Soluble interleukin-6 receptor (sIL-6R), a new prognostic factor in multiple myeloma

sIL-6R is a 55 kD soluble molecule mediating the interleukin-6 (IL-6) signal through the IL-6 receptor-associated transmembrane signal transducer, gp130. It has recently been suggested that sIL-6R serum levels may reflect disease severity in multiple myeloma (MM). We determined sIL-6R serum levels in 25 normal controls (NC) and in 80 MM patients at diagnosis and during the course of the disease. Measurements were done by ELISA. In NC, sIL-6R levels ranged from 14 to 40 ng/ml (median 28 ng/ml) whereas in MM patients the range was 10–200 ng/ml (median 38 ng/ml) ( P  < 0.01). 61 patients entered remission and 19 were resistant. Median sIL-6R value at diagnosis was 36 ng/ml (10–120) in responding patients, and 82 ng/ml (20–200) in non-responding patients ( P  < 0.001). During a follow-up from 12 to 89 months, sIL-6R values remained more or less stable in most patients. High sIL-6R levels correlated with poor survival.     

Hyper-interleukin (IL)-6-naemia in haemophagocytic lymphohistiocytosis

Clinical features in patients with haemophagocytic lymphohistiocytosis (HLH) have been demonstrated to be characterized by hypercytokinaemia. Previously, we reported the impact of high serum levels of interferon (IFN)-gamma and soluble IL-2 receptor (sIL-2R) on patient outcome; however, it was not known if serum levels of interleukin (IL)-6 also could be a prognostic factor. In a study during the active phase of disease in 25 cases of HLH in children and young adults (median age 3 years, range 0.1–23 years), we noted 12 cases which showed serum IL-6 >100 (normal <4.0) pg/ml. Five of these cases showed hyper-IL-6-naemia alone without hyper-IFN-gamma-naemia (group A) whereas seven cases showed both hyper-IL-6- and IFN-gamma-naemia (group B). Patient outcome did not differ between the patients with IL-6 >100 pg/ml and those with IL-6 <100 pg/ml, suggesting that high serum concentrations of IL-6 alone do not necessarily indicate poor prognosis in patients with HLH. Among the cases with hyper-IL-6-naemia (>100 pg/ml), underlying disorders causing haemophagocytosis were found to be different between groups A and B.     

Diminished production of interleukin-6 in chronic lymphocytic leukaemia (B-CLL) cells from patients at advanced stages of disease

The production of the cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) in B-CLL cells from 24 patients at different stages of chronic lymphocytic B-cell leukaemia (B-CLL) was investigated in vitro . In the majority of these cases, low spontaneous IL-6 production was measured. Mitogenic stimulation with phorbol 12-myristate 13-acetate (PMA) or PMA plus interleukin-2 (IL-2) resulted in a tremendous increase in TNF-α and IL-6 production in cells representing early stage (Binet A) disease. In contrast, very little, if any, production took place in cells from patients with advanced stage (Binet C) B-CLL. The results from stage B patients were intermediate. The most remarkable difference was recorded in PMA-stimulated (1 ng/ml) IL-6 production. In stimulated 72 h cultures, IL-6 concentrations were 1280 ± 1080 pg/ml for Binet A ( n  = 11), 757 ± 597 pg/ml for Binet B ( n  = 8) and 46.0 ± 84.0 pg/ml for Binet C ( n  = 5). The differences in IL-6 production between stage C v B and stage C v A were both statistically significant ( P  = 0.025). Similar effects, but to a lesser extent, were observed in TNF-α production. These results suggest that the varying capacity to produce IL-6 and TNF-α may play a role in B-CLL progression and in clinical manifestations of the disease.     

