Serum Concentrations Of Osteopontin Research Articles

Inflammation and autonomic balance in cirrhosis: Association between sympathetic nervous system and osteopontin, interleukin‐22, interleukin‐6 and interleukin‐1Ra concentrations according to portal hypertension and disease severity

AbstractBackgroundThe autonomic nervous system is linked to hyperdynamic circulation in cirrhosis and several studies have highlighted the crucial role that systemic inflammation elicits in altering sympathovagal equilibrium with the consequent reduction in heart rate variability (HRV).To investigate the correlation between time‐domain HRV parameters, serum cytokines concentrations and portal hypertension, we studied a cohort of patients with cirrhosis, accounting for etiology and treatments.MethodsIn this cross‐sectional, observational cohort study, 107 outpatients with non‐alcoholic cirrhosis were assessed consecutively by abdominal ultrasound and by upper gastrointestinal endoscopy to search for esophagogastric varices. 24‐h electrocardiogram Holter monitoring with time‐domain HRV measurement (square root of the mean of successive differences of Normal‐to‐Normal [NN] [RMSSD], standard deviation or the square root of variance [SDNN] and standard deviation of the means of the NN intervals calculated over a 5‐min period [SDANN]) was performed and serum concentrations of osteopontin (OPN), interleukin (IL)‐22, IL‐6, IL‐1Ra and IL‐17 were obtained in all patients.ResultsIL‐6, OPN, IL‐22 and IL‐1Ra concentrations in cirrhotic patients were associated with disease severity expressed by Child‐Pugh and MELD score, to some portal hypertension's indirect signs and some of its complications. A significant increase in systemic concentrations of OPN in patients with hepatocellular carcinoma was encountered. SDANN and SDNN values were indirectly related to serum levels of IL‐6, OPN, IL‐1Ra and IL‐22.ConclusionsThis study underlines the interaction between the alteration of the ANS and the activation of inflammatory pathways that characterize cirrhosis taking into account clinical characteristics and treatments.

Serum Osteopontin, KL-6, and Syndecan-4 as Potential Biomarkers in the Diagnosis of Coal Workers' Pneumoconiosis: A Case-Control Study.

Coal worker's pneumoconiosis (CWP) is a chronic occupational disease mainly caused by coal dust inhalation in miners. This study aimed to investigate the clinical value of Osteopontin (OPN), KL-6, Syndecan-4 and Gremlin-1 as serum biomarkers in CWP. We integrated reported lung tissues transcriptome data in pneumoconiosis patients with silica-exposed alveolar macrophage microarray data to identify four CWP-associated serum biomarkers. The serum concentrations of Osteopontin, Krebs von den Lungen-6 (KL-6), Syndecan-4 and Gremlin-1 were measured in 100 healthy controls (HCs), 100 dust-exposed workers (DEWs) and 200 patients of CWP. Receiver operating characteristic (ROC) curve analysis was used to determine the sensitivity, specificity, cut-off value and area under the curve (AUC) value of biomarkers. The pulmonary function parameters decreased sequentially, and the serum OPN, KL-6, Syndecan-4 and Gremlin-1 concentrations were increased sequentially among the HC, DEW and CWP groups. Among all participants, multivariable analysis revealed that these four biomarkers were negatively correlated with the pulmonary function parameters (all p<0.05). Compared with HCs, patients with higher OPN, KL-6, Syndecan-4 and Gremlin-1 had higher risk for CWP. The combination of OPN, KL-6, and Syndecan-4 can improve the diagnostic sensitivity and specificity of CWP patients differentiated from HCs or DEWs. OPN, KL-6 and Syndecan-4 are novel biomarkers that can be used for CWP auxiliary diagnosis. The combination of three biomarkers can improve the diagnostic values of CWP.

