Serum Soluble Interleukin-2 Receptor Research Articles

Harnessing Invariant Natural Killer T Cells for Cancer Therapy

Abstract SCI-20Natural killer T (NKT) cells are distinct innate lymphocytes that recognize lipid ligands in the context of nonclassical MHC molecules called CD1d. NKT cells have been broadly classified into two major types based on their T-cell receptors (TCRs). One group, termed type I invariant, or iNKT cells, bears a noncanonical conserved TCR (Va24/Vb11 in humans, and Va14 in mice), while others, termed type II NKT cells, express diverse TCRs. Recent studies have identified several naturally occurring lipid ligands recognized by these cells. iNKT cells are efficiently activated by α-galactosylceramide (α-GalCer), a lipid ligand first isolated from a marine sponge. Activation of iNKT cells in vivo leads to activation of NK cells, as well as downstream activation of adaptive immunity, leading to strong antitumor effects in mice. Several hematologic malignancies express CD1d and are attractive targets of NKT-targeted therapeutic approaches. Progression from premalignant gammopathy to clinical myeloma is associated with loss of the interferon-γ-secreting effector function of NKT cells. Adoptive transfer of α-GalCer-loaded dendritic cells (DCs) led to activation and expansion of circulating NKT cells in vivo in patients with advanced cancer. However, the functional properties of NKT cells were found to be impaired. Lenalidomide leads to enhanced activation and cytokine secretion by NKT cells in a ligand-dependent manner in culture. This led us to treat patients with early multiple myeloma with three cycles of low-dose lenalidomide and α-GalCer-loaded DCs. Preliminary studies from this trial show that this combination leads to activation of diverse innate cells, including NKT and NK cells, and upregulation of NKG2D and CD56. Activation of these innate lymphocytes also led to an increase in serum-soluble interleukin-2 receptor and induction of eosinophilia. Together, these data demonstrate the capacity of this combination to recruit several innate lymphocytes and mediate antitumor effects. In contrast to conventional MHC I/II restricted T cells, understanding the diversity and functional properties of lipid-reactive T cells is still in its infancy. The biology of NKT cells may have an impact, due to the cells’ immune-regulatory properties, in diverse inflammatory states, including cancer, atherosclerosis, and allergy. This research was supported in part by funds from the Translational Research Program of the Leukemia and Lymphoma Society. Disclosures:Dhodapkar:KHK: Research Funding; Celgene: Research Funding. Off Label Use: Lenalidomide in asymptomatic myeloma.

Prognostic Impact of Serum Soluble Interleukin-2 Receptor Values Just After Completion of R-CHOP in Diffuse Large B-Cell Lymphoma

