Higher Plasma Osteopontin Levels Research Articles

High Plasma Osteopontin Levels Are Associated with Serious Post-Acute-COVID-19-Related Dyspnea.

COVID-19 survivors commonly report persistent symptoms. In this observational study, we investigated the link between osteopontin (OPN) and post-acute COVID-19 symptoms and lung functional/imaging abnormalities. We recorded symptoms and lung imaging/functional data from previously hospitalized COVID-19 patients, who were followed for 4-84 weeks (122 patients/181 visits) post-symptom onset at our outpatient clinic. Circulating OPN was determined using ELISA. Plasma OPN levels were higher in symptomatic patients (compared with the asymptomatic ones); those with dyspnea (compared with those without dyspnea);those with a combination of serious symptoms, i.e., the presence of at least one of the following: dyspnea, fatigue and muscular weakness (compared with those with none of these symptoms); and those with dyspnea and m-MRC > 1 (compared with those with m-MRC = 0-1). Plasma OPN levels were inversely correlated with EQ-VAS (visual analog scale of the EQ-5D-5L health-related quality-of-life questionnaire) values. High-resolution CT or diffusion lung capacity (DLCO) findings were not related to circulating OPN. In the multiple logistic regression, the presence of symptoms, dyspnea, or the combination of serious symptoms were linked to female gender, increased BMI and pre-existing dyspnea (before the acute disease), while increased plasma OPN levels, female gender and pre-existing dyspnea with m-MRC > 1 were independently associated with severe post-COVID-19 dyspnea (m-MRC > 1). Using a correlation matrix to investigate multiple correlations between EQ-VAS, OPN and epidemiological data, we observed an inverse correlation between the OPN and EQ-VAS values. Increased circulating OPN was linked to the persistence of severe exertional dyspnea and impaired quality of life in previously hospitalized COVID-19 patients.

Higher Plasma Osteopontin Concentrations Associated with Subsequent Development of Chronic Shunt-Dependent Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage.

A matricellular protein osteopontin (OPN) is considered to exert neuroprotective and healing effects on neurovascular injuries in an acute phase of aneurysmal subarachnoid hemorrhage (SAH). However, the relationships between OPN expression and chronic shunt-dependent hydrocephalus (SDHC) have never been investigated. In 166 SAH patients (derivation and validation cohorts, 110 and 56, respectively), plasma OPN levels were serially measured at days1-3, 4-6, 7-9, and 10-12 after aneurysmal obliteration. The OPN levels and clinical factors were compared between patients with and without subsequent development of chronic SDHC. Plasma OPN levels in the SDHC patients increased from days 1-3 to days 4-6 and remained high thereafter, while those in the non-SDHC patients peaked at days 4-6 and then decreased over time. Plasma OPN levels had no correlation with serum levels of C-reactive protein (CRP), a systemic inflammatory marker. Univariate analyses showed that age, modified Fisher grade, acute hydrocephalus, cerebrospinal fluid drainage, and OPN and CRP levels at days 10-12 were significantly different between patients with and without SDHC. Multivariate analyses revealed that higher plasma OPN levels at days 10-12 were an independent factor associated with the development of SDHC, in addition to a more frequent use of cerebrospinal fluid drainage and higher modified Fisher grade at admission. Plasma OPN levels at days 10-12 maintained similar discrimination power in the validation cohort and had good calibration on the Hosmer-Lemeshow goodness-of-fit test. Prolonged higher expression of OPN may contribute to the development of post-SAH SDHC, possibly by excessive repairing effects promoting fibrosis in the subarachnoid space.

Prognostic Significance of Plasma Osteopontin in Patients with Locoregionally Advanced Head and Neck Squamous Cell Carcinoma Treated on TROG 02.02 Phase III Trial

High plasma osteopontin (OPN) levels have been reported to be an adverse prognostic factor in head and neck squamous cell carcinomas (HNSCC), correlate with tumor hypoxia, and be predictive of benefit from hypoxia-targeted therapy. We sought to confirm the prognostic and predictive significance of OPN in patients treated on a large international trial. Patients with stage III/IV HNSCC were randomized to receive definitive radiotherapy concurrently with cisplatin or cisplatin plus the hypoxic cell cytotoxin, tirapazamine (TPZ). Eligibility criteria for this prospective substudy included plasma sample availability for OPN assay by ELISA and absence of major radiation therapy deviations (N = 578). OPN concentrations were analyzed for overall survival (OS) and time to locoregional failure (TTLRF), adjusting for known prognostic factors. Additional analysis was carried out in patients with available tumor p16(INK4A) staining status. The median OPN level was 544 ng/mL (range: 7-2,640). High OPN levels were not associated with worse OS (relative HR, 1.03 for highest tertile) or TTLRF (relative HR 0.91 for highest tertile). There was no interaction between OPN and treatment arm for OS or TTLRF (P = 0.93 for OS; P = 0.87 for TTLRF). For the highest tertile the 2-year OS was 66% on control arm and 67% on TPZ arm (HR = 1.11, P = 0.67). Similarly for p16(INK4A) negative patients in the highest tertile, the 2-year OS was 61% on control arm and 63% on TPZ arm (HR = 1.05, P = 0.86). We found no evidence that high plasma OPN levels were associated with an adverse prognosis in HNSCC, or were predictive of benefit with hypoxia targeting therapy.