Diagnostic Role of Osteopontin in Interstitial Lung Disease

Objective: Early diagnosis of interstitial lung disease (ILD) is desirable not only to better define pathobiological mechanisms, but also to customize treatment protocols. As osteopontin (OPN) expression may be linked to the fibrotic remodelling in ILD, this present study was planned to evaluate the usefulness of its estimation in serum for the diagnosis of ILD.Material and Methods: Serum OPN levels were estimated by enzyme-linked immunosorbent assay in 52 diagnosed cases of ILD, that were then compared with 46 patients with chronic obstructive lung disease and 46 apparently healthy controls.Results: Median levels of serum OPN were found to be significantly higher in patients with ILD, 2.186 nanograms per milliliter (ng/ml), as compared to patients with chronic obstructive lung disease and healthy controls (1.687 and 1.923 ng/ml, respectively). The best cutoff levels of OPN, for diagnosis of ILD, was found to be &gt;1.08 ng/ml; with a sensitivity of 88.4% and specificity of 32.6%. Of the various subtypes, serum OPN levels were found to be highest in patients with idiopathic pulmonary fibrosis and interstitial pneumonia with autoimmune features; although the difference in levels between various subgroups was not found to be statistically significant (p-value=0.495).Conclusion: Serum concentration of OPN was found to be increased in patients with ILD and may be used to aid diagnosis. This opens new avenues for future research in patients with ILD, not only for the validation of the diagnostic abilities of OPN, but also as a potential target in its treatment.

Osteopontin Regulates Endometrial Stromal Cell Migration in Endometriosis through the PI3K Pathway

Endometriosis is generally characterized as a tumor-like disease because of its potential for distant metastasis and local tissue invasion, while whether osteopontin (OPN) plays a role in the pathogenesis of endometriosis has not been thoroughly investigated. We investigated the expression of OPN, urokinase plasminogen activator (uPA), phosphatidylinositol 3 kinase (PI3K), and phospho-PI3 kinase (p-PI3K) in endometrial stromal cells (ESCs). The serum concentration of OPN was determined by enzyme-linked immunosorbent assays (ELISA). OPN was downregulated to explore the corresponding change of uPA, p-PI3K, F-actin, and α-tubulin. The expression of OPN, uPA, PI3K, and p-PI3K was evaluated by western blot and quantitative real-time PCR (RT-qPCR) and the expression of F-actin and α-tubulin was confirmed by immunofluorescence assay. The proliferation and migration abilities of ESCs were investigated by CCK8, transwell, and wound scratch assays. Endometrial OPN, p-PI3K, and uPA expressions and serum OPN levels were increased in patients with endometriosis compared with the control. The expressions of p-PI3K, uPA, and α-tubulin were decreased by siRNA-OPN interference in ectopic ESCs. Activation and inhibition of the PI3K pathway apparently upregulate and downregulate uPA expression. Knockdown of OPN and inhibition of the PI3K pathway remarkably inhibited cell migration in ectopic ESCs. Meanwhile, activation of the PI3K pathway promoted the migration ability of ectopic ESCs. OPN may regulate the expression of uPA through the PI3K signal pathway to affect the migration ability of ESCs, indicating that OPN, uPA, and the PI3K pathway may be potential targets for interrupting development of endometriosis.

Serum concentration of osteopontin and interleukin 17 in psoriatic patients.