Abstract 1591 IntroductionThe use of fluorodeoxyglucose-positron emission tomography (PET) to aid the prognosis of patients with diffuse large B-cell lymphoma (DLBCL) after treatment with rituximab-containing combination chemotherapy was investigated. Several studies report that less than 20 % of patients who are PET-negative and more than 85 % of PET-positive patients will experience lymphoma recurrence. Since therapy for DLBCL recurrence remains a major problem, the ability to accurately predict the risk of relapse in PET-negative DLBCL patients after chemotherapy would be extremely beneficial. In this study we focused on levels of serum soluble interleukin-2 receptor (sIL-2R) since several reports indicate that sIL-2R at the time of diagnosis is closely linked to the prognoses of DLBCL patients. We measured sIL-2R levels in DLBCL patients shortly after R-CHOP therapy and investigated whether there was any correlation with patient prognoses. Patients and MethodsThis was a retrospective pooled analysis of DLBCL patients treated with R-CHOP in our institute. Patients were included if they were under the age of 80, had an International Prognostic Index (IPI) score of more than two, and had received R-CHOP with curative intent. Patients who received salvage chemotherapies due to insufficient responses to R-CHOP were also included. We excluded patients with low IPI scores as their sIL-2R levels at the time of diagnosis were usually in the normal range. Patients were also excluded if R-CHOP could not be continued for reasons other than disease progression. sIL-2R and PET analyses were performed when patients first visited the institute after completing 6–8 cycles of R-CHOP. Patients were divided into three groups: Group A consisted of patients who had completed R-CHOP, were PET-negative and whose sIL-2R levels had returned to normal (<600 mg/dl); Group B consisted of patients who had completed R-CHOP and were PET-negative, but whose sIL-2R levels had remained high (>=600mg/dl); Group C consisted of patients who had switched to salvage therapies as well as those who remained PET-positive after completing R-CHOP. Overall survival (OS) was assessed using the Kaplan-Meier method and the log-rank test was used for comparisons within each group. A multivariate Cox regression analysis was used to adjust for IPI scores. ResultsFrom January, 2006 to January, 2012, a total of 178 DLBCL patients aged less than 80 years were referred to our institution, and 70 of these patients were included in this analysis. The median age of patients was 68 years (range 37–79 years), 96 % had advanced stage DLBCL, and 77 % had elevated lactate dehydrogenase levels. 30% of patients had ECOG performance status (PS) less than 2. The median sIL-2R level at the time of diagnosis was 2676 mg/dl (range 612–48000 mg/dl). The numbers of patients assigned to groups A, B, and C were 28 (40 %), 18 (26 %), and 24 (34 %), respectively. A Fisher’s exact test showed no significant differences in IPI scores between the three groups (p=0.453). A Mann-Whitney test showed no significant differences in sIL-2R levels at the time of diagnosis between the three groups (A; median 2660 mg/dl, range 612–19000 mg/dl, B; 2905 mg/dl, 970–37100 mg/dl, C; 4347 mg/dl, 734–48000 mg/dl). Patients in groups A and B received 6–8 cycles of R-CHOP (median 7 cycles). Patients in group C received 1–4 salvage treatments (median 2 treatments) before or after completion of R-CHOP (median 6 cycles, range 2–8 cycles). After a median follow-up time of 36 months (range 5–60 months), 24 deaths had occurred (including 20 due to lymphoma), and the 3 year OS rate for the entire cohort was 65.5 % [95 % confidence interval (CI), 51.7–76.2 %]. The 3 year unadjusted OS rate of patients in groups A, B, and C was 95.2% [95%CI, 70.7–99.3%], 60.7% [95%CI, 31.3–80.6%] and 30.6% [95%CI, 12.5–51.0%], respectively (log-rank, p<0.001), (group A vs B; hazard ratio (HR), 10.8; 95%CI, 1.33–88.1; p=0.026, group B vs C; HR, 2.24; 95%CI, 0.91–5.54; p=0.079). Multivariate analysis including IPI score, revealed that 3 year OS for patients in group B was significantly inferior to that for patients in group A (HR, 6.26; 95%CI, 1.29–30.4; p=0.023), but was comparable with that for patients in group C. ConclusionDLBCL patients with an IPI score of more than 2 had an increased risk of relapse if their sIL-2R levels failed to return to normal following R-CHOP treatment, even if they completed 6–8 cycles of R-CHOP and were PET-negative. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

P1-156 - Early Relapse is Associated with the High Serum Soluble Interleukin-2 Receptor Level after the Sixth Cycle of R-CHOP Chemotherapy in Patients with Advanced Diffuse Large B-Cell Lymphoma

ABSTRACT Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma. The present study assessed retrospectively the clinical significance of the serum soluble interleukin-2 receptor (sIL-2R) level in patients with advanced DLBCL. Twenty-one patients (age; range, 56–87, median, 73-year old, 14 males/7 females) were newly diagnosed as having advanced DLBCL (stages III and IV) based on pathological findings of the biopsy specimen and by using computed tomography and positron emission tomography between 2006 and 2009. All the patients received 6–8 cycles of the combination of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) (R-CHOP) or THP-COP (pirarubicin, cyclophosphamide, vincristine and prednisolone) (R-THP-COP) and attained complete response at the end of the treatment. The follow-up period ranged between 12 and 73 months with the median of 37 months. The serum sIL-2R levels (normal range, 144–518 U/ml) were determined at least before and after the second and the sixth cycles of the chemotherapy were carried out. Although all the patients reached complete remission, six patients experienced the disease relapse within 1 year from the initiation of the treatment. sIL-2R levels before the chemotherapy ranged from 416 to 21300 U/ml (median 2609 U/ml). sIL-2R levels after the second cycle of the chemotherapy ranged from 276 to 1980 U/ml (median 675 U/ml). sIL-2R levels after the sixth cycle of the chemotherapy ranged from 364 to 822 U/ml (median 548 U/ml). The early relapse was significantly associated with the high sIL-2R levels at the sixth cycle of the treatment, while the sIL-2R levels were low in the patients with the durable remission. sIL-2R levels at the disease onset or after the second cycle of the treatment were not correlated to the duration of the remission. Thus, the present study suggested that the sIL-2R levels after the sixth cycle of the chemotherapy might predict the early relapse in patients with advanced DLBCL.

