Serum sIL-2R Levels Research Articles

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.

Relationship of Interleukin-6 Trans-Signaling and Coronary Heart Disease in Young Adults: a Case-Control Study in Indonesia

Interleukin-6 (IL-6) has been reported to be related to coronary heart disease (CHD). It is proposed that the IL-6 trans-signaling pathway is responsible for the inflammatory effect in diseases, including CHD. In Asian countries, CHD tends to occur in younger age. However, no study has yet been done to assess the relationship between IL-6 trans-signaling pathway and young CHD patients in Indonesia. To assess whether there is a relationship between the levels of some components in the IL-6 trans-signaling pathway, including soluble interleukin-6 receptor (sIL-6R), soluble glycoprotein 130 (sgp130), and intercellular adhesion molecule 1 (ICAM-1) and CHD in young adults. A case-control study was conducted including 33 young CHD patients and 33 non-CHD patients as the control group (age and sex matched with CHD group) at Eka Hospital Pekanbaru, Indonesia, from July to November 2018. CHD was confirmed by coronary angiography, while non-CHD patients were subjects with normal ECG, without history of chest pain and family history of CHD. All participants were checked for sIL-6R, sgp130, and ICAM-1 serum levels using ELISA assays tests. The results were evaluated statistically using Student’s t test. The sIL-6R level tended to be higher in the CHD group compared to the control group (70.19+49.38 ng/ml vs 49.42+38.79 ng/ml) but did not reach statistical significance (p=0.062). The sgp130 level was 428.38+358.79 ng/ml and 474.08+389.43 ng/ml in CHD and control group, respectively (p=0.622). While the ICAM-1 level was 1829.53+1882.37 pg/ml and 2078.16+1595.25 pg/ml in CHD and control group, respectively (p=0.565). The IL-6 trans-signaling pathway, reflected by sIL-6R, sgp130, and ICAM-1 serum levels, was not significantly related with CHD in young adults.

High Level of Serum Soluble Interleukin-2 Receptor Is Associated With Poor Survival in Patients With First Relapsed or Refractory Peripheral T-Cell Lymphoma, Not Otherwise Specified: A Retrospective Study

BackgroundPatients with relapsed or refractory peripheral T-cell lymphoma, not otherwise specified (R/R-PTCL-NOS) usually have short survival with conventional salvage chemotherapies. Prediction of poor survival in patients who undergo conventional salvage chemotherapies might help identify candidates for novel therapies that have been recently available for R/R-PTCL-NOS. However, no prognostic marker other than the second-line International Prognostic Index (sIPI) has been reported. We aimed to investigate the prognostic value of serum soluble interleukin-2 receptor (sIL-2R) level in patients with R/R-PTCL-NOS. Patients and MethodsWe retrospectively analyzed 37 patients with R/R-PTCL-NOS who underwent salvage chemotherapy. Serum sIL-2R level was measured within a week before salvage chemotherapy initiation. We determined the cutoff level of serum sIL-2R as 4.03 times the upper limit of normal by using receiver operating characteristic curve analysis. ResultsThe 3-year overall survival (3yOS) was 5.2% and 37.5% in high sIL-2R and low sIL-2R groups, respectively (P = .005). In multivariate analysis, high sIL-2R level was independently associated with lower 3yOS (hazard ratio, 2.30; 95% confidence interval, 1.04-5.11; P = .040). In subgroup analysis, high sIL-2R level did not affect 3yOS in patients with high-risk sIPI (NA [not available] vs. 7.1%; P = .354), but was significantly associated with poor 3yOS in patients with low-risk sIPI (NA vs. 60.0%; P = .037). ConclusionSerum sIL-2R is a useful prognostic marker for patients with R/R-PTCL-NOS. In particular, high sIL-2R level can identify groups of patients with low-risk sIPI who have poor prognosis. Our results suggest that novel therapeutic approaches might be necessary for patients with high-risk sIPI and/or high sIL-2R level.

Serum level of soluble interleukin-2 receptor is positively correlated with metabolic tumor volume on 18 F-FDG PET/CT in newly diagnosed patients with diffuse large B-cell lymphoma.

Diffuse large B‐cell lymphoma (DLBCL) is the most frequent subtype of non‐Hodgkin lymphoma. High total metabolic tumor volume (TMTV) calculated using 18F‐FDG PET/CT images at diagnosis predicts poor prognosis of patients with DLBCL. However, high cost and poor access to the imaging facilities hamper wider use of 18F‐FDG PET/CT. In order to explore a surrogate marker for TMTV, we evaluated the correlation between the serum levels of soluble interleukin‐2 receptor (sIL‐2R) and TMTV in 64 patients with DLBCL, and the results were verified in an independent validation cohort of 86 patients. Serum levels of sIL‐2R were significantly correlated with TMTV. ROC analysis revealed that the cutoff value of TMTV ≥150 cm3 or sIL‐2R ≥ 1300 U/mL could predict failure to achieve EFS24 with areas under the curve (AUC) 0.706 and 0.758, respectively. Each of TMTV ≥150 cm3 and sIL‐2R ≥1300 U/mL was significantly associated with worse 5‐year overall survival and event‐free survival. Importantly, each of sIL‐2R <1300 U/mL or TMTV <150 cm3 identified patients with favorable prognosis among NCCN‐IPI high‐intermediate and high‐risk group. Serum level of sIL‐2R represents a convenient surrogate marker to estimate metabolic tumor burden measured by 18F‐FDG PET/CT that can predict treatment outcomes of patients with DLBCL.