Psoriasis is a chronic, autoinflammatory disease characterized by activation and differentiation of naive T lymphocytes towards T helper CD4+ (including Th1 and Th17) and T cytotoxic CD8+. Osteopontin (OPN), which plays an important role in both physiological processes and inflammatory, neoplastic and autoimmune diseases, is also considered in the context of psoriasis pathogenesis. Current data indicates that OPN is a multifunctional protein involved in the modulation of Th1 and Th17 cellular responses, in stimulating keratinocyte proliferation, and in the regulation of cellular apoptosis. The assessment of OPN and interleukin 17 (IL-17) concentrations in the peripheral blood of psoriatic patients in comparison to healthy volunteers as well as the correlations of OPN and IL-17 with the severity of psoriasis. The study included 107 male psoriatic patients and 41 age-matched healthy men. The serum concentrations of IL-17 and OPN were examined using the enzyme-linked immunosorbent assay (ELISA) method. The skin change severity of psoriasis was assessed using the Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA), Physician Global Assessment (PGA), and Dermatology Life Quality Index (DLQI). Psoriatic patients had significantly higher concentrations of OPN (31.65 ng/mL on average) than the healthy volunteers (11.42 ng/mL on average) (p < 0.001). Interleukin 17 was also higher in psoriatic patients (0.53 pg/mL on average) compared to healthy volunteers (0.09 pg/mL on average) (p < 0.001). There was no significant correlation between OPN and IL-17 concentrations in psoriatic patients and in healthy volunteers. Psoriasis severity correlated positively to IL-17 serum concentration, but not to OPN. Although the study did not show a relationship between OPN and IL-17 concentrations in psoriatic patients, it should be emphasized that serum concentrations were significantly higher in the patients with psoriasis compared to healthy volunteers.

Osteopontin in the Pathogenesis of Aortic Dissection by the Enhancement of MMP Expressions.

The pathogenesis of aortic dissection (AD) is unclear. The aim of this study was to explore the relationship between osteopontin (OPN) and AD. Fifty AD patients were enrolled; 29 had hypertension with AD (H-AD) and 21 no hypertension with HD (NH-AD). Twenty-five healthy controls (NH-C) and 14 patients with hypertension (H-C) were also enrolled. Serum and aortic wall OPN levels were determined. Human vascular muscle cells (HVSMC) were stimulated by both low (1 μg/mL) and high (5 μg/mL) concentrations of OPN and cell proliferation as well as apoptosis was measured. Transforming growth factor-β (TGF-β), matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-9, TIMP-1, and TIMP-2 gene expressions by HVSMC were measured and Akt, IκB, Smad1/5/8 and Erk1/2 signaling pathways were detected. Our results showed that AD patients demonstrated significantly higher levels of serum and local OPN expressions compared to healthy controls. In those with hypertension, the serum concentrations of OPN were increased compared to those without hypertension. In in vitro culture, a high dose of OPN stimulation promoted the proliferation of HVSMC but did not affect cell apoptosis. Both concentrations of OPN enhanced MMP-2 gene expression and its activity in HVSMC. Moreover, Akt and IκB signaling pathways were significantly activated after OPN stimulation while the Smad1/5/8 and Erk1/2 signaling pathways were not changed. The addition of an IκB inhibitor significantly abrogated MMP-2 gene expression. Our data show that OPN may participate in the pathogenesis of AD by the enhancement of MMP-2 expression.

Polymorphisms in the Osteopontin Are Associated with Susceptibility to Ankylosing Spondylitis in a Han Chinese Population.

The aim of this study was to investigate whether osteopontin (OPN) variants are associated with susceptibility to ankylosing spondylitis (AS) in a Chinese population. Polymorphisms at the 9175th position in exon 7 of OPN and rs17524488 were genotyped using direct sequencing in 186 unrelated AS patients and 188 ethnically matched healthy controls. Serum concentration of OPN was measured by enzyme-linked immunosorbent assay (ELISA) in all participants. AS patients displayed significantly higher OPN serum levels than the controls (P < 001). A heterozygous, novel 9175 T>A in exon 7 of the OPN gene was found in this study. In healthy controls, subjects carrying the rs17524488 G/G genotype of the OPN display significantly higher OPN serum levels than the GG/GG genotype (P < 0.05). Plasma OPN level is implicated as an early diagnostic marker of AS. The novel 9175th- (exon 7) position polymorphism of OPN and rs17524488 were related to susceptibility to AS in a Chinese population, the rs17524488 G/G genotype may be involved in the pathogenesis of AS, and the precise molecular mechanism underlying the influence of OPN polymorphisms on the development of AS remains to be determined in the further prospective studies.