Association of the numbers of CD163+ cells in lesional skin and serum levels of soluble CD163 with disease progression of cutaneous T cell lymphoma

Classically activated macrophages produce IL-12, IL-23, and TNF-α, whereas alternatively activated macrophages (M2 cells) produce IL-10 and express several receptors such as mannose receptor and CD163. Tumor-associated macrophages exhibit M2 phenotype, whose presence has been associated with poor prognosis in various tumors. To investigate distribution of CD163(+) cells in lesional skin and serum levels of soluble CD163 (sCD163) in patients with cutaneous T cell lymphoma (CTCL), atopic dermatitis (AD), or psoriasis. The numbers of CD163(+) and CD68(+) cells in lesional skin of CTCL, AD, or psoriasis, and in normal skin were examined by immunohistochemistry. Serum soluble CD163 (sCD163) levels were quantified by enzyme-linked immunosorbent assay. The numbers of CD163(+) cells in lesional skin of CTCL, AD, or psoriasis were significantly larger than in normal skin. In CTCL, the numbers of CD163(+) or CD68(+) cells increased as more tumor cells infiltrated and they decreased after treatment with topical steroid and ultraviolet light. Moreover, CTCL patients with an increased number of CD163(+) cells showed worse prognosis. Serum sCD163 levels in patients with CTCL, AD, or psoriasis were significantly higher than those in normal controls. In CTCL patients, serum sCD163 levels significantly correlated with serum soluble interleukin-2 receptor and CCL17 levels. In AD patients, serum sCD163 levels correlated with serum IgE levels. The numbers of CD163(+) cells in lesional skin and serum sCD163 levels were associated with disease progression of CTCL. Further study focusing on CD163(+) cells in CTCL lesional skin would be an interesting research field.

Serum Soluble Interleukin-2 Receptor, Interleukin-6 and Tumor Necrosis Factor Alpha as Markers of Celiac Disease Activity

To evaluate the markers of lymphocyte activation (sIL-2R, IL-6 and TNF α) in the peripheral blood of newly diagnosed patients with celiac disease (CD) and patients with CD on Gluten free diet (GFD) for at least 2 y. The markers were correlated with conventional serological tests Anti-tissue transglutaminase (Anti-TTG) used for diagnosis and follow up of the disease; wherever possible. Thirty newly diagnosed cases of CD (on the basis of histopathology and serology) not on GFD were enrolled as Group 1 of the study. Thirty age and sex matched controls from the Pediatric Surgery OPD formed Group 2. Thirty cases of CD on GFD for at least 2 y (Group 3) were also enrolled in the study. Upper G.I. endoscopy was performed in all Group 1 patients and cytokine levels assayed by ELISA on serum obtained from all patients in Groups 1, 2, 3. Mean sIL-2R level in Group 1(1498.1+/-1234.31 pg/ml) and Group 3 (488.78+/-396.18 pg/ml) were significantly higher than the controls (336.27+/-218.67 pg/ml p < 0.05). Among the patients with CD, mean serum levels in Group 1 were higher than in Group 3 (p < 0.05). sIL-2R levels showed good correlation with tTg levels in Group 1 patients (p < 0.000, r = 0.69). Mean IL-6 levels in Group 1 were significantly higher (28.43+/-28.32 pg/ml) than Group 2(15.03+/-7.72 pg/ml p < 0.05) and Group 3(11.26+/-5.13 pg/ml p < 0.05). IL-6 levels were comparable between Groups 2 and 3 (p > 0.05).IL-6 levels showed good correlation with tTg levels in Group 1(p < 0.008, r = 0.471). Mean TNFα levels in Group 1(179.66+/-102.93 pg/ml), Group 2 (153.16+/-27.02 pg/ml) and Group 3 (166.67+/-28.95 pg/ml) were comparable (p > 0.05). TNFα levels showed poor correlation with tTg levels in Group 1 patients (p > 0.604, r = -0.099). sIL-2R and IL-6 levels have a good correlation with CD activity and can be used as reliable markers for detecting minimal transgression from GFD.

Serum Soluble Interleukin-2 Receptor is Increased in Malnourished and Immunosuppressed Patients With Gastric and Colorectal Cancer: Possible Influence of Myeloid-Derived Suppressor Cells.

BackgroundSoluble IL-2 receptor (sIL-2R) is the circulating form of a membrane receptor localized on lymphoid and some tumor cells; its biological function is not completely understood.MethodsSerum levels of sIL-2R in blood samples taken from 51 cancer patients (21 gastric and 30 colorectal) and 18 healthy volunteers were measured and found to be significantly higher in the patients.ResultsConcentrations were significantly inversely correlated to nutritional parameters, including total protein and short turnover proteins such as prealbumin, retinol binding protein and transferrin, as well as to the stimulation index, which is a classical parameter of cell-mediated immunity. Concentrations were significantly positively correlated to neutrophil count and inversely to lymphocyte count. Significantly elevated levels of circulating myeloid-derived suppressor cells (MDSCs) were found in patients; this was significantly correlated to sIL-2R levels.ConclusionsIncreased production of sIL-2R correlated with systemic inflammation, nutritional impairment and inhibition of cell-mediated immunity, and thus may be involved in immunological mechanisms inducing cancer cachexia. The same factors also appear to relate closely to induction of MDSCs.