Serum Soluble Interleukin-2 Receptor Is a Biomarker for Pneumocystis jirovecii Pneumonia among Patients with Rheumatoid Arthritis under Methotrexate Therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic joint inflammation and may manifest as interstitial pneumonia (IP). Methotrexate (MTX) is one of the main therapeutic drugs used for RA, but MTX could cause severe side effects, including Pneumocystis jirovecii pneumonia (PCP) and IP. Owing to similar symptoms, it is sometimes difficult to discriminate MTX therapy-associated PCP (MTX-PCP) and MTX therapy-associated IP (MTX-IP). Soluble interleukin-2 receptor (sIL-2R) is considered a marker of T-cell activation, and serum sIL-2R levels are elevated in RA and PCP. This led us to hypothesize that serum sIL-2R is a potential biomarker for discriminating MTX-PCP and MTX-IP. Accordingly, we carried out a retrospective analysis of 20 MITX-PCP cases, 30 MTX-IP cases, and as controls, 16 patients with RA-associated IP (RA-IP) and 13 patients with PCP without MTX treatment (PCP group). C-reactive protein and alveolar-arterial oxygen differences were higher in the MTX-PCP group than those in the RA-IP and MTX-IP groups. Importantly, serum levels of sIL-2R in MTX-PCP were significantly higher than those in other three groups. Based on the receiver operating characteristic curve, the cut-off level of sIL-2R resulting in the highest diagnostic accuracy for MTX-PCP was 1,311.5 U/mL, discriminating between MTX-PCP and other groups with 91.7% sensitivity and 78.6% specificity. Thus, patients with MTX-PCP show a higher degree of systemic inflammation, severe hypoxemia, and increased sIL-2R levels compared with those in MTX-IP cases. In conclusion, serum sIL-2R could be a biomarker for PCP diagnosis among patients with RA under MTX therapy.

Correlations between serum interleukin 6, serum soluble interleukin 6 receptor, and disease activity in systemic juvenile idiopathic arthritis patients treated with or without tocilizumab.

IntroductionInterleukin (IL)-6 is a proinflammatory cytokine involved in systemic juvenile idiopathic arthritis (SJIA). Since these patients are often treated with tocilizumab (TCZ), anti-IL-6 receptor (IL-6R) antibody, we investigated correlations between serum IL-6 and soluble IL-6R-levels and disease activity in SJIA patients treated with or without TCZ.Material and methods164 serum samples were taken from 42 SJIA patients treated with or without TCZ (69 and 95 samples, respectively). Patients were assigned to three groups according to disease status: 1) systemic (patients with systemic features and/or arthritis), 2) arthritis (patients with arthritis but no systemic features), and 3) inactive (clinically inactive disease). Disease activity was assessed using the Juvenile Arthritis Disease Activity Score-27 (JADAS-27) at the time of blood collection.ResultsIL-6 levels were highest in SJIA patients with predominant systemic features, while serum sIL-6R levels were highest in patients with persistent arthritis. Serum IL-6 correlated with JADAS-27 in patients treated with and without TCZ (r = 0.38 and r = 0.65, respectively), whereas serum sIL-6R levels correlated with JADAS-27 in patients treated without (r = 0.30) but not with (r = −0.14) TCZ. The sIL-6R/IL-6 ratio negatively correlated with JADAS-27 in patients treated with and without TCZ (r = –0.49 and r = –0.56, respectively).ConclusionsSerum IL-6 levels correlated more strongly with disease activity parameters than did sIL-6R levels and could be useful for monitoring disease activity in SJIA patients. The sIL-6R/IL-6 ratio might be a promising disease activity marker in both SJIA patients treated with and without TCZ.

Respiratory virus infections and inflammatory cytokines in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease

Objective: To investigate the characteristics of respiratory viral infections, and correlation between inflammatory cytokines and respiratory virus infections in patients with acute exacerbations of chronic obstructive pulmonary disease (COPD). Methods: A prospective cohort of patients with acute exacerbations of COPD was enrolled. The sputum of all patients were collected, and 15 respiratory viruses were detected using multi-channel real-time fluorescence quantitative PCR. The clinical characteristics associated with viral infections were analyzed. The peripheral blood of the patients was collected and cytokines including IL-6, IL-8, RANTES, IP-10, sIL-2R, IFN-γ, TNF-α in the serum were detected by ELISA. Association of these cytokines with respiratory viral infections was evaluated and a discriminant model was established. Results: A total of 99 patients with acute exacerbations of COPD were enrolled in this study. Thirty-four cases (34.3%, 34/99) were positive for viral detection. Among them, the positive rate of influenza A virus was the highest (38.2%, 13/34), followed by rhinovirus (35.3%, 12/34). Multifactor logistic regression analysis showed that, fever, COPD assessment test (CAT) score in stable stage, serum IP-10 and TNF-α levels were correlated with respiratory viral infections in patients with acute exacerbations of COPD. The levels of serum IP-10 and sIL-2R increased significantly in patients with influenza A virus. Conclusions: Respiratory viral infections were common in acute exacerbations of COPD. Influenza A virus and rhinovirus were the two most common viruses. Fever was a common symptom. Patients with severe respiratory symptoms at stable stage were susceptible to viral infection. Viral infection was associated with an increase in systemic inflammatory levels, most significantly in influenza virus infection. A discriminant model composed of fever, CAT score in stable stage, serum IP-10 and TNF-α levels can be used to predict respiratory viral infections in acute exacerbations of COPD.