Fenofibrate in the management of AbdoMinal aortic anEurysm (FAME): study protocol for a randomised controlled trial

BackgroundAbdominal aortic aneurysm (AAA) is a slowly progressive destructive process of the main abdominal artery. Experimental studies indicate that fibrates exert beneficial effects on AAAs by mechanisms involving both serum lipid modification and favourable changes to the AAA wall.Methods/designFenofibrate in the management of AbdoMinal aortic anEurysm (FAME) is a multicentre, randomised, double-blind, placebo-controlled clinical trial to assess the effect of orally administered therapy with fenofibrate on key pathological markers of AAA in patients undergoing open AAA repair. A total of 42 participants scheduled for an elective open AAA repair will be randomly assigned to either 145 mg of fenofibrate per day or identical placebo for a minimum period of 2 weeks prior to surgery. Primary outcome measures will be macrophage number and osteopontin (OPN) concentration within the AAA wall as well as serum concentrations of OPN. Secondary outcome measures will include levels of matrix metalloproteinases and proinflammatory cytokines within the AAA wall, periaortic fat and intramural thrombus and circulating concentrations of AAA biomarkers.DiscussionAt present, there is no recognised medical therapy to limit AAA progression. The FAME trial aims to assess the ability of fenofibrate to alter tissue markers of AAA pathology.Trial registrationAustralian New Zealand Clinical Trials Registry, ACTRN12612001226897. Registered on 20 November 2012.

Serum Osteopontin and Cytokeratin-18 in Chronic Hepatitis C Patients

Chronic hepatitis C is a global health problem; most patients are at risk for developing fibrosis and cirrhosis. Histological examination of liver biopsies is currently the gold standard for the detection of early liver damage, but there is a strong need for better noninvasive methods. The aim of this study was to evaluate the association between serum osteopontin (OPN) level, serum cytokeratin 18 M30 (CK-18 M30) neoepitope level and the histological severity of hepatic fibrosis in hepatitis C virus (HCV) induced patients. Subjects and methods: This study included 89 subjects, 70 with chronic hepatitis C virus infection, they were classified into 2 groups according to METAVIR fibrosis stage as follows: group I (stage 2 or less was considered as mild liver fibrosis) included 50 patient, group II (stage 3 or more was considered as extensive fibrosis) included 20 patients and 19 healthy matched age and gender as a control group. All subjects were submitted to the following: Through history taking, complete clinical examination, and serum concentrations of osteopontin and cytokeratin 18 M30 neoepitope were measured by enzyme linked immunosorbent assay (ELISA). The results revealed that there were high significant differences of OPN and CK-18 M30 between patients and control (P<0.001). There was a high significant difference of OPN (P<0.001) and a significant difference of CK-18 M30 (P=0.02) when compared between mild fibrosis and extensive fibrosis groups. There was a high significant correlation of serum OPN concentrations with severity of liver fibrosis degree (r=0.75, P<0.001), while the serum CK-18 M30 concentrations showed a significant correlation (r=0.33, P=0.005). In ROC curve serum OPN at the cut-off point of 3.1 ng/ml could discriminate mild from extensive fibrosis with sensitivity of 95%, serum CK-18 M30 at the cut-off point of 293 ng/ml could discriminate mild from extensive fibrosis with sensitivity of 70%. Finally from obtained study, results showed that serum OPN levels was better than CK-18 M30 in identification the degree of hepatic fibrosis and could be used as a biomarker to assess the stage of fibrosis in HCV patients which would help to reduce the number of liver biopsies.