Serum soluble interleukin-2 receptor (sIL-2R) level is associated with the outcome of patients with diffuse large B cell lymphoma treated with R-CHOP regimens

Serum concentration of soluble interleukin-2 receptor (sIL-2R) predicts the clinical outcome of patients with aggressive non-Hodgkin's lymphoma treated with the cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen without rituximab. In the present study, we aim to re-assess the prognostic significance of serum sIL-2R for diffuse large B cell lymphoma (DLBCL) patients treated with CHOP plus rituximab and to assess sIL-2R with subtype of DLBCL, such as GCB type and non-GCB type. Two hundred and thirty-three patients with DLBCL were enrolled between December 2002 and March 2008. To evaluate serum levels of sIL-2R, venous blood samples were drawn from patients immediately before initiation of treatment. Serum sIL-2R was determined by sandwich enzyme-linked immunosorbent assay. The 5-year overall survival (OS) rates for patients with sIL-2R levels of ≥2,000 (110 cases) and <2,000U/mL (123 cases) were 54.2% and 89.0% (P < 0.0001), respectively. Multivariate analysis using the proportional-hazards model revealed that serum sIL-2R (P = 0.0099) and extranodal involvement sites (P = 0.0392) were independent prognostic factors for OS and that clinical stage (P = 0.0168), performance status (P = 0.0181), sIL-2R (P = 0.0232), and LDH (P = 0.0316) were independent prognostic factors for progression-free survival in sIL-2R and every factor of the International Prognostic Index. Serum sIL-2R might be a useful prognostic factor for DLBCL patients in the rituximab era.

Adalimumab successful in sarcoidosis patients with refractory chronic non-infectious uveitis

IntroductionAdalimumab, a humanized monoclonal antibody targeted against TNF-α, has proved to be successful in the treatment of uveitis. Another anti-TNF-α agent, i.e., infliximab, has been reported of benefit in the treatment of refractory sarcoidosis. The aim of this prospective case series was to evaluate the effect of adalimumab on intraocular inflammatory signs and other relevant clinical manifestations (lung function, serological inflammatory parameters, and fatigue) of sarcoidosis.MethodsSarcoidosis patients with refractory posterior uveitis (n = 26, 17 females, 41 eyes in total) were systematically followed for 12 months after initiation of adalimumab 40 mg sc once a week. Inclusion criteria were non-responsiveness to prednisone and methotrexate (MTX) or intolerance to these drugs. Adjunctive therapy with prednisone and MTX was tapered during treatment with adalimumab. Localization and improvement, stabilization or deterioration of intraocular inflammatory signs was scored. Pulmonary function- and laboratory testing were performed and Fatigue Assessment Scale was completed. Results at baseline, 6 months, and 12 months were compared.ResultsChoroidal involvement resolved in 10/15 patients, five had partial improvement; vasculitis resolved in 1/1 patient; papillitis resolved in 7/8 patients, one had partial response; macular edema resolved in 5/8 patients, three had partial response; vitreous cleared completely in 5/5 patients. Overall outcome regarding intraocular inflammatory signs showed improvement in 22 patients (85%) and stabilization in four patients (15%). At 12 months, no recurrences were reported in those successfully treated. Laboratory parameters of inflammatory activity (C-reactive protein; serum angiotensin-converting enzyme and soluble interleukin-2 Receptor) improved (p < 0.01). Moreover, fatigue improved in 14/21 (67%) of the patients suffering from fatigue and the diffusion capacity for carbon monoxide (DLCO) improved in 7/8 (88%) of patients with a decreased DLCO (p < 0.01). The dosage of both prednisone and MTX could be tapered down significantly (p < 0.01 and p < 0.05, respectively).ConclusionsAdalimumab appeared successful in sarcoidosis patients with refractory chronic non-infectious uveitis showing improvement in intraocular inflammatory signs as well as in other relevant clinical indicators of disease activity. Future randomized studies are needed to determine the optimal dosage, dose interval and duration of therapy in refractory multisystemic sarcoidosis.

Somatostatin receptor scintigraphy in sarcoidosis

Material and methods 218 patients were studied. The degree of intensity of uptake and localization of sarcoidosis associated lesion (SAL) were determined. The degree of intensity was compared with serum angiotensin converting enzyme (ACE) and serum soluble interleukin-2 receptor (sIL-2R). Elevated levels of serum ACE and sIL-2R have been shown to be associated with active sarcoidosis. Typical patterns on SRS were compared to conventional chest CT-scans and x-rays.