Effects of aspirin on serum C-reactive protein and interleukin-6 levels in patients with type 2 diabetes without cardiovascular disease: a randomized placebo-controlled crossover trial

Aim:  Low-grade inflammation plays a pivotal role in atherogenesis in type 2 diabetes. Next to its antithrombotic effects, several lines of evidence demonstrate anti-inflammatory properties of aspirin. We determined the effects of aspirin on inflammation – represented by C-reactive protein (CRP) and interleukin-6 (IL-6) – in type 2 diabetic subjects without cardiovascular disease and assessed differential effects of aspirin 300 mg compared with 100 mg.
Methods:  A randomized, placebo-controlled, double-blind, crossover trial was performed in 40 type 2 diabetic patients. In two periods of 6 weeks, patients used 100 or 300 mg aspirin and placebo. Plasma CRP and IL-6 levels were measured before and after both periods.
Results:  Use of aspirin resulted in a CRP reduction of 1.23 ± 1.02 mg/l (mean ± s.e.m.), whereas use of placebo resulted in a mean increase of 0.04 ± 1.32 mg/l ( P  = 0.366). Aspirin reduced IL-6 with 0.7 ± 0.5 pg/ml, whereas use of placebo resulted in a mean increase of 0.2 ± 0.8 pg/ml ( P  = 0.302). There were no significant differences in effects on CRP and IL-6 between 100 and 300 mg aspirin.
Conclusions:  Our results indicate that a 6-week course of aspirin does not improve low-grade inflammation in patients with type 2 diabetes without cardiovascular disease, although a modest effect could not be excluded. No significant differential effects between aspirin 100 and 300 mg were found.     

''Lymphoid'' blast crisis of chronic myeloid leukaemia is associated with distinct clinicohaematological features

We measured the circulating levels of interleukin (IL)-6 in adult T-cell leukaemia/lymphoma (ATL) patients using an enzyme-linked immunosorbent assay. The IL-6 levels in 59 ATL patients (median 8.2 pg/ml; range < 1.0 to 185.7 pg/ml) were significantly higher than in 30 healthy controls (median < 1.0 pg/ml; range < 1.0 to 3.5 pg/ml) ( P  < 0.0001) or 32 human T-lymphotropic virus type-I (HTLV-I) carriers (median 4.2 pg/ml; range  < 1.0 to 13.3 pg/ml) ( P  = 0.002). Among the ATL patients, the IL-6 levels in the acute- or lymphoma-type patients were significantly higher than those in the chronic-type patients ( P  < 0.0001). The IL-6 levels were also higher in the patients with B symptoms than in those without B symptoms ( P  = 0.039), and were significantly correlated with increased serum lactate dehydrogenase (LDH) ( P  = 0.0004) and C-reactive protein (CRP) ( P  < 0.0001) and decreased serum albumin ( P  = 0.0003) values. The patients with elevated IL-6 levels had inferior overall survival periods compared to those with normal IL-6 levels ( P  = 0.025). ATL is a single disease entity, although its clinical features are quite diverse; the increased production of cytokines may cause the diversity of clinical features. The results of our study indicate that IL-6 is one such cytokine.     

肝癌患者血清、癌组织中IL-6表达及其性别差异

目的观察肝细胞癌（肝癌）患者血清及癌组织中IL-6的表达及其性别差异。方法采用ELISA法检测不同性别肝癌患者术前及健康者外周血血清中的IL-6,免疫组化法检测肝癌组织中的IL-6。结果肝癌患者术前血清IL-6中位水平为4.82 pg/ml,健康者为2.31 pg/ml,两者比较,P〈0.01;男性肝癌患者血清IL-6水平为4.96pg/ml,女性为3.87 pg/ml,两者比较,P〈0.05。血清IL-6水平以3.51 pg/ml为cut-off值,诊断肝癌的敏感度与特异度分别为88.9%、87.5%;血清IL-6水平≥3.51 pg/ml者多为男性、肿瘤直径较大、血管内癌栓、肿瘤无包膜患者（P均〈0.05）。肝癌组织中IL-6阳性率为77%（69/90）,其中男性患者为84%（56/67）,女性患者为57%（13/23）,两者比较,P〈0.05。结论肝癌患者血清IL-6水平比正常健康者明显升高,男性肝癌患者血清及癌组织中IL-6的表达均高于女性患者。     

Serial circulating concentrations of C-reactive protein, interleukin (IL)-4, and IL-6 in patients with acute left heart decompensation