Fenofibrate in the management of AbdoMinal aortic aneurysm (FAME)-2: the study protocol for a multi-centre, randomised, placebo-controlled trial

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; &lt;span lang="EN-IN"&gt;Abdominal aortic aneurysms (AAAs) are a leading cause of mortality worldwide but have no recognised medical therapy. Pre-clinical studies indicate that osteopontin plays an important role in the pathogenesis of AAA via a number of mechanisms. This trial aims to assess the potential of fenofibrate to favourably alter biomarkers associated with AAA pathology. &lt;/span&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; &lt;span lang="EN-IN"&gt;Fenofibrate in the management of AbdoMinal aortic anEurysm (FAME)-2 is a multi-centre, prospective, randomised, double-blind, placebo-controlled clinical trial to assess the effect of 24 weeks of oral therapy with 145 mg of fenofibrate on key pathological markers of AAA. A total of 140 participants with an AAA measuring between 35-49 mm will be randomly assigned to either 145 mg of fenofibrate once per day or identical placebo for a period of 24 weeks. Primary outcome measures will be serum concentrations of osteopontin and kallistatin. Secondary outcome measures will include serum levels of resistin, lipids, matrix metalloproteinases and pro-inflammatory cytokines, circulating concentrations of AAA biomarkers, and AAA diameter as assessed by ultrasound.&lt;/span&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; This study represents the next step in the assessment of a potential novel medical therapy for AAA.&lt;/p&gt;

Measurement of Serum Osteopontin and Interleukin-17 in Asthmatic Children in Saudi Arabia

Cytokines play an important role in the pathophysiology of asthma by affecting airway remodeling and allergic reactions. We aimed to measure the serum concentrations of osteopontin (OPN) and interleukin (IL)-17 in a group of asthmatic and normal children to test the association of these two cytokines with the severity of asthma in Saudi children. Our study included 50 asthmatic and 50 normal children. Serum cytokines were measured by ELISA technique. Pulmonary function tests were performed in the asthmatic children. Serum levels of OPN and IL-17 were significantly increased in asthmatic children in comparison to control group. Also, the concentrations of OPN and IL-17 were significantly associated with asthma severity. There was a significant positive correlation between OPN and IL-17 levels. In conclusion, our study suggests that OPN and IL-17 may play a role in childhood asthma and are strongly related to the disease severity.

Serum Osteopontin Concentrations in Relation to Coronary Artery Disease

Coronary artery disease (CAD) is a common form of vascular disease and is associated with high mortality and morbidity globally. It has been suggested that serum osteopontin (OPN) may be a useful biomarker of atherosclerosis and vascular calcification. The aim of this study was to assess the association between serum OPN levels and severity of CAD. Three hundred and four subjects were studied, 111 with clinically significant angiographically defined CAD (CAD+) (>50% stenosis), 96 with negative angiography (CAD-) (<50% stenosis) and 97 healthy controls. Fasting blood samples were collected from all patients before coronary angiography and serum OPN levels were determined using ELISA. Serum concentrations of OPN were significantly higher in both CAD+ (72.99 [51.05-103.64]) and CAD- (11.11 [8.11-18.23]) (p = 0.001) groups compared with the control group (5.99 [4.26-7.91]) (p = 0.001). CAD+ subjects also had higher serum OPN levels compared with CAD-subjects (p = 0.001). However, OPN levels were comparable between subgroups of CAD+ subjects stratified according to the number of narrowed vessels in angiography. The present results suggest a positive association between circulating OPN concentrations and the presence but not the extent of CAD.

Serum level of osteopontin as an inflammatory marker does not indicate disease activity or responsiveness to therapeutic treatments in patients with rheumatoid arthritis

Osteopontin (OPN) is known to be significantly involved in the pathogenesis of rheumatoid arthritis (RA). This study aimed to evaluate if the serum concentration of OPN in patients with RA before and after therapeutic treatments was correlated to disease activity and response to therapy. Blood samples from 40 patients with RA were collected at baseline and six months after starting treatment with disease-modifying antirheumatic drugs (DMARDs) and/or tumor necrosis factor (TNF)-α blockers. Serum levels of OPN were measured by ELISA. At baseline, the serum OPN level in RA patients was significantly higher than that of the healthy group. The OPN level at baseline in RA patients with severe disease activity as evaluated by DAS28 was slightly higher than that of those with moderate disease activity. The serum OPN level in RA patients was not significantly correlated with the DAS28 level. The serum OPN level in both responders and non-responders after therapy was significantly decreased regardless of responsiveness to therapy. Also, the OPN level at baseline did not affect the responsiveness to therapeutic treatments. In conclusion, serum OPN level was not correlated with disease activity or responsiveness of RA patients to therapeutic treatments.

