Malgorzata Matusiewicz

Acute-phase response proteins are related to cachexia and accelerated angiogenesis in gastroesophageal cancers

Abstract Background: Accurate outcome prediction in gastroesophageal malignancies is challenging. Acute-phase response proteins (APRPs) have been claimed to be independent prognosticators, although the basis for their association with prognosis remains unexplained. We hypothesized that, similarly to pancreatic and lung cancers, changes in APRPs in gastroesophageal malignancies are associated with cachexia and accelerated angiogenesis. Methods: C-reactive protein (CRP), albumin and transferrin serum levels were evaluated and the Glasgow Prognostic Score (GPS) calculated. These data were compared with concentrations of circulating interleukin (IL)-1, IL-6 and IL-8, tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF)-A, VEGF-C and midkine in 96 gastroesophageal cancer patients (49 with cachexia) and 42 healthy subjects. Results: Albumin and CRP levels were altered in the cancer patients, with further CRP elevation in those with cachexia. Transferrin was decreased only in the cachectic patients. The interrelationships between the APRPs were strengthened in cachexia and only then were APRPs correlated with the cytokines elevated in gastroesophageal cancer-related cachexia: IL-6, IL-8, VEGF-A and midkine. GPS corresponded well to transferrin, IL-1, IL-6, IL-8, TNF-α, VEGF-A and midkine concentrations. Conclusions: Cachexia in gastroesophageal cancers is associated with changes in APRP concentrations. This, together with a direct relationship of APRPs with accelerated angiogenesis, may constitute a foundation for the association of APRPs and GPS with outcome in these malignancies. Clin Chem Lab Med 2008;46:359–64.

Paraoxonase-1 status in Crohn's disease and ulcerative colitis

Background: Paraoxonase 1 (PON1) is an extracellular enzyme, which in the gastrointestinal tract may act as a local detoxifier, antioxidant, immunomodulator, and/or quorum‐quenching factor. There are no data on PON1 activity in Crohns disease (CD). Methods: PON1 phenotype and activity were determined spectrophotometrically in 52 subjects with CD, 67 with ulcerative colitis (UC), and 99 healthy individuals, and related to lipid peroxidation and disease phenotype, clinical and biochemical activity, and therapeutic strategy. Diagnostic utility of PON1 was evaluated by ROC analysis and compared with C‐reactive protein (CRP). Results: In comparison with controls (166 U), PON1 was reduced only in active CD (110 U, P < 0.0001) and UC (126 U, P < 0.0001), and correlated with disease activity (r = −0.47, P = 0.001 in CD and r = −0.50, P < 0.001 in UC). PON1 significantly correlated with erythrocyte sedimentation rate (ESR) (r = −0.36), platelets (r = −0.35), interleukin‐6 (r = −0.45), hemoglobin (r = 0.29), transferrin (r = 0.46), albumin (r = 0.60) in CD, and CRP (r = −0.29), ESR (r = −0.37), platelets (r = −0.43), leukocytes (r = −0.50), interleukin‐6 (r = −0.45), hemoglobin (r = 0.34), transferrin (r = 0.54), and albumin (r = 0.50) in UC. PON1 correlated positively with lipids but not with their peroxidation markers (thiobarbituric acid‐reactive substances, lipid hydroperoxides, ox‐LDL, and ox‐LDL autoantibodies). PON1 phenotype B (protective against IBD) tended to be less frequent in IBD patients than controls, and associated with lower concentration of inflammatory indices. PON1 was a poorer indicator of CD or UC than CRP. Conclusions: PON1 was reduced in IBD, despite treatment with antioxidant 5′‐aminosalicylate derivatives. PON1 reflected disease activity, inflammation severity, and anemia but not lipid peroxidation. The diagnostic power of PON1 was insufficient for its clinical application.

