Maria Kowalska

Pretreatment serum levels of cytokines and cytokine receptors in patients with non-small cell lung cancer, and correlations with clinicopathological features and prognosis. M-CSF - an independent prognostic factor.

Objectives: Cytokines are potential new serum markers, especially desirable for malignancies with poor prognosis like non-small cell lung cancer (NSCLC). Methods: Cytokines, tumor necrosis factor α (TNFα), interleukin (IL)-6 and IL-8, soluble TNF (sTNF) RI, sTNF RII, soluble IL-2 receptor-α, IL-1 receptor antagonist (IL-1ra), IL-10, vascular endothelial growth factor, basic fibroblast growth factor, and macrophage (M-CSF) and granulocyte colony-stimulating factor, as well as tumor markers – carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and CYFRA 21.1 – were assessed in the sera of 103 untreated NSCLC patients, and these cytokines and tumor markers were refered to clinical parameters of the disease and to the overall survival of patients evaluated during a 6-year follow-up. Results: Most of the factors analyzed were found to be elevated in the sera of NSCLC patients, and increases in IL-6, IL-8 and sTNF RI were noted in the greatest proportion of stage I patients. Most cytokine/cytokine receptor levels revealed higher sensitivity than the standard tumor markers; IL-6 and IL-1ra levels were significantly different in patients with squamous cell versus adenocarcinoma; IL-6 and IL-10 were related to the tumor size, while IL-6 and M-CSF levels significantly increased with disease progression. A significant prognostic value of pretreatment serum M-CSF and CEA levels in NSCLC patients has been shown, but only M-CSF proved to be an independent prognostic factor. Conclusions: Increased pretreatment serum M-CSF level is a significant independent predictor of poor survival in patients with NSCLC.

Clinical significance of serum cytokine measurements in untreated colorectal cancer patients: soluble tumor necrosis factor receptor type I--an independent prognostic factor.

The aim of this study was to exploit the potential clinical use of circulating cytokine measurements in colorectal cancer (CRC) patients. The levels of cytokines and cytokine receptors were assessed by ELISA in the sera of 50 healthy volunteers and 157 patients with previously untreated CRC and then related to clinicopathological features and prognosis. All tumors were verified histologically as colorectal adenocarcinomas and staged according to TNM classification. The levels of circulating interleukin (IL)-6, IL-8, macrophage colony-stimulating factor (M-CSF) and interleukin 1 receptor antagonist (IL-1ra) significantly increased with the clinical stage of CRC, and the levels of IL-6, soluble tumor necrosis factor (sTNF) receptor type I (RI), soluble interleukin 2 receptor α and TNFα with tumor grade, while IL-6, IL-8, M-CSF, IL-1ra and sTNF RI levels significantly rose with bowel wall invasion. None of the cytokine or soluble cytokine receptor levels were influenced by age, gender and colon versus rectum localization. sTNF RI, IL-8, IL-6 and vascular endothelial growth factor measurements demonstrated the highest diagnostic sensitivity. sTNF RI was found elevated in the greatest percentage of all CRC patients, in the greatest proportion of stage I patients and presented the best diagnostic sensitivity. In addition, the sTNF RI level strongly correlated with tumor grade and invasion and proved to be an independent prognostic factor.

CRP, TNFα, IL-1ra, IL-6, IL-8 and IL-10 in blood serum of colorectal cancer patients

Blood serum cytokines: TNFα, IL-lra, IL-6, IL-8, IL-10 as well as CRP were investigated in patients with colorectal cancer, prior treatment and 1,10 and 42 days after surgery. There was an increase of the levels of CRP, IL-6 and IL-10 in most patients 24 hours after surgery. The levels of IL-1ra were elevated in patients in stage C and in several patients in stage B of the disease and there was a decrease of circulating TNFα in stage B patients. On day 10 and 42 after surgery, the levels of cytokines followed various patterns.

Serum cytokine levels and the expression of estrogen and progesterone receptors in breast cancer patients

Abstract Background: The aim of this study was to assess the correlation between serum concentrations of cytokines and soluble cytokine receptors in breast cancer patients and the expression of estrogen and progesterone receptors in tumor cells. Methods: The study comprised 158 female breast cancer patients before treatment and 50 healthy individuals as a reference group. Results: The study revealed significantly higher concentrations of most cytokines in breast cancer patients compared to the reference group. Assessment of the correlation between cytokine concentrations in serum and the expression of estrogen and progesterone receptors in tumor cells showed significantly higher interleukin-8 (IL-8) concentrations in patients lacking progesterone receptors in comparison to patients with these receptors. The concentrations of cytokines and their soluble receptors as a function of the expression of estrogen and progesterone receptors were also analyzed in two age groups. In younger patients, aged 50years and below, no significant differences were found between serum cytokine concentrations and the expression of both estrogen and progesterone receptors. In patients older than 50years, significantly higher IL-8 concentrations were observed in individuals lacking progesterone receptors, whereas IL-1ra was significantly higher in those lacking estrogen receptors. Conclusions: IL-1ra and IL-8 concentrations in serum, together with a lack of estrogen and progesterone receptors in tumor cells, in breast cancer patients older than 50years could represent additional predictive factors for this disease. Clin Chem Lab Med 2006;44:1092–7.