Osteopontin in bone mineral density of very old Brazilians

Recent evidence suggests that changes in plasma levels of osteopontin (OPN) may be a promising marker for early diagnosis of bone disorders. We hypothesized that a frequent OPN gene polymorphism may be useful for identifying very old individuals with alterations in plasma OPN levels and consequently at risk of abnormal bone density scores. Men and women (80years or older) living in the Brazilian Federal District underwent assessments with dual energy X-ray absorptiometry for bone mineral density (BMD) of the femoral neck, femoral head and lumbosacral (L1 to S5) regions. Clinical inspection was performed to assess other physical traits and to exclude co-morbidities (cardiovascular, autoimmunity, infections or neoplastic diseases). Serum concentrations of OPN were determined with an enzyme-linked immunosorbent assay, whereas the A7385G polymorphism (rs1126772) was determined by direct sequencing of a polymerase chain reaction product. Among the two hundred and ten subjects enrolled, no differential scores for bone mineral density could be observed across genotypes, but a greater content of circulating OPN was found among carriers of the A allele (P≤0.05) even after adjustments. Serum OPN levels were negatively correlated with femoral neck density (P=0.050 for BMD; P=0.032 for T scores) but not with scores of the other regions investigated. Analyses with the sample dichotomized to age and body mass revealed that this inverse relationship was noticeable only among those aged within the highest and weighing within the lowest intervals. Our findings indicate elevated circulating osteopontin levels in patients with decreased bone mineral density, consistent with a modest contribution of an OPN allelic variation to its expression. Assessing the clinical relevance of our findings demands forthcoming studies.

Comparison of Serum Osteopontin Levels in Patients with Stable and Chronic Obstructive Pulmonary Disease and Exacerbation

Methods: Serum samples were obtained from 22 healthy control subjects, 18 stable COPD patients, and 15 COPD with exacerbation patients. Serum concentrations of osteopontin were measured by the ELISA method. Results: Serum levels of osteopontin were higher in patients with acute exacerbation than with stable COPD and in healthy control subjects (62.4±51.9 ng/mL, 36.9±11.1 ng/mL, 30±11 ng/mL, test for trend p=0.003). In the patients with COPD exacerbation, the osteopontin levels when the patient was discharged from the hospital tended to decrease compared to those at admission (45±52.1 ng/mL, 62.4±51.9 ng/mL, p=0.160). Osteopontin levels significantly increased according to patient factors, including never-smoker, ex-smoker and current smoker (23±5.7 ng/mL, 35.5±17.6 ng/mL, 58.6±47.8 ng/mL, test for trend p=0.006). Also, osteopontin levels showed a significantly negative correlation with forced expiratory volume in one second (FEV 1%) predicted in healthy controls and stable COPD patients (r=−0.389; p=0.013). C-reactive protein (CRP) was positively correlated with osteopontin levels in patients with COPD exacerbation (r=0.775; p=0.002). Conclusion: The serum levels of osteopontin increased in patients with COPD exacerbation and tended to decrease after clinical improvement. These results suggest the possible role of osteopontin as a biomarker of acute exacerbation of COPD.