Elevation of circulating interleukin-8 is related to lymph node and distant metastases in esophageal squamous cell carcinomas—Implication for clinical evaluation of cancer patient

The presence of lymph node metastasis (LNM) is an important factor in clinical evaluation of esophageal cancer patients. Biological markers able to support detection of metastatic lymph nodes are sought after. Interleukin-8 (IL-8) is overexpressed by many cancers and involved in cancer dissemination. We investigated the relationship between circulating IL-8 and clinicopathological features of esophageal squamous cell carcinoma (ESCC), and evaluated the diagnostic potential of IL-8, with reference to the key angiogenic and lymphangiogenic factors: vascular endothelial growth factors A and C (VEGF-A and VEGF-C). We found elevated IL-8 levels in ESCC patients, correlated with tumor size and cancer dissemination, especially LNM. Circulating IL-8 correlated with lymphangiogenic VEGF-C rather then angiogenic VEGF-A. The association weakened in metastatic cancers, suggesting divergent mechanism of IL-8 involvement in the dissemination process. The cytokine levels correlated with platelets and neutrophils, pointing at these cells as possible sources of circulating IL-8. We demonstrated IL-8 that positively correlated with inflammation status of ESCC patients. Circulating IL-8 was a better indicator of ESCC dissemination than VEGF-A or VEGF-C. Yet, the detection rates were not satisfactory enough to allow for the recommendation of IL-8 determination as an adjunct to the clinical evaluation of lymph node involvement in ESCC patients.

Serum midkine depends on lymph node involvement and correlates with circulating VEGF-C in oesophageal squamous cell carcinoma

Abstract Lymph node metastasis (LNM) is a key factor for selection of treatment method and patients’ prognosis in oesophageal squamous cell carcinoma (ESCC). However, no biomarkers able to support the clinical detection of LNM have been reported. Recently, vascular endothelial growth factor C (VEGF-C) was found to be a more accurate marker of LNM in lung cancer than computed tomography. Midkine is a multifunctional cytokine involved in cancer development. We investigated circulating midkine levels in ESCC patients (n=73) compared with those in healthy subjects (n=42) with double-antibody-sandwich indirect enzyme-linked immunosorbent assay (DASI-ELISA). We found that midkine was elevated in ESCC and involved in metastatic disease. Serum midkine (sMK) was a good marker of LNM, evaluated both clinically and pathologically, as revealed by ROC analysis. It also correlated with serum levels of VEGF-C. The increase of sMK was related to cancer cells, although a weak correlation was observed between sMK and platelet and leucocyte counts.

Circulating midkine in Crohn's disease: Clinical implications

Background: A noninvasive marker facilitating differential diagnosis in Crohns disease (CD) is sought after. Midkine is a heparin‐binding growth factor of angiogenic and chemotactic properties, positively evaluated as a tumor marker, and a possible association with CD has not yet been investigated. Methods: Circulating midkine was measured in 91 CD patients and 108 controls and related to disease clinical and biochemical activity, inflammation severity, and angiogenesis. Midkine diagnostic value in comparison with C‐reactive protein (CRP) was evaluated by receiver operating characteristic (ROC) analysis. Results: Circulating midkine was elevated both in quiescent and active disease compared to controls (147, 506, and 93 pg/mL, respectively), and corresponded well with disease activity (r = 0.49, P < 0.001). Midkine significantly correlated with inflammatory indices: CRP (r = 0.49), erythrocyte sedimentation rate (r = 0.31), leukocytes (r = 0.48), platelets (r = 0.52), albumin (r = −0.49), transferrin (r = −0.47), and IL‐6 (r = 0.54); hematological variables: hemoglobin (r = −0.38), hematocrit (r = −0.43), and iron (r = −0.58); angiogenic factors: vascular endothelial growth factor‐A (r = 0.42), fibroblast growth factor‐2 (r = 0.54), and platelet‐derived growth factor‐BB (r = 0.57). Midkine elevation corresponded well (r = −0.41) with the drop in paraoxonase‐1 activity—a quorum‐quenching factor. Midkine as a marker of active CD had sensitivity and specificity of 86% and 97%, respectively, whereas CRP was 83% and 92%. Conclusions: CD is associated with an elevation of midkine, which corresponds well with disease activity and reflects the severity of inflammatory response and exacerbation of pathological angiogenesis. Midkine performance as a disease marker was slightly better than that of CRP. Its high specificity and likelihood ratios for positive test results might recommend midkine as a possible “ruling in” marker in CD. Inflamm Bowel Dis 2009