Significance of Soluble Interleukin-2 Receptor to Predict Prognosis and Support Decision-Making on Watchful Waiting for Stage II-IV Follicular Lymphoma Patients in the Rituximab Era

Background: Follicular lymphoma (FL) shows indolent clinical course and the optimal management strategy includes watchful waiting (WW). To define prognostic models for WW in clinical practice, we focused on serum soluble interleukin-2 receptor (sIL-2R) in the era of rituximab (R).Methods: To evaluate risk stratification of patients with FL, we employed the current retrospective study. The data and follow-up information of patients were collected from three medical centers. The diagnosis of FL is made by the WHO criteria. Eligible patients were aged 18-90 years, previously untreated, and diagnosed between 2004 and 2016. WW was considered as an initial approach for patients with asymptomatic, no organ damage by lymphoma, or lacking bulky disease. Progression-free survival from diagnosis (PFS1) was defined as the time from diagnosis to disease progression requiring therapy in WW, first progression after frontline active therapy, or death from any cause. Progression free survival after active therapy (PFSA) was defined as the time from anti-lymphoma therapy to progression or death, and PFS2 was defines as the time from diagnosis to secondary progression or death from any cause. This study was approved by the independent ethics committee or institutional review board at participating institutions.Results: Total 291 patients with newly diagnosed FL with stage II-IV and with grade 1-3a were included. Of these, 12.7% of patients were older than 75 years, 45% were men, 62.5% had stage IV disease, 18.9% were elevated LDH, 16.7% were beta 2-microglobulin (B2m) beyond 3 mg/L, 7.2% were grade3a, and 32.0% were FLIPI-high. The serum levels of B2m and sIL-2R were measured in each center, and the examination rates were 88.6% and 100%, respectively. In a simple linear regression, statistic correlation between serum B2m and sIL-2R of individual patients were confirmed with R-squared of 0.4 and P-value of <0.001. The sIL-2R of 1000 IU/mL was correlated with B2m of nearly 1.2 mg/L. The proportion of patients with sIL-2R ≤500, >500 ≤1000, and >1000 were 18.9%, 26.8%, and 54.3%, respectively. Total 89 patients (30.6%) had a first-line management strategy of WW, and during the median follow-up of 6.9 years, 52 patients required active therapy consisted of R-CHOP like (100%). The other 202 patients received frontline active therapy, included R-CHOP like (82.7%), R-CVP (12.9%), R-bendamustine (1%), or R-monotherapy (3.4%), and only 5 patients received R-maintenance. With a median follow-up of 5.5 years, there were 8 deaths in WW and 22 in frontline active therapy, demonstrating no difference in overall survival (P = 0.3). Based on multivariate analysis, factors associated with PFS1 are sIL-2R of ≤500, >500 ≤1000 IU/mL, and >1000 IU/mL (HR, 1.34; 95% CI 1.03-1.74) and stage IV (HR 1.71, 95% CI 1.11-2.63), while gender, age >75 years, B2m >3.0 mg/L, elevated LDH, and histological grade were not significant. When divided into three groups using sIL-2R, 6-year PFS1 were 74.2%, 51.4%, and 40.3%, respectively (P <0.001) in the entire patients, and were 65.2%, 41.4%, and 20.7%, respectively (P <0.001) among patients with WW. Overall, PFS1 of patients with WW was not so favorable as those with frontline active therapy (HR 1.43; 95% CI 1.01-2.02, P = 0.043), but PFS2 was equivalent (HR 1.57; 95% CI 0.76-3.27, P = 0.22). Among patients with sIL-2R ≤1000 IU/L, 6-year PFS1 was equally favorable in patients with WW compared to frontline active therapy (51.9% vs. 70.4%, P = 0.06; Figure 1), and 6-year PFSA was also equally favorable (80.6% vs. 67.7%, P = 0.75). On the contrary, among patients with sIL-2R >1000 IU/L, WW was associated with inferior PFS1 (HR 3.00; 95% CI 1.48-3.89; Figure 1) and PFS2 (HR 2.87; 95% CI 1.25-6.60) compared with frontline active therapy. The rate of histological transformation (HT) was similar: 5 in WW vs. 4 in frontline active therapy (P = 0.1). Median time to HT from diagnosis was 6.0 years (1.2-7.0) in WW, which was quite longer compared to 1.3 years (0.3-1.8) in frontline active therapy (P = 0.01). Secondary myeloid malignancies had developed in 4 patients at median 3.6 years (2.5-6.2) after frontline active therapy.Conclusion: For FL patients, the usefulness of sIL-2R is demonstrated for predicting intervals from starting WW until therapy requirements. In addition to general guidelines, the variable of sIL-2R ≤1000 IU/L at diagnosis was the simple indicator to recommend WW to postpone active therapy without impairing prognosis. DisclosuresNo relevant conflicts of interest to declare.

A Prospective Observational Study Evaluating Sarcopenia By Using the Bioelectrical Impedance Analysis in Elderly Patients with Hematologic Malignancies

