 1⁄4 0.036). The presence of t(11;14) was associated with lower levels of sIL-6R (p 1⁄4 0.009). The presence of t(14;16) was associated with higher levels of 2m (p 1⁄4 0.022), and lower serum levels of DKK-1 (p 1⁄4 0.023). The presence of gain 1q21 was associated with higher levels of sTK (p 1⁄4 0.026), sIL-6R (p 1⁄4 0.01), and lower serum levels of PINP (p 1⁄4 0.030). Conclusion: This showed that some cytogenetic changes have an impact on individual components of the cytokine network in MM. The presence of adverse cytogenetic changes is associated with higher levels of neoplastic mediators (sTK, sIL-6R, 2m) and a decrease in levels of bone formation parameters (sOPG, PINP and DKK-1). Identified data complete the image of biology of neoplastic processes in MM. Supported by IGA CR NT 12451/5, NT 14400, NT 14393

IL-6, IL-18, sIL-2R, and TNFα proinflammatory markers in depression and schizophrenia patients who are free of overt inflammation

Major depressive disorder (MDD) and schizophrenia are associated with inflammatory processes. Studies have shown that these disorders exhibit increase in the level of one or more proinflammatory markers. However, these studies did not exclude patients with obvious inflammation (i.e., CRP>6mg/L). Therefore, a comprehensive study should include those inflammatory disorders. In the present study, the inflammatory natures of MDD and schizophrenia were investigated. To achieve this goal, serum levels of interleukin-6 (IL-6), interleukin-18 (IL-18), tumor necrosis factor alpha (TNFα), and soluble interleukin 2 receptor (sIL-2R) in depressed and schizophrenic patients were obtained and compared with those of the control group. Results showed a significant increase (p<0.05) in serum levels of IL-6, IL-18, TNFα, and sIL-2R in MDD and schizophrenic patients compared with the control group. Also patients with schizophrenia group showed higher levels of the inflammatory markers than MDD and control groups. The current study concluded that the immunological response in the MDD and schizophrenic patients groups was significantly stimulated. These disorders may be considered an inflammatory disorder because of elevated levels of proinflammatory cytokines in spite of lacking an overt inflammation. Furthermore results of this study suggested the possibility of the use of anti-inflammatory drugs as adjuvant therapy in schizophrenic and depressive disorders.

Serum level of soluble interleukin-2 receptor correlates with CD25 expression in patients with T lymphoblastic lymphoma

Acute lymphoblastic leukaemia/lymphoma (ALL/LBL) is an aggressive form of non-Hodgkin's lymphoma (NHL) affecting B-cells or T-cells, respectively. The serum level of soluble interleukin-2 receptor (sIL-2R) is known to reflect the...

The Link Between Cardio-Metabolic Risk Factors, Serum sIL-2R and Echocardiography Data in Type 2 Diabetes

This study aimed to demonstrate the link between the inflammatory process, cardio-metabolic risk factors and echocardiogra phy data in type 2 diabetic (T2D) patients. A total number of fifty-two patients (12 male and 40 females) with a median age of 57 year were enrolled in this study. Anthropometric measurements that related to the cardio-metabolic risk factors and blood pressure were measured. Fasting serum glucose, lipid profiles and soluble interleukin -2 receptor (sIL-2R) using the technique of enzyme linked immunnosorbent assay (ELISA) were determined. The patients categorized according to the presence of metabolic syndrome components using the National Cholesterol Education program (NCEP) definition. Echocardiography data that related to systolic and diastolic left ventricular dysfunction were recorded using B-mode ultrasound with a frequency of 2-4MHz. There was non-significant difference in echocardiography data that related to systolic and/or diastolic dysfunction and the cardio-metabolic risk factors. The mean serum sIL-2R level was 3.469±3.062 pg/ml (range: 1.316-12.5); it inversely and non-significantly correlated with ejection fraction (r = - 0.12) and atherogenic index (r=-0.148). There is a link between the left ventricular systolic function and the circulating sIL-2R in asymptomatic T2D, which does not relate to the components of metabolic syndrome