Paraoxonase 1 (PON1) status in gastroesophageal malignancies and associated paraneoplastic syndromes — Connection with inflammation

OBJECTIVE To evaluate the status and diagnostic utility of antioxidant paraoxonase 1 (PON1) in gastroesophageal cancers. DESIGN AND METHODS PON1s arylesterase/paraoxonase activities and phenotype were determined in 82 cancers and 57 controls, and related to clinicopathological features, anemia and cachexia coexistence, cholesterol levels, liver function panel, and inflammatory and angiogenic indices. RESULTS PON1s activities were decreased in cancer. Arylesterase activity correlated with cancer T and N stages, being an N1-independent predictor. Both activities correlated with transferrin, albumin, CRP and inflammation-based Glasgow Prognostic Score, and arylesterase activity also with interleukin-6 and midkine. Phenotype A (Q192 homozygotes) was associated with lower transferrin and higher TNF-alpha concentrations. PON1s arylesterase activity reflected anemia severity, being correlated with hemoglobin, hematocrit, and iron. PON1 arylesterase activity negatively correlated with alkaline phosphatase and gamma-glutamyl transferase, but not with bilirubin, aminotransferases, HDL or LDL cholesterol. PON1 moderately indicated cancer presence and regional metastasis. CONCLUSIONS PON1 activity decreases in gastroesophageal cancers and corresponds to inflammation severity and cancer-related anemia. PON1 decrease indicates lymph node metastasis, but its moderate predictive power does not recommend PON1 determination alone for clinical application.

Matrix metalloproteinase-9: its interplay with angiogenic factors in inflammatory bowel diseases.

Matrix metalloproteinase- (MMP-) 9 is one of the main metalloproteinases reported to be involved in extracellular matrix degradation and recently also in triggering of angiogenic switch in the course of inflammatory bowel diseases (IBD). The goal of our studies was to estimate in one experimental setting the levels of MMP-9 in sera of Crohns Disease (CD) and ulcerative colitis (UC) patients and to evaluate its possible diagnostic potential in comparison with other biochemical markers and selected proinflammatory and angiogenic factors. The study group included 176 subjects (CD = 64, UC = 85, control = 27). Concentrations of serum MMP-9 were significantly higher in active than inactive forms of IBD, being higher in active UC than in active CD. Both in the case of CD and UC serum MMP-9 positively correlated with disease activity, IL-6 levels, platelet and leukocyte count, midkine, and PDGF-BB, as well as in UC with ESR and in CD with CRP, IL-1, and VEGF-A. Diagnostic accuracy of MMP-9 in distinguishing active UC from active CD was 66%, and displayed higher specificity than CRP (79.0% versus 61.6%, resp.). Evaluation of serum MMP-9 concentrations could aid in differentiation of active UC from active CD. MMP-9 correlated better with inflammatory and angiogenic parameters in CD than in UC.

Circulating leptin and inflammatory response in esophageal cancer, esophageal cancer-related cachexia-anorexia syndrome (CAS) and non-malignant CAS of the alimentary tract.