[Introduction] Sarcopenia is characterized by age-related decline of skeletal muscle plus low muscle strength and/or physical performance. Previous studies have confirmed the association of sarcopenia and adverse health outcomes, such as falls, disability, hospital admission, long term care placement, poorer quality of life, and mortality, which denotes the importance of sarcopenia in the health care for older people. Population-based studies reported that the prevalence of sarcopenia in Japanese healthy adults aged≥60 years was 8.5% among men and 8.0% among women. Sarcopenia was recently identified as a poor prognostic factor in patients with solid tumors. In cancer patients, sarcopenia is associated with treatment failure, chemotherapy toxicity, and a shorter time to tumor progression related to survival. In contrast to solid tumors, the clinical relevance of sarcopenia in hematologic malignancies is still unknown. The present study investigated the prevalence of sarcopenia based on the criteria of the Asian Working Group for Sarcopenia (AWGS) in elderly patients with hematologic malignancies.[Patients and Methods] We prospectively analyzed 56 elderly patients aged≥60 years with hematologic malignancies diagnosed at our institution between 2015 and 2018. Appendicular skeletal muscle mass (ASM) was measured at diagnosis by using multifrequency bioelectrical impedance analysis (BIA) (InBody 720). BIA is suitable for body composition monitoring in elderly patients as a fast, noninvasive, and convenient method. Skeletal muscle index (SMI) was defined as the ratio of ASM divided by height in square centimeters. We also evaluated physical function by using short physical performance buttery (SPPB). Sarcopenia was defined according to the AWGS algorithm, in which the patient has low muscle mass, and low muscle strength or low physical performance. Low muscle mass was defined as a skeletal muscle index (SMI: ASM/height2) of <7.0kg/m2 in men and <5.7kg/m2 in women. Pre-sarcopenia was defined as having only low muscle mass. Low muscle strength was defined as a handgrip strength of <26kg in men and <18kg in women; and low physical performance, as a gait speed of <0.8m/sec. The study protocol was approved by the Institutional Review Board of Yokohama Municipal Citizen's Hospital, and it was carried out in accordance with the Declaration of Helsinki.[Results] Median age at diagnosis was 77 years (60-93 years), with 34 males and 22 females. The diagnosis included non-Hodgkin lymphoma (NHL, n=36), multiple myeloma (MM, n=9), myelodysplastic syndrome (MDS, n=10), and acute myeloid leukemia (AML, n=1). The prevalence of low muscle mass (pre-sarcopenia) was 41% (14/34) in men and 77% (17/22) in women. The prevalence of low muscle strength was 35% (12/34) in men and 41% (9/22) in women. The prevalence of low physical performance status (Gait speed:<0.8m/sec) was 6% (2/34) in men and 9% (2/22) in women. The prevalence of sarcopenia based on a diagnosis of low muscle mass, low muscle strength, and low physical performance was 24% (8/34) in men and (8/22) 36% in women. The prevalence of low SPPB score (<10) was 9% (3/34) in men and 18% (4/22) in women. Among 36 NHL patients, the diagnosis included DLBCL (n=15), FL (n=10), MALT (n=3), SMZBCL (n=3), MCL (n=2), and others. The prevalence of sarcopenia was 25% (5/20) in men and 50% (8/16) in women. The mean age was 83 years in the sarcopenic group (n=13, 36%) and 73 years in the non-sarcopenic group (n=23, 64%) (p=0.0001). Sarcopenic patients displayed a similar level of serum albumin, LDH, sIL2-R, and BMI when compared with patients who were not sarcopenic. However, sarcopenic patients displayed significantly lower levels of serum dehydroepiandrosterone-sulfate (DHEA-S) and a higher CCI score than patients who were not sarcopenic. Sarcopenic patients failed to complete the treatment planned as compared with non-sarcopenic patients (p=0.001).[Conclusion] These results demonstrated that the prevalence of sarcopenia in elderly patients with hematologic malignancies is higher than that in the Japanese general elderly population. In particular, the prevalence of sarcopenia in female NHL patients is higher than that in male NHL patients. Several factors such as age, serum DHEA-S or comorbidities may affect the incidence of sarcopenia. Since our results are based on a small-sized analysis, further large prospective studies are warranted to verify this conclusion. DisclosuresNo relevant conflicts of interest to declare.

Serum Soluble Interleukin-2 Receptor As a Surrogate Biomarker of Metabolic Tumor Volume Measured By 18F-FDG PET/CT in Diffuse Large B-Cell Lymphoma

Background. Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of non-Hodgkin lymphoma. High total metabolic tumor volume (TMTV) or total lesion glycolysis (TLG) calculated using 18F-FDG PET/CT images at diagnosis predicts poor prognosis of patients with DLBCL. However, high cost and poor access to the imaging facilities hamper wider use of 18F-FDG PET/CT.Methods. In order to explore a surrogate marker for TMTV/TLG, we evaluated the correlations between the serum levels of soluble interleukin-2 receptor (sIL-2R) and TMTV/TLG in 64 patients with DLBCL, and the results were verified in an independent validation cohort of 86 patients. The study procedures were in accordance with the Helsinki Declaration and institutional ethical guidelines, conducted under the auspices of the institutional ethics committee, and approved by the institutional review boards.Results. In the training cohort(n=64), OS and EFS were significantly lower in patients with TMTV≥150cm3 than in those with less than 150cm3 [5-year OS; 84.0% vs 29.1%, P=0.000194, 5-year EFS; 71.4% vs 28.7%, P=0.000384]. We also found that TLG≥1500cm3 at diagnosis predicted significantly inferior OS and EFS[5-year OS; 84.0% vs 31.7%; P=0.000477, 5-year EFS; 70.2% vs 30.6%, P=0.00107].Pearson's correlation tests demonstrated highly significant positive correlations between sIL-2R and TMTV[R2=0.490; P=0.00004] and between sIL-2R and TLG[R2=0.543; P=0.00000357]. Serum sIL-2R≥1300 U/ml was a strong prognostic factor both for worse OS and EFS[5-year OS; 85.2% vs 25.9%, P=0.000035, 5-year EFS; 72.0% vs 26.8%, P=0.000076].In a univariate analysis, B symptom, LDH, sIL-2R, TMTV and TLG were associated with poor 5-year OS; and B symptom, LDH, PS, sIL-2R, TMTV and TLG were identified as poor prognostic factors for 5-year EFS. We performed multivariate analysis that included sIL-2R and all factors in NCCN-IPI; age, LDH, clinical stage, ECOG PS and major organ involvement. In this multivariate analysis, age and sIL-2R were independently associated with poor 5-year OS(age; HR, 4.44; 95% CI, 1.05 to 18.7, P=0.0424, sIL-2R; HR, 4.45; 95% CI, 1.04 to 19.1, P=0.0444). Another multivariate analysis that included TMTV and all factors for NCCN-IPI demonstrated that TMTV was an only independent prognostic factor for 5-year OS(HR, 3.87; 95% CI, 1.08 to 13.8; log-rank, P=0.0373).Subgroup analyses included the patients with NCCN-IPI High-Int and High(n=49) demonstrated that the cut off value of TMTV 150cm3 stratified treatment outcomes in this poor prognostic group [5-year OS; 75.0% vs 27.7%, P=0.0355, 5-year EFS; 66.7% vs 29.7%, P=0.0493]. Similar results were obtained using the cut-off value of sIL-2R 1300U/mL [5-year OS; 75.0% vs 25.9%, P=0.0182, 5-year EFS; 58.3% vs 29.7%, P=0.0499].In the validation cohort(n=86), Kaplan-Meier curves showed that OS and EFS in patients with TMTV≥150cm3 was again lower than in those with TMTV<150cm3[5-year OS; 87.0% vs 59.5%, P=0.016, 5-year EFS; 72.8% vs 52.3%, P=0.0154]. We also found that TLG≥1500 cm3 at diagnosis predicted inferior OS and EFS as TMTV did[5-year OS; 84.8% vs 59.3%, P=0.0157; log-rank, 5-year EFS; 74.8% vs 45.8%, P=0.000604]. Kaplan-Meier curves showed that sIL-2R≥1300 U/ml was a strong prognostic factor both for worse OS and EFS[5-year OS; 86.3% vs 61.8%, P=0.0188, 5-year EFS; 85.0% vs 46.8%, P=0.000413]. Pearson's correlation tests gave similar results that there were positive correlations between sIL-2R and TMTV [R2=0.461; P=0.00000631], and between sIL-2R and TLG[R2=0.720; P=0.0000017987]. In a univariate analysis, TMTV and TLG were associated with poor 5-year OS, whereas sIL-2R, TMTV and TLG were identified as poor prognostic factors for EFS. In a multivariate analysis including sIL-2R, age and sIL-2R were associated with poor 5-year OS. In another multivariate analysis including TMTV showed that age, LDH and TMTV were independent prognostic factor for 5-year OS. Altogether, we could validate the prognostic significances of sIL-2R, TMTV, and TLG, and positive correlation between sIL-2R and metabolic values, such as TMTV and TLG, confirming that sIL-2R is a surrogate biomarker of these metabolic values.Conclusion. Serum level of sIL-2R represents a convenient surrogate marker to estimate metabolic tumor burden measured by 18F-FDG PET/CT that can predict treatment outcomes of patients with DLBCL.Disclosures. No relevant conflicts of interest to declare. [Display omitted]