Rheumatoid arthritis complicated with immunodeficiency-associated lymphoproliferative disorders during treatment with adalimumab

A 71-year-old woman was diagnosed with rheumatoid arthritis in 2002. Treatment was started with methotrexate and she was switched to adalimumab in 2006. In May 2008, she started complaining of swelling of the left axilla and the left elbow lymph nodes, and adalimumab was discontinued in December. Her lymphadenopathy did not resolve and she was admitted to hospital with fever in May 2009. Subsequent laboratory examinations showed that serum alkaline phosphatase, gamma-glutamyl transpeptidase, C-reactive protein, and soluble interleukin-2 receptor levels were 3,078 IU/l, 510 IU/l, 20 mg/dl, and 7,290 U/ml, respectively. Gallium scintigraphy showed high-intensity areas in the above-mentioned lymph nodes. She suddenly progressed to jaundice and died of pulmonary edema on the 25th day of hospitalization. Autopsy indicated large atypical cells with a distorted nucleus that had multiplied in the above-mentioned lymph nodes. On immunohistochemical staining these cells showed positive staining for CD15, CD30, PAX-5, Epstein-Barr virus (EBV) early small RNA (EBER), and LMP-1. Reactivation of EBV was diagnosed via EBV antibodies and an EBV DNA determination. We considered that she had developed EBV-associated lymphoproliferative disorders due to immunodeficiency caused by adalimumab administration. Reactivation of EBV associated with adalimumab and the relationship of this reactivation to malignant lymphoma have been rarely reported.

Hepatitis C Virus-Related Lymphomagenesis in a Mouse Model

B cell non-Hodgkin lymphoma is a typical extrahepatic manifestation frequently associated with hepatitis C virus (HCV) infection. The mechanism by which HCV infection leads to lymphoproliferative disorder remains unclear. Our group established HCV transgenic mice that expressed the full HCV genome in B cells (RzCD19Cre mice). We observed a 25.0% incidence of diffuse large B cell non-Hodgkin lymphomas (22.2% in male and 29.6% in female mice) within 600 days of birth. Interestingly, RzCD19Cre mice with substantially elevated serum-soluble interleukin-2 receptor α-subunit (sIL-2Rα) levels (>1000 pg/mL) developed B cell lymphomas. Another mouse model of lymphoproliferative disorder was established by persistent expression of HCV structural proteins through disruption of interferon regulatory factor-1 (irf-1_/_/CN2 mice). Irf-1_/_/CN2 mice showed extremely high incidences of lymphomas and lymphoproliferative disorders. Moreover, these mice showed increased levels of interleukin (IL)-2, IL-10, and Bcl-2 as well as increased Bcl-2 expression, which promoted oncogenic transformation of lymphocytes.

Serum soluble interleukin-2 receptor in patients with pulmonary mycobacterial diseases

Serum soluble interleukin-2 receptor (sIL-2R) levels were measured in patients with untreated pulmonary tuberculosis (24 cases), patients with multidrug-resistant intractable pulmonary tuberculosis (7 cases) and patients with pulmonary non-tuberculous mycobacteriosis (27 cases). Serum sIL-2R levels were elevated in patients with pulmonary mycobacterial diseases and were elevated in untreated pulmonary tuberculosis patients than in other patients. In patients with new tuberculosis, serum sIL-2R levels were higher in patients with extensive lesions. Serum sIL-2R level showed significant positive correlation with serum C-reactive protein level and erythrocyte sedimentation rate, and significant negative correlation with serum albumin level. In patients with intractable tuberculosis and patients with non-tuberculous mycobacteriosis, serum sIL-2R levels were lower than in patients with new tuberculosis. Even in patients with extensive lesions, serum sIL-2R levels were not elevated. Lower levels of serum sIL-2R, marker of immunocompetent cell activity, suggested that immunocompetent cell activity was suppressed in intractable tuberculosis and in non-tuberculous mycobacteriosis.