BACKGROUND: Interleukin (IL)-6 has recently been shown to have negative inotropic effects, and several studies have reported increases in circulating concentrations of this cytokine in patients with depressed left ventricular ejection fraction and chronic left heart failure. However, most previous clinical studies have measured cytokines in compensated chronic heart failure. HYPOTHESIS: The purpose of this study was to examine the temporal evolution of circulating concentrations of C-reactive protein (CRP) and cytokines in patients with cardiomyopathy and acute cardiac decompensation, free of infection and unstable angina. METHODS: The time course of circulating concentrations of CRP, an anti-inflammatory cytokine interleukin (IL)-4, and a proinflammatory cytokine IL-6 were studied in eight patients with cardiomyopathy and acute cardiac decompensation in the absence of infection or unstable angina. Control samples were obtained from eight age-matched asymptomatic subjects. RESULTS: Increased circulating concentrations of CRP (2.6 +/- 0.8 mg/dl), IL-4 (164.6 + 36.5 pg/ml), and IL-6 (17.1 +/- 5.1 pg/ml) were found in all eight patients during acute cardiac decompensation; these values decreased significantly with the resolution of symptoms of cardiac decompensation (0.5 +/- 0.1 mg/dl, 77.8 +/- 23.6 pg/ml, 2.3 +/- 0.1 pg/ml, respectively, p < 0.05 for both). There was a significant correlation between peak CRP and peak IL-6 (p < 0.05). CONCLUSIONS: In patients with acute left heart decompensation in the absence of infection or coronary events, CRP, IL-4, and IL-6 increased and returned toward normal levels as the symptoms of heart failure resolved. Since the changes in concentrations of CRP, IL-4, and IL-6 in patients with heart failure are dynamic, the distinction between compensated and decompensated state is important when discussing the significance of acute reactive proteins or cytokines in the pathogenesis of heart failure.     

Increased leukotriene B4 and interleukin-6 in exhaled breath condensate in cystic fibrosis

Chronic neutrophilic airway inflammation is an important feature of cystic fibrosis (CF). Noninvasive inflammatory markers may be useful in monitoring CF. Leukotriene B4 (LTB4) and interleukin (IL)-6 are inflammatory mediators that are increased in chronic neutrophilic inflammation. The aim of this study was to assess whether LTB4 and IL-6 were increased in exhaled breath condensate of CF patients and whether they could be used to monitor inflammation. Twenty patients with CF (13 males, age of 28 +/- 9 years) were recruited together with 15 age-matched healthy subjects (8 males, age 35 +/- 7 years). LTB4 and IL-6 levels were markedly elevated in patients with acute exacerbations (28.8 +/- 4.3 and 8.7 +/- 0.4 pg/ml) compared with control subjects (6.8 +/- 0.7 and 2.6 +/- 0.1 pg/ml, p < 0.0001). We also observed a decrease of exhaled LTB4 and IL-6 concentrations after antibiotic treatment in six patients who were followed until clinically stable (31.1 +/- 4.4 and 9.5 +/- 0.4 pg/ml vs. 18.8 +/- 0.8 and 6.4 +/- 0.2 pg/ml, respectively) and an increase in 15 CF patients infected with Pseudomonas aeruginosa (34.3 +/- 5.0 and 9.3 +/- 0.3 pg/m) compared with those infected with other bacteria (18.3 +/- 0.7 and 6.9 +/- 0.5 pg/ml). These findings suggest that LTB4 and IL-6 levels are increased in exhaled breath condensate of patients with CF during exacerbation and could be used to monitor airway inflammation in these patients.     

Measurement of whole body interleukin-6 (IL-6) production: prediction of the efficacy of anti-IL-6 treatments