Serological lymphocytic activity and patient-reported outcomes in Sjögren's syndrome.

This study was set to investigate whether serum markers of lymphocytic activity are associated with patient-reported outcomes in Sjögren's syndrome (SS). Forty-six patients with SS were included in this cross-sectional study. Patients with monoclonal gammopathy, history of malignant lymphoma, or with secondary SS were excluded. Serum levels of IgG, β2-microglobulin (β2M), soluble interleukin-2 receptor (sIL2-R), and free light chains (FLC) were assessed. Systemic disease activity was measured by the EULAR SS disease activity index (ESSDAI). Patient-reported symptoms were recorded by visual analogue scales (VAS) of pain, fatigue, and dryness, as compiled in the EULAR SS patient-reported index (ESSPRI). Depressive symptoms were determined by the Patient Health Questionnaire 9 (PHQ-9). Serum concentrations of κFLC (r = 0.491, p = 0.001), λFLC (r = 0.326, p = 0.027), and β2M (r = 0.421, p = 0.004) correlated with the ESSDAI, whereas sIL-2R and IgG did not. No correlations between serum markers of lymphocytic activity and the ESSPRI, or single VAS measures of pain, dryness, or fatigue, were found. In patients with VAS fatigue scores in the upper quartile, sIL-2R serum levels were even decreased (p = 0.019). Only depressive symptoms as determined by PHQ-9 were positively correlated with fatigue (r = 0.536, p < 0.001). In this well-defined cohort of patients with SS, serological lymphocytic activity was not correlated with patient-reported outcomes and sIL-2R levels were even decreased in patients with high fatigue scores. Only depressive symptoms were correlated with fatigue. This highlights the need to further understand the link between inflammation and disease characteristics in SS.

Effect of allogeneic blood transfusion on levels of IL-6 and sIL-R2 in peripheral blood of children with acute lymphocytic leukemia.

Effect of allogeneic blood transfusion on the expression of interleukin-6 (IL-6) and soluble interleukin-2 receptor (sIL-2R) in peripheral blood of children with acute lymphoblastic leukemia (ALL) was investigated. A total of 91 ALL children admitted to Nanfang Hospital from June 2014 to January 2017 were selected as the study group. Patients were randomly divided into allogeneic blood transfusion group (n=38) and non-transfusion group (n=53). In addition, a total of 64 healthy children were also selected from June 2014 to January 2017 as the control group. Patients in allogeneic blood transfusion group were transfused with red blood cell suspension and machine-collected platelets, while patients in non-transfusion group were not treated with blood transfusion. Peripheral venous blood was collected before and at 4, 8 and 12 weeks after blood transfusion to prepare serum. Serum IL-6 and sIL-2R levels were measured by enzyme-linked immunosorbent assay (ELISA). Before transfusion, serum levels of IL-6 and sIL-2R were significantly lower in the study group than those in control group (p<0.05), and no significant differences in serum levels of IL-6 and sIL-2R were found between the allogeneic blood transfusion and non-transfusion group. After transfusion, serum levels of IL-6 and sIL-2R were stable for 12 weeks in the non-transfusion group, while IL-6 and sIL-2R levels were significantly increased in the allogeneic blood transfusion group. The results showed that serum level of IL-6 and sIL-2R was increased in ALL patients with allogeneic blood transfusion, which resulted in reduced antibody production and decreased cellular immunity. The patients had low immunity, and attention should be paid on the pathogen infection prevention.