Prognostic significance of plasma osteopontin in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with chemoradiation on TROG 02.02 phase III trial.

5506 Background: High plasma osteopontin (OPN) levels have been reported to be an adverse prognostic factor in HNSCC, to correlate with tumor hypoxia and to be predictive of benefit from hypoxia targeted therapy. We sought to confirm the prognostic and predictive significance of OPN in patients treated on a large international trial. Methods: Patients with previously untreated Stage III or IV HNSCC were randomized to receive definitive radiotherapy concurrently with cisplatin or cisplatin plus the hypoxic cell cytotoxin, tirapazamine (TPZ). As previously reported there were no significant differences in any outcome parameter by randomization arm. Eligibility criteria for this prospective substudy included availability of plasma samples and absence of major radiation therapy deviations. Plasma OPN was measured by ELISA. OPN concentrations according to tertiles and median were analysed for overall survival (OS), and time to locoregional failure (TTLRF), adjusting for prognostic factors (site, T category, N category, hemoglobin, performance status). An additional analysis was performed in patients with available p16 immunohistochemistry results. Results: 578/853 patients were eligible and had a median OPN level of 544 µg/L (range: 7 - 2640). High OPN levels were not associated with worse overall survival (HR 1.03 for highest tertile and 0.98 for middle tertile, p=0.95) or time to locoregional failure (HR 0.91 for highest and 0.93 for middle, p=0.91). There was no interaction between OPN and treatment arm for OS or TTLRF (p=0.51 for both). For the highest tertile the 2-year OS was 70% on control arm and 71% on TPZ arm (HR=1.11, p=0.67). Similarly for p16 negative patients in the highest tertile, the 2 year OS was 69% on control arm and 73% on TPZ arm (HR=1.13, p=0.82). Conclusions: In contrast to previous reports we found no evidence that high plasma OPN levels were associated with an adverse prognosis in HNSCC, or were predictive of benefit with hypoxia targeting therapy. Supported by 1 R01 CA118582 and NHMRC project grant.

Osteopontin protects against cardiac ischemia-reperfusion injury through late preconditioning

Osteopontin (OPN) has been considered as a proinflammatory cytokine. A protective role for OPN in ischemic injury was demonstrated recently. Because proinflammatory cytokines play an important role in induction of late preconditioning, we deduce that OPN may induce late preconditioning in myocardium. Fifty consecutive patients scheduled for mitral valve replacement (MVR) were investigated. Osteopontin and high-sensitivity C-reactive protein levels in plasma before surgery were determined. Nuclear factor kappa B and signal transducer and activator of transcription 3 (STAT3), two main transcription factors involved in late preconditioning, were investigated by electrophoretic mobility shift assay. The effector proteins in late preconditioning, including inducible nitric oxide synthase and cyclooxygenase-2, were evaluated by immunoblotting. Cardioprotective effects were assessed by creatine kinase MB (CK-MB) and cardiac troponin T (cTnT) leakage postoperatively. The protective effects of OPN on neonatal cardiomyocytes against anoxia-reoxygenation-induced injury were also tested. The protein synthesis inhibitor cycloheximide (CH) was used in this model to test if new protein synthesis was necessary for its cardioprotective effects. There was no perioperative death in the groups. We found that patients with higher plasma OPN levels (167 +/- 35 ng/ml vs 63 +/- 13 ng/ml) had more activated extent of transcription factors, higher expression of effector proteins, and better cardioprotective effects, assessed by CK-MB and cTnT. An in vitro experiment also revealed that OPN had a cardioprotective effect 24 h after pretreatment. However, the protective effect was blocked by the protein synthesis inhibitor CH. Osteopontin can protect against cardiac ischemia-reperfusion injury through late preconditioning.