A major limitation on the therapeutic use of cytokine antagonists is that the amount of cytokine to be neutralized in vivo is not presently known. We previously reported that anti-interleukin-6 (IL-6) monoclonal antibody (MoAb) administered to a patient with multiple myeloma (MM) induced high amounts of IL-6 to circulate in the form of monomeric immune complexes. Based on this observation, the present study developed a new methodology to estimate daily IL-6 production in 13 patients with MM or renal cancer who received anti-IL-6 MoAb. Treatment was considered effective when the production of C-reactive protein (CRP) was inhibited. The production of this acute-phase protein by hepatocytes is dependent on the activation of IL-6 gp130 transducer. Inhibition of tumor proliferation was also evaluated in patients with MM. In 7 of 13 patients whose CRP production was completely inhibited (> 96%) and who showed some antitumoral effects, whole-body IL-6 production in vivo was less than 18 micrograms/d (median, 5.7 micrograms/d; range, 0.5 to 17.5 micrograms/d). In the other 6 patients, subtotal inhibition of CRP production and a lack of antitumoral response were associated with high IL-6 production (median, 180 micrograms/d; range, 18 to 358 micrograms/d). These in vivo observations were consistent with mathematical modeling that predicted that anti-IL-6 MoAb treatment would be efficient only in low IL-6 producers. These data indicate the difficulty of neutralizing IL-6 with a single anti-IL-6 MoAb in vivo and call for new strategies to avoid accumulation of IL-6 in the form of stable immune complexes.     

Radioimmunoassay for the measurement of serum IL-6 and its correlation with tumour cell mass parameters in multiple myeloma.

Interleukin-6 (IL-6) was demonstrated to be a strong autocrine or paracrine plasmocytoma cell growth factor in humans. Using a bioassay, high serum IL-6 (S-IL-6) levels were correlated with disease severity in plasma cell dyscrasias. Since other cytokines could interfere with the bioassays, we developed a specific radioimmunoassay to study S-IL-6 levels in 102 patients with monoclonal gammopathy (MG). S-IL-6 level was studied by a double antibody radioimmunoassay using a rabbit polyclonal anti-IL-6 antibody and a human recombinant IL-6 as the standard. The lowest value of the standard significantly different from zero was found to be 78 pg/ml. Within-run and between-run precisions were characterized by a mean coefficient of variation of 3.72 and 5.5%, respectively. The mean analytical recovery was found to be 113% and the immunochemical identity of IL-6 standard and S-IL-6 was shown by dilution tests. IL-6 was detected in all tested sera. Sera from 66 healthy volunteers and 43 patients with acute leukemia or malignant lymphoma were tested as controls. In healthy subjects, S-IL-6 values were 294 +/- 86 pg/ml. MG were classified as multiple myeloma (MM), macroglobulinemia, and MG of undetermined significance (MGUS). The distribution of S-IL-6 levels in patients with MG was significantly higher than in healthy subjects but lower than in patients with acute leukemia or Hodgkin's lymphoma. Results obtained in 55 patients with MM were related to other biological parameters. S-IL-6 levels correlated with bone-marrow plasmacytosis (P less than .0005), serum-lactate dehydrogenase (S-LDH; P less than .005), serum beta 2 microglobulin (S -beta 2m; P less than .01), and serum calcium (S-Ca; P less than .025) and inversely correlated with haemoglobin (P less than .025). Our results indicate that 1) radioimmunoassay is suitable for the measurement of human IL-6 in serum; 2) high S-IL-6 levels are observed in a small number of patients with MG; and 3) S-IL-6 level correlates with tumour cell mass in patients with overt MM.     

Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity

OBJECTIVE: To determine the value of the erythrocyte sedimentation rate (ESR) and plasma interleukin-6 (IL-6) as biologic markers for monitoring disease activity in giant cell arteritis (GCA). METHODS: Twenty-five patients with biopsy-proven GCA were enrolled into a prospective treatment study. Therapy was initiated with prednisone, 60 mg/day, followed by a predetermined tapering schedule. Patients were monitored monthly for clinical signs of active vasculitis and laboratory parameters indicative of inflammation, including elevated ESR (>30 mm/hour) and elevated plasma IL-6 concentrations (>6.1 pg/ml). RESULTS: Upon initiation of corticosteroid treatment, clinical signs of GCA disappeared in all patients; however, 60% of the patients developed symptoms of recurrent disease, on 1 or more occasions, while the prednisone dosage was being reduced. These 31 disease flares diagnosed over 550 days were associated with symptoms of systemic inflammation but did not result in vascular complications. The ESR was elevated in 76% of the patients prior to initiation of treatment (median 65 mm/hour) and normalized by day 28 of therapy (median 6 mm/hour). The median ESR remained in the normal range during the followup period. Plasma IL-6 levels, which were abnormal in 92% of untreated patients (median 16 pg/ml), were partially responsive to the initial high doses of corticosteroids by day 28 (median 6 pg/ml), but levels did not completely normalize with continued therapy. Elevation of the ESR was seen during only 58% of all disease flares, but 89% of disease recurrences were associated with increased plasma IL-6 levels (P = 0.03). CONCLUSION: Plasma IL-6 is more sensitive than ESR for indicating disease activity in untreated and treated GCA patients. Standard corticosteroid regimens only partially suppress vascular inflammation. Smoldering disease activity may expose GCA patients to the risk of progressive vascular disease (e.g., formation of aortic aneurysms) and chronic systemic complications such as IL-6-mediated osteopenia.     