Treatment Effects upon Prolactin and Soluble Receptor of Interleukin-2 in Psoriatic Patients

Psoriasis vulgaris is a chronic inflammatory hyper-proliferative disease of the skin, scalp, nails, and joints. It has been hypothesized that prolactin (PRL) may modulate the skin immune system and be involved in the pathogenesis of psoriasis. Psoriasis exerts significant, negative impact on patients' quality of life. Relatively high rates of depression are reported in patients with psoriasis. The aim of this work was to study the possible role of PRL in the pathogenesis of psoriasis and its correlation with the disease activity, clinically, molecular and emotional status of patients. A total of 41 samples were analyzed - 21 new patients with psoriasis vulgaris before treatment and 20 after therapy - were included in this study. In all patients, we determined skin disease activity according to the PASI index, the psychological impact measured with HAMA and HAMD scales and the quality of their life measured by DLQI. The concentration of prolactin in the serum was measured by enzyme-linked immunosorbent assay (ELISA), and the concentration of soluble receptor of IL-2 was measured with automated immune chemiluminescent system - IMMULITE procedure. The PRL and sIL2R serum levels were significantly decreased after three months of therapy, at least 50% with a p value <0.00001. Clinical, hormonal, molecular correlations between before and after therapy were measured with a statistically significant result. Correlations between HAMA-PRL and DLQI-PRL before therapy were not statistically significant, only the relationship between HAMD and PRL was demonstrated. After treatment, we obtained a significant clinical, psychological and paraclinical (especially serum levels of prolactin and sIL2R) decreased and relevant response on all the patients treated and analyzed. Prolactin seems to have a role in the pathogenesis of psoriasis and may represent a cause and/or a consequence of psoriasis pathology. The most likely scenario is that PRL enhances interferon-induced chemokine production in keratinocytes, thereby facilitating cutaneous T-cell infiltration. This raises the intriguing light that PRL may offer a novel future therapeutic target in psoriasis and other skin diseases that worsen in response to psychological distress.

Serum Soluble Interleukin 2 Receptor Level as a Marker of Acute Rejection in Pediatric Kidney Transplant Recipients

Background: Despite advances in immunosuppression, acute allograft rejection remains one of the key factors affecting patient and graft survival in pediatric kidney transplantation. The aim of the study is to evaluate the role of serum soluble IL2 receptor (sIL2R) level as a noninvasive assessment parameter of acute rejection (AR). Method: Serum sIL2R level was measured (using enzyme-linked immune-sorbent assay technique) in 60 pediatric kidney transplant recipients (30 recipients with AR and 30 transplant recipients with stable graft function). Results: The mean values of sIL2R level in patients experiencing AR (14.8 ± 6.54) ng/mL were significantly higher than that in patients with stable graft functions (6.44 ±1.95) ng/mL (p = 0.0001). In addition; patients with AR proved by graft biopsy had their mean values of sIL2R level (16.19 ± 7.48) ng/mL significantly higher than that of other recipients in the study population (p = 0.032). Conclusion: Serum sIL2R level may serve as a noninvasive diagnostic indicator in pediatric kidney transplant recipients experiencing AR.

Serum soluble interleukin-2 receptor as a biomarker in immunoglobulin G4-related disease

Objectives: Serum soluble interleukin-2 (IL-2) receptor (sIL-2R) might reflect disease activity in immunoglobulin G4-related disease (IgG4-RD). We aimed to elucidate the clinical significance of blood markers, including sIL-2R, in patients with IgG4-RD.Methods: We enrolled 59 patients with IgG4-RD and investigated the association between blood markers (white blood cells, C-reactive protein, sIL-2R, IgG, IgG4, IgE, total hemolytic complement), and clinical indices.Results: At baseline, serum sIL-2R (Rs = 0.532, p < .001) and IgG4 (Rs = 0.545, p < .001) levels showed significant correlation to the number of organs involved. During follow-up period (median, 70 months; range, 7–195 months), 40 patients were treated with corticosteroids. Receiver operating characteristic (ROC) analysis showed that baseline sIL-2R levels most accurately predicted patients requiring glucocorticoid treatment (area under the ROC curve, 0.807). Among the 46 patients who improved, sIL-2R and IgG4 levels decreased in 42 and 41 patients, respectively. Among them, serum sIL-2R levels decreased to a normal range in 42 patients (91%), whereas IgG4 levels normalized in 19 (41%).Conclusion: The serum sIL-2R level is a potential biomarker for IgG4-RD that may reflect the number of involved organs and may predict patients requiring glucocorticoid treatment.

Soluble Interleukin-2 Receptor: A Potential Marker for Monitoring Disease Activity in IgG4-Related Disease.

Background IgG4-related disease (IgG4-RD) is a fibroinflammatory condition. T-cells play a crucial role in the pathogenesis, and therefore, serum soluble interleukin-2 receptor (sIL-2R) may be a potential biomarker. Method We studied the levels of sIL-2R in 26 histologically proven IgG4-RD patients with available serum sIL-2R and compared them to those in newly diagnosed and untreated sarcoidosis patients (n = 78) and controls (n = 101) and the serum sIL-2R levels in patients after treatment of IgG4-RD (n = 15). The disease activity was measured using the IgG4-Related Disease Responder Index (IgG4-RD RI). Results Median serum sIL-2R in IgG4-RD patients was 4667 pg/ml compared to 1515 pg/ml in controls (P < 0.001) and 6050 pg/ml in sarcoidosis patients (P = 0.004 compared to IgG4-RD). All IgG4-RD patients had elevated serum sIL-2R levels compared to the reference value of <2500 pg/ml in controls and 85% elevated serum IgG4; however, these did not correlate with each other. Both serum sIL-2R and IgG4 levels declined significantly after treatment (P = 0.001 and P = 0.01, resp.). Before treatment, serum sIL-2R level and IgG4-RD RI did not correlate with each other. However, the decrease in serum sIL-2R upon treatment did correlate significantly (P = 0.04) with the decrease in disease activity assessed by IgG-RD RI. Conclusion Serum sIL-2R is elevated in IgG4-RD reflecting the inflammatory process with enhanced T-cell activation. Furthermore, serum sIL-2R might serve as a potential marker of response to treatment in IgG4-RD.