Dynamic changes and the significance of T-cell subsets and serum soluble interleukin-2 receptor in neonates with hyperbilirubinemia

Objective To investigate the dynamic changes and the clinical significance of T-cell subsets and serum soluble interleukin-2 receptor （sIL-2R）in neonates with hyperbilirubinemia.Methods Thirty-one neonates with hyperbilirubinemia, admitted to the hospital from Decembr 1,2006 to January 31, 2007, were enrolled and divided into two subgroups： severe jaundice group and mild jaundice group according to the bilirubin level. Thirty-two age-mached healty newborns were as controls（control group Ⅰ）. The T-cell subsets and sIL-2R of peripheral venous blood samples from these neonates were measured and compared. Sixteen of these 31 neonates with hyperbilirubinemiawere followed up and another twenty-six age-mached healty newborns were as controls（control group Ⅱ ）. The level of serum bilirubin in convalescence of sixteen hyperbilirubinemia neonates and control group Ⅱ were tested and analyzed also. Results The levels of CD3, CD4, CD4/CD8 in the neonates with hyperbilirubinemia were lower compared with those of control group Ⅰ [（54.0±5.1）% vs （62.0±4.7）%, （26.8±5.0）% vs （43.0±4.7）%, 0.8±0.1 vs 1.4±0.2] （P〈0.01）, but was higher in convalescence than in peak phase[ （62.4±3.3）% vs （55.1±4.2）%, （43.6±2.5）% vs （26.1±4.4）%, 1.4 ± 0.1 vs 0.8±0.1] （P〈0.01）. The peak level of sIL-2R in the hyperbilirubinemia group was （319.4± 185.2） kU/L, higher than that in the convalescence [（129.7±99.3） kU/L] and in the control group Ⅱ [（171.9±102.2） kU/L] （P〈0.01）. The serum bilirubin level showed negative correlation with CD4/CD8 （ r = -0.99, P 〈 0.01 ） and positive correlation with sIL-2R （r=0.95, P〈0.05）. The sIL-2R level was negatively correlated with CD4/CD8 （r=-0.92, P〈0.05）. Conclusions Neonates, when suffering from hyperbilirubinemia, are immunosuppressed which may recover with the alleviation of jaundice. Key words: Hyperbilirubinemia,neonatal T-lymphocytes subsets Receptors,interleukin-2

IL-6/IL-6R as a potential key signaling pathway in prostate cancer development

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in prostate regulation and in prostate cancer (PC) development/progression. IL-6 acts as a paracrine and autocrine growth stimulator in benign and tumor prostate cells. The levels of IL-6 and respective receptors are increased during prostate carcinogenesis and tumor progression. Several studies reported that increased serum and plasma IL-6 and soluble interleukin-6 receptor levels are associated with aggressiveness of the disease and are associated with a poor prognosis in PC patients. In PC treatment, patients diagnosed with advanced stages are frequently submitted to hormonal castration, although most patients will eventually fail this therapy and die from recurrent castration-resistant prostate cancer (CRPC). Therefore, it is important to understand the mechanisms involved in CRPC. Several pathways have been proposed to be involved in CRPC development, and their understanding will improve the way to more effective therapies. In fact, the prostate is known to be dependent, not exclusively, on androgens, but also on growth factors and cytokines. The signaling pathway mediated by IL-6 may be an alternative pathway in the CRPC phenotype acquisition and cancer progression, under androgen deprivation conditions. The principal goal of this review is to evaluate the role of IL-6 pathway signaling in human PC development and progression and discuss the interaction of this pathway with the androgen recepto pathway. Furthermore, we intend to evaluate the inclusion of IL-6 and its receptor levels as a putative new class of tumor biomarkers.The IL-6/IL-6R signaling pathway may be included as a putative molecular marker for aggressiveness in PC and it may be able to maintain tumor growth through the AR pathway under androgen-deprivation conditions. The importance of the IL-6/IL-6R pathway in regulation of PC cells makes it a good candidate for targeted therapy.

Clinical Relevance of Elevated Levels of Serum Soluble Interleukin-2 Receptor alpha (sIL-2Rα) in Patients with Non-Hodgkin’s Lymphoma

Levels of soluble interleukin-2 receptor alpha (sIL-2Rα) are known to increase in the sera of patients with certain malignancies, including malignant lymphoma. This study aimed to assess the clinical significance of the sIL-2Rα level in non-Hodgkin's lymphoma (NHL). We used ELISA to measure the sIL-2Rα levels in 48 newly diagnosed and untreated patients with NHL and evaluated the correlation between the sIL-2Rα levels and clinical characteristics and the International Prognostic Index (IPI). We monitored serum sIL-2Rα in 7 patients to compare the changes in their clinical progress with these levels. High levels of serum sIL-2Rα (≥ 2,000 U/mL) correlated well with parameters defining the high risk group according to the IPI, i.e., high tumor burden at diagnosis (stage III+IV) and lactate dehydrogenase ≥ 472 U/L. The levels were also associated with B symptoms, bone marrow involvement, and poor response to therapy. The sIL-2Rα level decreased during complete remission and was elevated during disease progression or relapse. A high level of sIL-2Rα was significantly associated with a low survival rate. These results suggest that serum sIL-2Rα might be useful as a biomarker for evaluating the prognosis of patients with NHL at the time of diagnosis and during therapy. A well-controlled, large-scale study is needed to clarify the clinical significance of sIL-2Rα in specific groups of NHL.