Changes in serum interleukin-6 levels as possible predictor of efficacy of tocilizumab treatment in rheumatoid arthritis

Objectives: We aimed to evaluate the association between the change in serum IL-6 during the clinical course of tocilizumab (TCZ) therapy and rheumatoid arthritis (RA) disease activity or occurrence of adverse events.

Methods: General laboratory data including serum IL-6 levels and physical findings were obtained every 4 weeks, and, in addition, at the time when any adverse events occurred.

Results: The proportion achieving Clinical Disease Activity Index (CDAI) remission at 52 weeks was significantly lower in 20 patients with serum IL-6?≥?30?pg/ml at 12 weeks than 24 patients with serum IL-6?Conclusion: Serum IL-6 levels from 12 to 24 weeks after TCZ initiation better reflect the efficacy of TCZ at 52 weeks.     

Study of interleukin-6 production in Alzheimer's disease

There is a growing body of evidence which supports the hypothesis of faulty immune regulation and autoimmunity or inflammatory processes as viable mechanisms of the pathogenesis of Alzheimer's disease. The aim of this study was to evaluate the IL-6 level in serum of patients with AD and to analyze the correlation between IL-6 and this disease. Serum samples from 47 patients with clinically diagnosed Alzheimer's disease (27 women and 20 men, mean age 70.43 +/- 10.82 years, range 40-89 years) as compared to 47 controls (25 women and 22 men, mean age 70.17 +/- 10.64 years, range 40-89 years) were analyzed for IL-6 by ELISA (R&D Systems). The interleukin-6 levels were significantly higher in AD patients (234 pg/ml, range 85-567 pg/ml) as compared to control group (67 pg/ml, range 38-181 pg/ml); p < 0.001. It was evident from the study that increased production of IL-6 cytokine is found in AD patients, suggesting abnormal cellular immunity in these patients. Interleukin-6 plays a role in the pathogenesis of Alzheimer's disease. Our results suggest that high peripheral IL-6 secretion levels may be responsible for acute-phase proteins observed in the serum of AD patients. We find these results very promising for the consideration of future treatment of AD patients.     

Serum level of interleukin-16 in multiple myeloma patients and its relationship to disease activity

Interleukin-16 (IL-16) is a chemoattractant of CD4+ lymphocytes, and it has been implicated in the pathogenesis of various inflammatory diseases. There is evidence that it may have a role in multiple myeloma (MM). In the present study, we determined the serum level of IL-16 both before and after treatment of MM and related it to inflammatory markers and survival. Forty-eight newly diagnosed MM patients were included in the study. Disease stage was defined using the Durie-Salmon classification system (10 patients were in stage I, 19 in stage II, and 19 in stage III). After standard treatment, 22 patients reached the plateau phase and were re-evaluated. The following serum parameters were measured: IL-16, IL-6, alpha-1 antitrypsin (alpha1AT), and C-reactive protein (CRP). Survival was determined as the number of months elapsed since original diagnosis. The mean +/- SD of serum IL-16 was 343 +/- 195 pg/ml in the pre-treatment MM group and 101 +/- 30 pg/ml in the control group. All measured parameters were higher in the patient group compared to healthy controls. Furthermore, IL-16, IL-6, alpha1AT, and CRP were significantly increased with increasing stage of disease, from stage I to stage III (P<0.01). All parameters decreased significantly following effective chemotherapy (P<0.002). Patients with a high level of IL-16 (>430 pg/ml) displayed an inferior survival time in comparison to those with lower levels of IL-16. In the pre-treatment group, IL-16 correlated with alpha1AT and IL-6 (r=0.374, P<0.01 and r=0.454, P<0.002, respectively). IL-16 may play a role in multiple myeloma; however, further functional studies are required.     