The Role of Soluble Interleukin-2 Receptor (sIL-2r) in Diagnosis of Adult Hemophagocytic Lymphohistiocytosis (HLH): A Single Center Retrospective Study

Purpose: Serum soluble interleukin-2 receptor (sIL-2r) is considered an important disease marker in hemophagocytic lymphohistiocytosis (HLH). High levels of sIL2r are indicative of T-cell activation, and sIL2r > 2400 U/mL was 93% sensitive and 100% specific for pediatric HLH in the HLH-2004 diagnostic criteria. [1] There are no published data on its performance characteristics in adults and very limited data in children. [2] We conducted a retrospective study to examine the diagnostic sensitivity and specificity of sIL-2r in diagnosing HPS/HLH, to assess how it varies with disease severity, determine its prognostic significance and ability to discriminate between subgroups of HPS/HLH.Methods: Retrospective data was collected on adult patients with at least one sIL-2r level at Vancouver General Hospital in Vancouver, Canada between March 2012 and April 2017. Patients were subdivided into HLH and non-HLH groups. Sensitivity, specificity, prognosis associated with sIL-2r >10,000U/ml, utility as a marker of disease activity and mean sIL-2r between subgroups of HLH were evaluated. Non-HLH patients did not have convincing evidence to suggest HLH and did not receive HLH-specific therapy. Serum sIL-2r levels were enzyme-linked immunosorbent assay (ELISA; Siemens IMMULITE Immunoassay platform, adult reference range 241-846 U/ml).Results: 81 patients were included, 41 with HLH and 40 with an alternate diagnosis (non-HLH). Non-HLH diagnoses included sepsis, histiocyte disorders, multiple transfusions, liver disease, cardiac disease, autoimmune disease/vasculitis, and other inflammatory diseases. The sensitivity of sIL-2r >2400 U/ml was 93% (95% CI 0.79 - 0.98) and specificity 63% (95% CI 0.46 - 0.77). Specificity improved to 93% (95% CI 0.79 - 0.98) with a threshold of sIL-2r >10,000U/ml. Based on ROC curves, sIL2r is a good diagnostic test (AUC of 0.86) with a threshold that optimizes sensitivity and specificity of 2785U/ml and ferritin is a fair test (AUC 0.78) with an optimal threshold of 5775 ug/L. Similar to ferritin, sIL-2r levels correlated with disease activity in seven HLH patients that had multiple sIL-2r levels drawn during their disease course. Within the HLH group, sIL-2r >10,000U/ml was not associated with worse prognosis. Higher sIL-2r levels were seen in malignancy associated HLH (MAHS) as compared to infection associated HLH (IAHS) and macrophage activation syndrome (MAS).Conclusion: sIL-2r >2,400U/ml is a sensitive test for diagnosis of adult HPS/HLH and has utility in monitoring disease activity. At higher levels (sIL-2r >10,000U/ml), this biomarker loses sensitivity but gains specificity in diagnosing HPS/HLH. Higher sIL-2r levels may indicate MAHS when the underlying etiology is unclear. In adults, secondary HPS/HLH is much more common than primary HLH, and all patients in this study were presumed to be secondary. The defining features of secondary HPS/HLH are pathologic immune activation and hypercytokinemia leading to end organ damage. SIL-2r is elevated in numerous conditions associated with T-cell activation and inflammation, such as lymphoma and autoimmune lymphoproliferative syndrome (ALPS), and larger prospective studies of adults with these and other conditions are needed to better define the specificity of increased sIL-2r for HPS/HLH. Since adult secondary HPS/HLH is increasingly diagnosed and treated in many centers, diagnostic criteria for adult secondary HPS/HLH should incorporate markers of hypercytokinemia and immune activation.

Diagnostic Value of Serum-Soluble Interleukin 2 Receptor Levels vs Angiotensin-Converting Enzyme in Patients With Sarcoidosis-Associated Uveitis

New and improved diagnostic tests for sarcoidosis-associated uveitis are needed because the currently available laboratory diagnostic biomarkers (eg, lysozyme and angiotensin-converting enzyme [ACE]) are lacking in high sensitivity and specificity. To compare the value of soluble interleukin 2 receptor (sIL-2R) with ACE as diagnostic biomarkers of sarcoidosis in patients with uveitis. A cross-sectional retrospective study was conducted using data collected from 249 consecutive patients with uveitis at the Erasmus University Medical Center uveitis outpatient clinic, Rotterdam, the Netherlands, from April 3, 2013, through November 25, 2015. Measurements of sIL-2R and ACE in serum samples and data extraction from patient files were conducted from December 2016 through February 2017, and analysis from April to May 2017. Serum levels of sIL-2R and ACE and chest radiographic findings were assessed. Receiver operating characteristics analysis was used to determine the probability that individual tests correctly identified patients with sarcoidosis. The Youden Index was used to determine the optimal cutoff points for serum sIL-2R and ACE levels to define sarcoidosis in patients with uveitis. Data were analyzed from 249 patients with uveitis who had their serum sIL-2R and ACE levels determined and underwent chest radiography. Mean (SD) age at the time of sampling was 51 (16) years, 161 patients (64.7%) were women, and 191 (76.7%) were white. Although patients with sarcoidosis-associated uveitis had the highest mean (SD) serum sIL-2R (6047 [2533] pg/mL) and ACE (61 [38] U/L) levels, elevated serum sIL-2R levels were also found in patients with HLA-B27–associated (4460 [2465] pg/mL) and varicella-zoster virus–associated (5386 [1778] pg/mL) uveitis. Serum sIL-2R and ACE levels were significantly correlated (Pearson correlation coefficient, 0.205; P = .001, 2-sided), but no association was found between uveitis activity and sIL-2R (Spearman rank correlation coefficient [ρ], 0.070, P = .27) nor uveitis activity and ACE (ρ, −0.071; P = .27). The highest Youden index for sIL-2R alone was 0.45, corresponding to an optimal cutoff of 4000 pg/mL and providing 81% (95% CI, 74%-89%) sensitivity and 64% (95% CI, 56%-72%) specificity alone but combined with chest radiography yielded 92% sensitivity and 58% specificity. Chest radiography combined with sIL-2R at a cutoff of 6000 pg/mL resulted in 77% sensitivity and 73% specificity. Combined chest radiography and serum ACE levels at the standard cutoff of 68 U/L resulted in 70% sensitivity and 79% specificity. This cross-sectional study demonstrates that sIL-2R is a useful marker for diagnosing sarcoidosis in patients with uveitis and has slightly better diagnostic value than ACE.