Increased serum osteopontin is a risk factor for osteoporosis in menopausal women

Osteopontin (OPN)-deficient mice are resistant to ovariectomy-induced osteoporosis. Therefore, we hypothesized that women with OPN overexpression may show less resistance to postmenopausal osteoporosis. In this study, we first demonstrated that serum OPN levels could be used as a biomarker for the early diagnosis of osteoporosis in postmenopausal women. Animal studies indicate that OPN-deficient mice are resistant to ovariectomy-induced osteoporosis. From 2004 to 2006, 124 women over the age of 45 were enrolled in a menopausal group, while another 95 women, from 25 to 45 years of age with regular menstruation, were enrolled into a childbearing age group. The serum concentrations of OPN were calculated using the enzyme-link immunosorbent assay method, and bone mineral densities were determined with dual energy X-ray absorptiometry. Serum OPN levels had a significant positive correlation with age (menopausal group, p < 0.0001) and a negative correlation with body weight, height, hip bone mineral density, and T-scores in the menopausal group. In contrast, there was a positive correlation with the E2 concentration and height, but there was no significant association with the above variables in the childbearing age group. Additionally, high serum OPN levels (>14.7 ng/ml) was a significant risk factor causing menopausal osteoporosis (odds ratio = 2.96, 95% confidence interval, 1.055-8.345). Serum OPN levels could be used as a biomarker for the early diagnosis of osteoporosis in postmenopausal women.

Serum Osteopontin Levels are Highly Prognostic for Survival in Advanced Non-small Cell Lung Cancer: Results from JMTO LC 0004

The Japan-Multinational Trial Organization (JMTO) lung cancer (LC) 0003 was a prospective randomized phase III trial investigating advanced non-small cell lung cancer comparing paclitaxel (P) plus carboplatin (C) versus vinorelbine (V), gemcitabine (G) followed by docetaxel (D). This trial was conducted with Southwest Oncology Group (SWOG) 0003 using a common arm of PC. An analysis of SWOG 0003 samples showed that low osteopontin (OPN) plasma levels were highly prognostic for a better outcome. We performed an independent investigation to validate these results using samples from Japanese patients enrolled in the JMTO LC 0004, a correlative study associated with JMTO LC 0003. A total of 20 ml of blood was collected before treatment from patients enrolled in JMTO LC 0003. Serum concentrations of OPN and basic fibroblast growth factor (bFGF) were measured by enzyme-linked immunosorbent assay. Effects of OPN and bFGF levels on tumor response, progression-free survival (PFS), and overall survival (OS) were examined. Seventy-one samples were obtained, including 32 specimens from the PC arm and 39 from the VGD arm. There were no significant relationships between either OPN or bFGF levels with patient characteristics. In an analysis of clinical outcome, low OPN levels correlated with better OS and progression-free survival (hazard ratio [HR] = 0.57; 95% confidence interval [CI], 0.33-0.97; p = 0.037, HR = 0.42; 95% CI, 0.25-0.70; p = 0.001, respectively) and high bFGF levels correlated with better OS (HR = 0.53; 95% CI, 0.31-0.90; p = 0.018). Consistent with the findings from SWOG 0003, low OPN serum levels were significantly associated with a favorable prognosis in the JMTO LC 0004. Additionally, high bFGF levels were associated with improved survival.

Serum Osteopontin as a Predictive Marker of Responsiveness to Methotrexate in Juvenile Idiopathic Arthritis