Progressive external ophthalmoplegia as initial manifestation of sporadic late-onset nemaline myopathy

Sporadic late-onset nemaline myopathy (SLONM) is a rare disease and typically presents in patients older than 40 years with slowly progressive weakness in a limb-girdle distribution and unremarkable family history [1, 2]. Serum creatine kinase is usually normal, and electromyography may show myopathic changes. Nemaline rods in affected muscle fibers are considered the histopathological hallmark of nemaline myopathy and are mainly found within the sarcoplasm, inside of myonuclei, or both [3]. Ocular involvement has never been described in a patient with SLONM. We report a patient with SLONM suffering from prominent involvement of external ocular muscles. A 60-year-old female patient was reexamined for a chronic progressive oculopharyngeal syndrome that was present for 6 years. Initial symptoms were double vision and ptosis, followed by weakness of eye-closure. Two years after the onset of symptoms, she presented an exclusive picture of external ophthalmoplegia. During the following years she was unable to open or close her eyes voluntarily, lost her ability to whistle or smile, developed a hoarse voice and swallowing difficulties. There was no diurnal variation of symptoms, or fatigability. Family history for neuromuscular diseases was unremarkable. On examination she had complete bilateral ptosis and palsy of extraocular muscles, while pupillar size and pupillar reactions to light and accommodation were normal. She had a myopathic face with atrophy of masseter and temporalis muscles, severe bilateral facial palsy, and severe dysphonia. Strength was MRC grade 4 for neck flexion, head rotation, and neck extension. Further neurological examination was normal, notably fundoscopy and proximal and distal limb strength. Laboratory examinations provided normal values for standard parameters, serum creatine kinase, a comprehensive panel of autoimmune antibodies, including antibodies against acetylcholine receptor or muscle-specific kinase, anti-HIV 1/2 antibodies, and p24 antigen. Serum ACE, soluble Interleukin-2 receptor levels, serum and urine calcium levels, and repeated imaging studies ruled out sarcoidosis. Protein electrophoresis and immunofixation did not show any paraprotein, findings that rule out an association with HIV, sarcoidosis, or monoclonal gammopathy, as described in some patients in the literature [4–7]. MRI revealed symmetric atrophy of ocular muscles and fatty degeneration of pterygoideus medialis and masseter muscles, no signs of edema or contrast enhancement. Thorough neuromuscular transmission studies as well as spinal cord and brain imaging were unremarkable. No other organs were involved. Muscle biopsy of the sternocleidomastoideus revealed numerous rods, which appeared to be O. Wengert A. Meisel Department of Neurology, Charite-Universitatsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany

Serum Cytokine Alteration is Associated With Optic Neuropathy in Human Primary Open Angle Glaucoma

The purpose of this study is to compare human serum levels of TH1 and TH2 cytokines between 2 stages of primary open-angle glaucoma (POAG) and nonglaucomatous controls. Thirty-two patients with primary POAG and 26 normal control subjects were enrolled into this study. The 32 patients with POAG were divided into 2 subgroups according to their mean defect (MD) with MD better than -12 dB and worse than -12 dB on the visual field. Enzyme-linked immunosorbent assay was used to assay for the levels of TH1 cytokines serum soluble interleukin-2 receptor (sIL-2R), interleukin (IL)-2, IL-12p40, IL-12p70, IL-23, tumor necrosis factor (TNF)-alpha, interferon-gamma, and TH2 cytokines IL-4, IL-6 in the peripheral serum. Patients with mild glaucomatous neuropathy exhibited significant elevations in IL-4 (P<0.0001) and IL-6 (P=0.0302) compared with the controls, whereas higher concentrations of IL-4 (P<0.0001) and IL-6 (P=0.0084) were found in patients with severe glaucomatous neuropathy. The level of IL-12p70 was significantly increased in both the MD >/=12 dB (P<0.0001) and MD <12 dB (P<0.0001) groups. A significant decrease in TNF-alpha levels were observed in MD <12 dB group compared with the controls (P=0.0464), and TNF-alpha levels in MD <12 dB group were lower than MD >/=12 dB group (P=0.0328). No significant differences in serum concentrations of IL-2, sIL-2R IL-12p40, IL-23 and interferon-gamma were found between MD <12 dB group, MD >or=12 dB group, and control group. Significant alterations of serum TH1 and TH2 cytokines are associated with glaucoma, suggesting the possibility that abnormal immune environments contribute to the glaucomatous neuropathy of POAG.