Serum IL-6 and IL-12 levels in breast cancer patients

Previous studies indicated that interleukins 6 & 12 are multifunctional cytokines which regulate of immune response and cancer cell proliferation. We measured serum levels of these cytokines in 40 females with breast cancer and examined their correlation with clinicopathological variables including stages of the disease and estrogen and progesterone receptor expression on tumor cells. Serum levels of IL-6 (mean =111.38 pg/ml) as well as IL-12 (mean=1142.75 pg/ml) were significantly increased in breast cancer patients as compared to controls (mean 1.75 pg/ml &19.90 pg/ml respectively). A statistically significant correlation was found between levels of IL-6 as well as IL-12 and progression of the tumor (P < 0.05). However, no statistical difference was found in serum levels of these cytokines between metastatic and non-metastatic cases. Both cytokines negatively correlated with estrogen and progesterone receptor expression on tumor cells. In conclusion, serum levels of IL-6 and IL-12 are highly elevated in breast cancer patients and correlate with tumor progression. Assays for serum levels of IL-6 and IL-12 can be used as predictive non-invasive tests for tumor progression in breast cancer patients.     

Incidence of apoptosis and cell proliferation in multiple myeloma: correlation with bcl-2 protein expression and serum levels of interleukin-6 (IL-6) and soluble IL-6 receptor

We evaluated the in vivo incidence of apoptosis and cell proliferation in multiple myeloma (MM) and investigated the correlation of both cellular events with histological tumour stage and grade, bcl-2 protein expression, serum IL-6 and sIL-6R. MATERIAL AND METHODS: The TUNEL method was used to assess apoptosis and immunohistochemistry to assess the expression of proliferating cell nuclear antigen (PCNA) and bcl-2 protein in 30 bone marrow biopsy specimens. The apoptotic index (AI) and proliferative index (PI) were defined as the percentage of TUNEL and PCNA positive plasma cells, respectively. RESULTS: The mean AI was 0.162% and the mean PI 27.44%. A positive correlation between AI and PI was found (r = 0.44, P = 0.017). PI was also correlated with tumour grade (P = 0.015). The mean bcl-2 protein expression was 70% and did not correlate with AI or PI, but was higher in specimens taken at first diagnosis than in specimens taken after response to treatment (P = 0.035). The mean serum IL-6 and sIL-6R values were 9.43 pg mL-1 and 47.27 ng mL-1, respectively. These parameters did not correlate with AI or PI. CONCLUSIONS: The results indicate that MM might be among the malignancies with very low incidence of apoptosis. Proliferative activity increased in parallel with tumour histological grade. A positive correlation between apoptosis and proliferation was observed, but the incidence of these two cellular events seems not to be related to the bcl-2 protein expression and the serum levels of IL-6 and sIL-6R.     

Sites of interleukin-6 release in patients with acute coronary syndromes and in patients with congestive heart failure

This study examines the source of elevated interleukin-6 (IL-6) levels in patients with acute coronary syndrome (ACS) and congestive heart failure (CHF). IL-6 is elevated in the peripheral blood of patients with ACS and CHF, but it is not known if this proinflammatory cytokine is from a cardiac or extracardiac source. Blood samples were obtained from the femoral artery, femoral vein, left main coronary artery, and coronary sinus in 57 patients during cardiac catheterization. IL-6 levels from 12 patients with ACS and 12 patients with CHF were compared with the IL-6 levels in 33 patients who had neither of these clinical conditions. Median IL-6 levels in the peripheral and coronary circulation were a minimum fivefold higher in patients with ACS or CHF relative to control patients. An elevated transcardiac IL-6 gradient (coronary sinus-left main level) was present in patients with ACS (median 5.2; 25th and 75th percentiles 3.9 and 29.3 pg/ml, respectively) compared with control patients (median 0, -0.7 and 0.5 pg/ml; p < 0.001), but not in patients with CHF (median 0.4, -0.7 and 3.5 pg/ml; p = NS). Elevated IL-6 levels in patients with ACS derive from a cardiac source, presumably from "inflamed" coronary plaques and areas of myocardial necrosis, whereas elevated levels in patients with CHF are most likely the result of extracardiac production.     