We investigated the association between esophageal cancer and cachexia-anorexia syndrome (CAS) of the alimentary tract and leptin, an adipocytokine crucial for body weight regulation, a modulator of inflammatory/immune response, implication of which in cancer and CAS development remains debatable. Circulating leptin was measured in 135 esophageal cancer patients (51 non-cachectic and 84 cachectic) and 83 controls (63 non-cachectic and 20 cachectic) and referred to cancer stage, CAS, and inflammatory and nutritional indices. Leptin was down-regulated in cancer patients and cachectic controls as compared to non-cachectic controls, with more pronounced hypoleptinemia in advanced cancers. Leptin correlated directly with BMI, TNF-alpha, albumin, and hemoglobin and indirectly with IL-6, IL-8, and hsCRP. The correlations, except for hsCRP, were more pronounced in females. BMI alone (females) and BMI and hsCRP (males) were independent predictors of leptin explaining over 60% of its variability. Following adjustment for BMI and gender, cancer-related CAS but not cancer itself negatively affected leptin. Leptin and BMI were independently associated with cancer-related and non-malignant CAS with diagnostic accuracy of 93% in identifying subjects with CAS. Pro-inflammatory, angiogenic and mitogenic properties of leptin do not seem to be important for esophageal cancer development but hypoleptinemia, independently from co-occurring reduction of adiposity, appears to be strongly associated with esophageal cancer-related CAS and non-malignant CAS of the alimentary tract.

Platelet-derived growth factor-BB reflects clinical, inflammatory and angiogenic disease activity and oxidative stress in inflammatory bowel disease.

OBJECTIVES The goal of the studies was the evaluation of platelet-stored (serum) and circulating (plasma) pools of platelet-derived growth factor (PDGF)-BB in inflammatory bowel disease (IBD) and the assessment of a possible application of PDGF as the disease marker. DESIGN AND METHODS Serum and plasma PDGF-BB were measured in 134 IBD patients and 81 controls and evaluated with respect to the disease status, endoscopic, inflammatory, and angiogenic activity. The diagnostic utility was evaluated using ROC analysis. RESULTS PDGF was increased exclusively in active IBD regardless the disease type and associated with its clinical and endoscopic activity. Serum- and plasma-PDGF were poorly interrelated. Plasma-PDGF better reflected oxidative stress whereas serum-PDGF reflected inflammation and angiogenesis. In multivariate analysis, platelets alone explained about 30% in the PDGF variability and seemed to mediate most of the observed relationships. CONCLUSIONS IBD is associated with the increases in platelet-stored and circulating PDGF, which correspond with the disease clinical, endoscopic, inflammatory, and angiogenic activity and IBD-associated oxidative stress. However, PDGF as an active-IBD marker was not better than currently applied C-reactive protein, erythrocyte sedimentation rate and platelets.

Clinical relevance of circulating midkine in ulcerative colitis

Abstract Background: Non-invasive biochemical markers are needed to support the diagnosis of ulcerative colitis (UC), an incurable disease of unknown pathology. Midkine is an angiogenic cytokine, chemotactic towards neutrophils and macrophages, and a T-regulatory cell suppressor. Methods: Serum midkine was measured immunoenzymatically in 93 UC patients and 108 healthy subjects, and evaluated with respect to disease status, endoscopic, inflammatory and angiogenic activity. The diagnostic value of midkine was compared to C-reactive protein (CRP) using receiver operating characteristics (ROC) analysis. Results: Midkine was higher (p<0.0001) in inactive (199 ng/L) and active UC (351 ng/L) compared with controls (93 ng/L), and reflected disease activity (r=0.427, p<0.001). Midkine was correlated with CRP, erythrocyte sedimentation rate (ESR), leukocytes, platelets, interleukin-6, paraoxonase-1, albumin, transferrin, iron, hemoglobin, and hematocrit. Midkine correlated with angiogenic factors: vascular endothelial growth factor-A and platelet-derived growth factor-BB. As a marker of UC, midkine showed a diagnostic accuracy of 85%, sensitivity of 72%, specificity of 82%, whereas CRP showed 83%, 65% and 91%, respectively. As a marker of active UC, midkine showed a diagnostic accuracy of 87%, sensitivity of 84%, specificity of 75%, whereas CRP showed 75%, 63% and 83%, respectively. Combined assessment of midkine and CRP improved sensitivity but substantially decreased specificity. Conclusions: UC is associated with increased circulating midkine, which corresponds with clinical, endoscopic, inflammatory and angiogenic activity, and anemia. Performance of midkine as a marker of UC or active UC was comparable to that of CRP. Clin Chem Lab Med 2009;47:1085–90.