Serum soluble tumour necrosis factor receptor type I concentrations independently predict prognosis in patients with breast cancer

Abstract Background: The aim of this study was to exploit the potential clinical use of circulating cytokine assessment in patients with breast cancer. Methods: The following circulating cytokines were measured in 210 histopathologically confirmed, untreated breast cancer patients: interleukin 6 (IL-6), tumour necrosis factor-α (TNFα), interleukin 8 (IL-8), soluble tumour necrosis factor receptor type I (sTNF RI), sTNF RII, interleukin 1 receptor antagonist (IL-1ra), interleukin 10 (IL-10), macrophage colony-stimulating factor, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The patients have been followed-up for 10 years. Results: bFGF and VEGF showed the highest diagnostic sensitivity. Only IL-6 concentrations were related to the clinical stage. A high percentage of patients in clinical stage I showed increased serum sTNF RII, VEGF and bFGF concentrations, of which only sTNF RII was found to be increased in a smaller percentage of patients with more advanced disease compared with patients with early stage disease. Patients aged 50 years and more presented with significantly higher concentrations of sTNF RI, IL-10, IL-6 and VEGF compared with younger patients. In multivariate analysis, a significant value of pretreatment serum sTNF RI concentrations, next to stage and oestrogen receptors status, was its utility as an independent prognostic factor of the overall survival in patients with breast cancer. Conclusions: Serum sTNF RI may be considered an additional, independent and clinically useful factor of poor prognosis in patients with breast cancer. Clin Chem Lab Med 2010;48:1481–6.

The value of tumor marker and cytokine analysis for the assessment of regional lymph node status in cervical cancer patients.

The aim of the study was to evaluate the utility of the measurements of the circulating tumor markers, squamous cell carcinoma antigen (SCCA), CA125, carcinoembryonic antigen (CEA), cytokeratin fragment 19 (CYFRA 21.1), and the cytokines, interleukin-6 and vascular endothelial growth factor (VEGF), to estimate regional lymph node involvement in patients with cervical cancer. The study comprised 182 untreated patients with cervical cancer. The regional lymph node status was assessed either by the postsurgical histopathologic examination or by the computed tomography (CT). Concentrations of SCCA, CEA, and CA125 were determined using the Abbott Instruments system, of CYFRA 21.1 by the Roche kits, and of IL-6 and VEGF by the ELISA of R&D Systems (Minneapolis, MN). For the statistical analyses, Mann–Whitney U test and χ2 test were applied. Serum levels of SCCA, CEA, CA125, CYFRA 21.1, IL-6, and VEGF were measured in patients with specified pelvic and para-aortic lymph node status. SCCA, CA125, and IL-6 levels were found to be significantly higher in patients with lymph node metastases than in those with no lymph node involvement. Also, the percentage of patients with simultaneously elevated concentrations of SCCA and CA125 or SCCA and IL-6 differed depending on the lymph node status and was significantly higher in the series of patients with lymph node metastases. Simultaneous assessment of serum levels of SCCA and CA125 or SCCA and IL-6 in patients with cervical cancer may be useful for the regional lymph node evaluation, especially in patients with advanced stages, when the lymph nodes are examined only by CT, with no histologic confirmation.

Cytokines as potential tumour markers.

BACKGROUND Cytokines and cytokine receptors contribute importantly to each step of cancer development and progression, and deregulated levels of cytokines and cytokine receptors can be detected in cancer patients locally and systemically. OBJECTIVE This review aims to outline and discuss the current status of cytokines and their receptors as potential diagnostic, prognostic, predictive and risk indicators, exemplified in cervical, ovarian, breast, prostate, colorectal, gastric, and non-small cell lung cancers and in sarcomas. METHODS The Medline database was searched for articles on the relevant cancers, published in the English language, using combinations of the following keywords: cytokine, interleukin, growth factor, diagnostic, prognostic, predictive, serum, ascitic and expression. The searches yielded over 2000 papers, and an arbitrary selection of the cited literature was made to present the developments in the field. RESULTS/CONCLUSION Cytokines, unspecific by definition, present certain patterns of deregulation, often related to clinical characteristics of cancer patients. Some cytokines, most often VEGF, IL-6 and EGFR, present a value of independent prognostic indicators. So far, only local EGFR and HER2 expression assessment in a few cancer types has been accepted for routine use, to qualify patients for a targeted therapy. The authors believe that cytokines may contribute importantly to cancer management in the future; to more likely to indicate prognosis, to identify patients who might benefit from a particular treatment, to monitor treatment response and disease recurrence, and, finally, possibly as part of a larger panel of tumour markers, to improve diagnosis.