Clinical significance of osteopontin expression in cervical cancer

New diagnostic markers, other than squamous cell carcinoma (SCC) antigen, are needed for the detection of cervical cancer. Osteopontin (OPN) is a candidate frequently associated with several human malignancies. The purpose of this study was to evaluate the clinical significance of OPN expression as a diagnostic and prognostic biomarker for cervical cancer. Immunohistochemical staining of tissue from 97 cervical cancer cases and 22 healthy subjects was performed in order to determine the source of elevated plasma OPN levels. In addition, plasma OPN levels of 81 patients with cervical cancer, 34 patients with carcinoma in situ (CIS) of the uterine cervix, and those of 283 healthy women were measured with a commercially available solid-phase sandwich enzyme-linked immunosorbent assay (ELISA). The correlation between OPN levels and clinical features were examined and compared to SCC antigen levels in the cervical cancer cases. Immunohistochemical staining revealed OPN immunoreactivity in 67.0% (65/97) of cervical cancer tissues, and the immunostaining score in the cervical cancer tissue sections was 2.06 (95% CI, 1.70-2.42). There was no significant difference in immunostaining scores based on age, tumor size, and tumor stage, but higher scores (3.0< score <or=6.0) were significantly correlated with overall survival (P = 0.002) and disease-free survival (P = 0.033). Plasma OPN levels in women with cervical cancer (mean 355.8 ng/ml) were significantly higher (P < 0.001) than those of women with CIS (mean: 185 ng/ml) and healthy controls (mean 100 ng/ml). Within the cervical cancer patients, OPN levels correlated with increasing tumor size (P = 0.008) and tumor stage (P < 0.001). The sensitivity and specificity of OPN in detecting cervical cancer was 50.6 and 95.0%, respectively (cutoff value 215.5 ng/ml). Using a combination of markers proved to bring more sensitive results than using one marker (sensitivity: 65.4%, specificity: 90.9%). High plasma OPN levels (>215.5 ng/ml) were also correlated with disease-free survival (P = 0.038). These results suggest that plasma OPN levels are potentially useful as a diagnostic and prognostic biomarker for cervical cancer.

Elevated plasma osteopontin as marker for distant metastases and poor survival in patients with renal cell carcinoma

To evaluate diagnostic and prognostic significance of plasma osteopontin (OPN) in patients with renal cell carcinoma (RCC). The retrospective study included 80 patients with RCC (pN0M0, n = 32; pN1M0, n = 11; M1, and n = 37), and 52 healthy controls (27 females and 25 males). OPN, the bone marker bone-specific alkaline phosphatase (bALP) and carboxyterminal telopetide of type-I collagen (ICTP), and the enzymes alanine aminotransferase (ALAT), and gamma-glutamyltransferase (GGT) were evaluated together with Memorial Sloan-Kettering Cancer Center (MSKCC) laboratory parameters. Data were analyzed by receiver-operating characteristics (ROC), survival analysis, and Cox proportional hazards regression model. OPN and ICTP levels in RCC patients with distant metastases were significantly elevated (medians 115 and 4.7 microg/l, P < 0.001) compared to those without metastases (31.1 and 2.5 microg/l) and controls (28.9 and 2.1 microg/l) but did not differ between patients with bone or non-bone metastases. Both bALP and ALAT were not different between all study groups, while GGT was only increased in patients with non-bone metastases. In ROC analysis, OPN showed the best discrimination between patients with and without metastases (area under the curve: 0.888). High OPN values were associated with poor survival (Kaplan-Meier analysis, log-rank test, P = 0.002). Multivariate Cox regression with forward and backward stepwise elimination confirmed plasma OPN as independent predictive survival factor in RCC patients. Our results show that high plasma OPN levels are associated with distant metastases and poor survival in RCC patients. The use of OPN as potential marker to monitor new treatment strategies in patients with advanced RCC should be evaluated in prospective studies.

Preoperative plasma osteopontin level as a biomarker complementary to carbohydrate antigen 125 in predicting ovarian cancer

New biomarkers other than carbohydrate antigen (CA) 125 are needed for the detection of ovarian cancer. Osteopontin (OPN) is one of the candidates identified by high-throughput complementary DNA microarray techniques. We evaluated the preoperative plasma OPN level as a diagnostic biomarker for ovarian cancer in comparison with CA125. Preoperative plasma OPN and CA125 levels were measured and compared in 32 patients with ovarian cancer, 34 patients with benign ovarian tumor, 30 patients with other gynecologic cancers and 31 healthy women. Preoperative plasma OPN levels were also assessed according to tumor stage, the volume of ascites and histological types. The sensitivity and specificity for predicting ovarian cancer was compared between OPN and CA125. Preoperative plasma OPN levels were significantly higher in patients with ovarian cancer than in those with benign ovarian tumor, in other gynecologic patients or in healthy women. Stage IV ovarian cancer patients and ovarian cancer patients with ascites had higher plasma OPN levels than those without ascites and in a lower stage. There was no relation between OPN and the histological type. The sensitivity of preoperative plasma OPN in detecting ovarian cancer was 81.3% and almost reached that of CA125. The specificity was moderate. Sensitivity increased to 93.8% with the combination of CA125, compared to 84.4% with CA125 alone. Preoperative OPN is a useful biomarker for predicting ovarian cancer. It is especially useful when used complementary to CA125. Larger studies of patients with ovarian cancer showing a low CA125 level or in early stages of ovarian cancer are needed.