High IL-6 levels in ascitic fluid correlate with reactive thrombocytosis in patients with epithelial ovarian cancer

Summary. Non-haematopoietic malignancies are commonly associated with thrombocytosis. The aetiology of tumour-associated thrombocytosis is still unclear but may be related to tumour-derived thrombopoietin-like factors. Epithelial ovarian tumour cells have been shown to release IL-6 in vitro and high IL-6 levels have been identified in ascites of patients with ovarian cancer. Since IL-6 is a potent stimulator of megakaryocytopoiesis we examined IL-6 production at the tumour site and its relationship to serum IL-6 levels and circulating platelet counts in patients with ovarian cancer. Forty patients undergoing exploratory laparotomy for epithelial ovarian cancer [stage I + II: 6 (15%); stage III: 25 (62.5%); stage IV: 9 (22.5%)] and 24 women with benign ovarian conditions were evaluated. Sera were available from 39 cases with ovarian cancer and from 19 cases with benign ovarian tumours. Ascites was obtained from 35 patients with ovarian cancer. IL-6 activity in serum and ascitic fluid was determined by the standard B9 proliferation assay (detection level: 1 pg/ml). IL-6 bioactivity was detectable in 22 (56%) sera from patients with ovarian cancer, but in only five (26%) of the serum samples obtained from benign cases (P < 0.001). Serum IL-6 levels in patients with ovarian cancer were significantly higher (median 3 pg/ml; range < 1 to 1221 pg/ml) than in patients with benign ovarian conditions (median 0 pg/ml; range < 1 to 4 pg/ml) (P < 0.001). However, much higher concentrations of IL-6 were measured in malignant ascites specimens (median 22 100 pg/ml; range < 1 to 182 600 pg/ml). IL-6 bioactivity in serum and ascites samples was completely inhibited by a neutralizing goat antihuman IL-6 antiserum. Thrombocytosis (platelet counts > 400 × 10⁹/l) occurred in 25 (62.5%) of the 40 patients with ovarian cancer, but in only two (8%) of the 24 cases with benign ovarian tumours. In eight (20%) cases with malignant disease platelet counts ranged between 600 × 10⁹/l and 1060 × 10⁹/l. IL-6 bioactivity in ascitic fluid correlated significantly with circulating platelet counts (r = 0.5916; P < 0.001). Maximum IL-6 bioactivity in ascites and highest platelet counts occurred in patients with undifferentiated ovarian adenocarcinoma or advanced disease. In conclusion, these observations strongly suggest a role for IL-6 in the development of tumour-associated thrombocytosis.     

Soluble interleukin-6 receptor as a prognostic factor in multiple myeloma

Interleukin-6 (IL-6) is a major growth factor for the clonal malignant plasma cells in multiple myeloma (MM). The effect of IL-6 may be enhanced by soluble IL-6 receptor (sIL-6R). As there is a clinical need for improved stratification of MM patients at diagnosis, we have studied the role of sIL-6R as a prognostic marker in 207 newly diagnosed MM patients. Serum sIL-6R concentration was above the upper reference limit in 47% of the patients at diagnosis. The concentrations of sIL-6R and two other prognostic factors, IL-6 and β-2 microglobulin (β2M), were all significantly higher in the patients who died within 3 years compared with those who survived. However, serum sIL-6R did not show linear correlation with IL-6 or β2M levels. In univariate logistic regression analysis sIL-6R was a significant predictor of 3-year mortality. Kaplan-Meier analysis showed that raised levels of sIL-6R were associated with shorter survival. When the patients were stratified into four groups according to their serum IL-6 and sIL-6R levels, the patients with normal serum levels of both parameters had clear survival benefit. As β2M was the most powerful prognostic factor in the multivariate analysis, the patients were also stratified according to their serum β2M and sIL-6R levels. The patients with raised levels of both β2M and sIL-6R had shorter survival than the patients in the other three groups. Thus, measurement of these parameters at diagnosis would help to stratify MM patients.