Clinical significance of serum CA-125 and soluble tumor necrosis factor receptor type I in cervical adenocarcinoma patients.

Hypothesis: The purpose of this study was to answer the question whether the measurement of the pretreatment tumor markers and cytokine levels would be of clinical use in patients with cervical adenocarcinoma. Methods: CA-125, carcinoembryonic antigen (CEA), and squamous cell carcinoma (SCC), as well as interleukin 6 (IL-6), IL-8, vascular endothelial growth factor, IL-1 receptor antagonist, soluble tumor necrosis factor receptor type I (sTNF RI), and sTNF RII, were assessed in the sera of 120 cervical adenocarcinoma patients. Results: CA-125 presented a better diagnostic sensitivity than did CEA and SCC, whereas the concentration of most cytokines, except for sTNF RII, revealed higher sensitivity, than did the standard tumor markers. The highest sensitivity was found for sTNF RI. The concentrations of the examined parameters were found to be significantly higher in patients with advanced stage (IIB-IV) as compared with patients with I-IIA stage. [Float1]Serum concentration of IL-6 was the only one that differs significantly, depending on the histological grade. During the 3-year follow-up, 25 patients relapsed, and 73 patients were disease-free. Significantly higher pretreatment serum concentrations of the examined parameters (except for SCC and IL-1 receptor antagonist) were found in patients who developed recurrences. Soluble tumor necrosis factor receptor type I and CA-125 were found to present the highest sensitivity, with areas under the receiver operating characteristic curve of 0.833 and 0.809, respectively. As the result of univariate analysis, CA-125, CEA, sTNF RII, IL-6, sTNF RI, and clinical stage were considered factors of poor prognosis. Multivariate analysis has proven that CA-125 and clinical stage were the only significant independent prognostic factors of the disease-free survival. Conclusion: CA-125 is an independent prognostic factor for disease-free survival. Our results have also demonstrated that sTNF RI is probably the most useful marker in cervical adenocarcinoma patients, especially in the early stages of disease.

Serum macrophage colony-stimulating factor (M-CSF) in patients with Hodgkin lymphoma

Macrophage colony-stimulating factor (M-CSF) was recently implicated by in vitro studies as a survival and proliferation factor for Hodgkin/Reed-Sternberg cells. We evaluated pre-treatment serum M-CSF levels in 66 patients with histopathologic diagnosis of classical Hodgkin lymphoma (HL) and looked for possible correlations with baseline clinical characteristics. Significantly higher M-CSF serum concentrations were found in patients with bulky mediastinal mass, systemic symptoms, and elevated ESR but not LDH. There was no significant association between M-CSF level and sex, clinical stage, number of lymph node areas involved, and histopathological subtype of HL. We conclude that serum M-CSF levels are frequently elevated in HL patients and are significantly related to the presence of bulky mediastinal mass and systemic symptoms. These observations may indicate a pathogenetic role of M-CSF in Hodgkin lymphoma.

Procollagen I amino-terminal propeptide as a potential marker for multiple myeloma

OBJECTIVES Investigating relationship between bone markers, cytokines and conventional prognostic parameters in patients with multiple myeloma (MM) and to assess the clinical application of bone turnover markers. DESIGN AND METHODS Sixty-four patients with MM were examined before treatment and followed for survival for over 7 years. Serum concentrations of bone markers and cytokines were determined by the Roche and R&D kits, respectively. Standard deviation scores (SDS) were employed to normalize values. RESULTS Collagen fragments (beta-CTX) were elevated in 47%, procollagen I amino-terminal propeptide (PINP)-in 28%, and osteocalcin (OC) in 11% of patients. The values of the SDS of PINP and OC, but not beta-CTX significantly decreased with MM stage. beta-CTX inversely correlated with vascular endothelial growth factor (VEGF) and albumin, and directly correlated with serum macrophage colony-stimulating factor (M-CSF). OC values correlated with albumin and beta2-microglobulin. PINP inversely correlated with LDH. The SDS values of PINP were significantly lower in MM patients with advanced bone disease. CONCLUSIONS Circulating PINP concentration may be a useful marker for monitoring of treatment of multiple myeloma patients with bone lytic lesions, in particular, of patients treated with preoteasome inhibitors.