The associations of circulating CD4+CD25high regulatory T cells and TGF-β with disease activity and clinical course in patients with adult-onset Still's disease

Objective. To determine circulating levels of CD4+CD25high regulatory T (Treg) cells and transforming growth factor-β (TGF-β) in patients with adult-onset Still's disease (AOSD) and to examine the associations with disease activity and clinical course of this disease. Methods. The frequencies of circulating CD4+CD25high Treg cells in 52 active AOSD patients, 42 active systemic lupus erythematosus (SLE) patients, and 22 healthy controls (HCs) were determined using flow cytometry analysis. Levels of serum TGF-β and soluble interleukin-2 receptor (sIL-2R) were measured by enzyme-linked immunosorbent assay. Results. Significantly lower levels of circulating CD4+CD25high Treg cells and serum TGF-β were found in AOSD patients and SLE patients than those found in HCs. Levels of circulating CD4+CD25high Treg cells and TGF-β were inversely correlated with disease activity scores for AOSD patients and SLE patients. Circulating CD4+CD25high Treg cell frequencies were positively correlated with serum TGF-β levels for patients with both diseases. Levels of circulating CD4+CD25high Treg cells and TGF-β significantly increased, paralleling clinical remission and the decrease in levels of C-reactive protein and soluble interleukin-2 receptor after effective therapy in AOSD patients. AOSD patients with monocyclic course had significantly higher levels of circulating CD4+CD25high Treg cells and TGF-β compared to those with polycyclic and chronic articular course. Conclusion. Diminished levels of circulating CD4+CD25high Treg cells and TGF-β, and inverse correlation with disease activity in patients with AOSD and SLE might be involved in the pathogenesis of both diseases. Increased levels of circulating CD4+CD25high Treg cells or TGF-β might be associated with a favorable clinical course in AOSD patients.

Analysis of the Effect of Serum Interleukin-6 (IL-6) and Soluble IL-6 Receptor Levels on Survival of Patients with Colorectal Cancer

The correlations of serum interleukin-6 and soluble interleukin-6 receptor concentrations with clinicopathological features and survival of patients with colorectal cancer were studied. We measured the serum levels of interleukin-6 and soluble interleukin-6 receptor in 99 colorectal cancer patients at the Chang Gung Memorial Hospital, Taiwan. The interleukin-6 and soluble interleukin-6 receptor levels were tested for their association with each other, and with the clinical parameters and outcomes. Both interleukin-6 and soluble interleukin-6 receptor concentrations were significantly higher in colorectal cancer patients than in normal individuals. Unlike patients with serum interleukin-6 levels >10 pg/ml, who have increased carcinoembryonic antigen levels and shorter survival, serum soluble interleukin-6 receptor levels >800 pg/ml were found in patients with stages I-II and no regional lymph nodal invasion and appeared to be a positive prognostic factor for improved survival. Especially, patients with serum interleukin-6 <10 pg/ml and soluble interleukin-6 receptor >800 pg/ml lived significantly longer. Nonetheless, the multivariate analysis showed that only tumor-node metastasis stage, metastatic status and serum interleukin-6 level were independent prognostic factors, whereas the serum soluble interleukin-6 receptor level became marginally important for survival. We suggest the clinical relevance of interleukin-6 and soluble interleukin-6 receptor for the survival of colorectal cancer patients. From a practical point of view, detection of the serum interleukin-6 level alone, rather than combined measurement of interleukin-6 and soluble interleukin-6 receptor, may be sufficient to independently predict survival in colorectal cancer patients.

A study on interleukin 2 and soluble interleukin 2 receptor in serum and bronchoalveolar lavage fluid from patients with farmer's lung

Interleukin 2 (IL-2) and soluble Interleukin 2 receptor (IL-2R) were assayed in serum and bronchoalveolar lavage fluid (BALF) from patients with farmer's lung. Patients with farmer's lung had significantly higher levels of soluble IL-2R in serum and BALF than normal controls. The level of soluble IL-2R was correlated with the disease activity, and fell to within the normal range after successful treatment with corticosteroids. On the other hand, asymptomatic dairy farmers with precipitating antibodies against Micropolyspora faeni antigen or Thermoactinomyces vulgaris antigen had the same levels of soluble IL-2R in their serum and BALF as normal controls. IL-2 levels in serum and BALF were significantly higher in patients with farmer's lung than in normal controls; however, asymptomatic patients had low levels comparable to those of normal controls. These results indicate that soluble IL-2R could be a sensitive parameter for evaluation of the activity of this disease. It is also suggested that the IL-2/IL-2R system is important in the pathogenesis of hypersensitivity pneumonitis.