Value of serum inflammatory factors in differential diagnosis of systemic juvenile idiopathic arthritis and sepsis in children

Objective To evaluate the value of soluble interleukin 2 receptor (sIL-2R), interleukin (IL)-6, IL-10 and tumor necrosis factor-α (TNF-α) used in differential diagnosis of systemic juvenile idiopathic arthritis (sJIA) and sepsis in children. Methods Each of 41 children with sJIA and sepsis were enrolled and 41 healthy children were selected as the healthy control group at Children′s Hospital of Nanjing Medical University from January 2015 to July 2017.Levels of serum sIL-2R, IL-6, IL-10, TNF-α and peripheral blood levels of white blood cells (WBC), hemoglobin (Hb), platelets (PLT), high sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR) and procalcitonin (PCT) were compared between the sJIA group and sepsis group before treatment and those of the healthy control group. Results Peripheral blood levels of WBC, Hb, PLT, CRP, ESR and PCT in the healthy control group were (8.43±2.35)×109/L, (124.46±8.76) g/L, (298.45±100.23)×109/L, (11.32±5.76) mg/L, (18.32±9.33) mm/1 h, (0.27±0.17) μg/L and the levels of serum sIL-2R, IL-6, IL-10, TNF-α were (483.24±255.33) kU/L, (7.38±4.02) ng/L, (5.45±3.06) ng/L, (8.23±3.03) ng/L, respectively.Peripheral blood levels of WBC, Hb, PLT, CRP, ESR and PCT in the sJIA group before treatment were (17.53±7.98)×109/L, (105.76±13.33) g/L, (389.43±176.34)×109/L, (88.32±43.21) mg/L, (55.32±34.23) mm/1 h, (0.53±0.24) μg/L and the levels of serum sIL-2R, IL-6, IL-10, TNF-α were (945.35±436.75) kU/L, (132.39±58.43) ng/L, (7.02±5.12) ng/L, (14.32±7.95) ng/L.Peripheral blood levels of WBC, Hb, PLT, CRP, ESR and PCT in sepsis group before treatment were (16.88±6.54)×109/L, (102.95±20.18) g/L, (302.87±124.45)×109/L, (60.41±33.24) mg/L, (53.75±28.43) mm/1 h, (2.84±1.76) μg/L and the levels of serum sIL-2R, IL-6, IL-10, TNF-α were (2 476.36±1 574.11) kU/L, (39.47±20.32) ng/L, (6.31±4.04) ng/L, (15.87±6.32) ng/L.Blood levels of WBC, CRP, ESR, PCT, sIL-2R, IL-6 and TNF-α in the sJIA and the sepsis group were significantly higher than those in healthy control group.Serum levels of sIL-2R and PCT in the sJIA group were obviously lower than those in the sepsis group, but the level of IL-6 was higher than that in the sepsis group. Conclusion Combined detection of blood sIL-2R, IL-6 and PCT can provide a reference and reduce mistaken diagnosis of sJIA and sepsis in the earlier clinical stage. Key words: Soluble interleukin 2 receptor; Interleukin-6; Interleukin-10; Tumor necrosis factor-α; Systemic juvenile idiopathic arthritis; Sepsis

Influence of inhaled budesonide and salbutamol on oxidative stress and serum inflammatory cytokines in children with bronchial asthma

Objective To observe the clinical effect of budesonide combined with salbutamol in the treatment of children with bronchial asthma, and its influence on oxidative stress and serum interleukin-2(IL-2), soluble IL-2 receptor (sIL-2r) levels. Methods 70 children with bronchial asthma were divided into observation group and control group according to the different treatment, 35 cases in each group.The observation group was inhaled budesonide combined with salbutamol, the control group was given salbutamol inhalation therapy.The clinical efficacy of the two groups was observed, and the changes of serum oxidative stress factor, IL-2 and sIL-2r levels before and after treatment in the two groups were compared. Results In the observation group, 20 cases were cured, 7 cases were markedly effective, effective in 5 cases, the total effective rate was 94.3%.In the control group, 17 cases were cured, 6 cases were markedly effective, effective in 4 cases, the total effective rate was 77.1%.The total effective rate between the two groups had statistically significant difference(χ2=26.543, P<0.05). After treatment, the malondialdehyde (MDA), end products(AOPP) of the observation group were (16.26±1.76)U/L, (42.123±5.745)μmol/L, respectively, which were lower than those of the control group [(22.16±2.84)U/L, (63.63±6.22)μmol/L, t=23.354, 25.348, all P<0.05]. The glutathione peroxidase (GSH-PX), superoxide dismutase(SOD) of the observation group were (236.46±32.25)ng/L, (19.643±3.587)ng/L, respectively, which were higher than those of the control group [(197.43±18.42)ng/L, (18.244±2.446)ng/L, t=18.943, 15.123, all P<0.05]. The IL-2, sIL-2r levels of the observation group were (5.28±2.65)μg/L, (30.376±2.147)mg/L, respectively, which were significantly lower than those of the control group [(9.84±3.22)μg/L, (37.564±1.323)mg/L], the differences were statistically significant(t=21.378, 24.643, all P<0.05). Conclusion Inhaled budesonide combined with salbutamol in the treatment of children with bronchial asthma is helpful to control the symptoms of asthma, and can inhibit oxidative stress, reduce serum sIL-2r and IL-2 levels, it is worthy of promotion. Key words: Asthma; Administration, inhalation; Salbutamol; Budesonide; Child