To evaluate if serum concentrations of osteopontin (OPN) at baseline in patients with juvenile idiopathic arthritis (JIA) represent a potential predictor of responsiveness to methotrexate (MTX). At diagnosis, 60 children with active JIA received MTX in addition to nonsteroidal antiinflammatory drugs. After 12 months of MTX treatment, 30 patients were defined as responders; the 30 nonresponders received anti-tumor necrosis factor-alpha therapy (etanercept) in addition to MTX; this group was then enrolled for an additional 12-month study period. No patient had received steroids within 6 weeks before entering the study. Fifty healthy children matched for sex and age acted as controls. OPN serum levels were measured at baseline, before MTX, and then at 6 and 12 months. In the nonresponder patients, OPN was evaluated again after 6 and 12 months of etanercept treatment. At baseline, OPN values were significantly higher (p = 0.0003) in JIA patients than in controls, with no significant differences among the different JIA subtypes. At baseline, OPN levels were lower in responders than in nonresponder patients (14.16 +/- 10.1 microg/ml vs 33.2 +/- 18.1 microg/ml, respectively). After 12 months of MTX treatment, OPN levels were significantly reduced in comparison to baseline in both responder and nonresponder groups (p = 0.0017, p = 0.0048, respectively). In nonresponders, etanercept significantly reduced OPN levels at 6 and 12-month followup in comparison to baseline (p = 0.002, p = 0.008, respectively). No significant differences were found among OPN levels and disease activity. Serum levels of OPN at baseline represent a possible marker to predict the responsiveness to MTX in patients with JIA.

A genetic polymorphism in transforming growth factor beta receptor‐2 is associated with serum osteopontin

Osteopontin (OPN) is a secreted glycoprotein demonstrated to play an important role in inflammation. Transforming growth factor beta and a related signalling pathway have been implicated in control of OPN secretion. We examined the relationship between transforming growth factor beta receptor-1 and -2 (TGFBR1 and 2) single nucleotide polymorphisms (SNP) and serum OPN in 296 men from the Health in Men Study. Serum concentrations of OPN and 58 SNPs for TGFBR1 and 2 were assessed. One SNP in TGFBR2 was associated with serum OPN (TGFBR2 g.20690C>T, SNP ID rs4522809, P = 0.0007) after adjusting for multiple testing. This study suggests that polymorphism in TGFBR2 are associated with altered secretion of OPN, supporting a role for transforming growth factor beta in OPN production.

Osteopontin and basic fibroblast growth factor are associated with prognosis in advanced non-small cell lung cancer (JMTO LC 0004)

19025 Background: A prospective randomized phase III trial for advanced non-small cell lung cancer (NSCLC) compared paclitaxel (P) plus carboplatin (C) vs. vinorelbine (V), gemcitabine (G) followed by docetaxel (D) in the Japan-Multinational Trial Organization (JMTO LC0003) (Kawahara ASCO 06). This trial was conducted jointly with SWOG 0003 using a common arm of PC. Pharmacogenomic studies of samples from both trials demonstrated significant associations between genotype and clinical outcome (Gandara ASCO 07). Previous analysis of SWOG 0003 samples showed that elevated osteopontin (OPN) plasma levels were highly prognostic (Mack ASCO 05). Our correlative study (JMTO LC 0004) of JMTO LC 0003 was originally designed to assess β-tubulin mutations, which was determined to be insignificant. We elected to study and validate OPN as a prognostic marker, using stock samples under additional approval of JMTO IRB. Method: A total of 20 ml of blood was collected prior to treatment from patients enrolled in JMTO LC0003. Serum concentrations of OPN and basic fibroblast growth factor (bFGF) were measured by ELISA. The relationships between OPN, bFGF levels and patients characteristics were examined using χ2 test, including treatment arm, age, smoking status, histology, clinical stage, performance status, weight loss and LDH. Effect of OPN and bFGF levels on progression-free survival (PFS) and overall survival (OS) were examined by multivariate analysis adjusted by treatment arm, smoking status, clinical stage, performance status, weight loss and LDH. Results: Seventy-one samples were obtained, including 32 specimens from the PC arm and 39 from the VGD arm. There were no significant relationships between either OPN or bFGF levels with patient characteristics. However, smokers tended to have higher OPN levels (p=0.083). In analysis of clinical outcome, low OPN levels correlated with better PFS (p<0.001), and high bFGF correlated with better OS (p=0.003). Conclusion: Consistent with findings from SWOG 0003, low OPN serum levels were significantly associated with a favorable prognosis in the JMTO LC 0004. Additionally, high bFGF levels were associated with improved survival. No significant financial relationships to disclose.