Serum Levels In Cancer Patients Research Articles

Machine-learning-based Analysis Identifies miRNA Expression Profile for Diagnosis and Prediction of Colorectal Cancer: A Preliminary Study.

The stage of colorectal cancer (CRC) at the day of diagnosis has the greatest influence on survival rate. Thus, for CRC, which is mainly identified as advanced disease, non-invasive, molecular blood or stool tests could boost the diagnosis and lower mortality. Evaluation of miRNA expression levels in serum of patients diagnosed with CRC is a potential tool in early screening. Screening can be supported by machine learning (ML) as a tool for developing a cancer risk predictive model based on genetic data. miRNA was isolated from the serum of 8 patients diagnosed with CRC and 10 patients from a control group matched for age and sex. The expression of 179 miRNAs was determined using a serum/plasma panel (Exiqon). Determinations were conducted using real-time PCR technique on an Applied Biosystems QuantStudio3 device in 96-well plates. A predictive model was developed through the Azure Machine Learning platform. A wide panel of 29 up-regulated miRNAs in CRC were identified and divided into two subgroups: 1) miRNAs with significantly higher serum level in cancer patients vs. controls (24 miRNAs) and 2) miRNAs detected only in cancer patients and not in controls (5 miRNAs). Re-analysis of published miRNA profiles of CRC tumours or CRC exosomes revealed that only 2 out of 29 miRNAs were up-regulated in all datasets including ours (miR-34a and miR-25-3p). Our research suggests the potential role of overexpressed miRNAs as diagnostic or prognostic biomarkers among CRC patients. Such clustering of miRNAs may be a potential direction for discovering new diagnostic panels of cancer (including CRC), especially using ML. The low correspondence between deregulation of miRNAs in serum and tumour tissue revealed in our study confirms previously published reports.

YKL-40 protein expression in human tumor samples and human tumor cell line xenografts: implications for its use in tumor models

BackgroundYKL-40, also known as non-enzymatic chitinase-3 like-protein-1 (CHI3L1), is a glycoprotein expressed and secreted mainly by inflammatory cells and tumor cells. Accordingly, several studies demonstrated elevated YKL-40 serum levels in cancer patients and found YKL-40 to be correlated with a poor prognosis and disease severity in some tumor entities. YKL-40 was suggested to be involved in angiogenesis and extracellular matrix remodeling. As yet, however, its precise biological function remains elusive.MethodsAs YKL-40 protein expression has only been investigated in few malignancies, we employed immunohistochemical detection in a large multi-tumor tissue microarray consisting of 2,310 samples from 72 different tumor entities. In addition, YKL-40 protein expression was determined in primary mouse xenograft tumors derived from human cancer cell lines.ResultsYKL-40 could be detected in almost all cancer entities and was differently expressed depending on tumor stage and subtype (e.g., thyroid cancer, colorectal cancer, gastric cancer and ovarian cancer). While YKL-40 was absent in in vitro grown human cancer cell lines, YKL-40 expression was upregulated in xenograft tumor tissues in vivo.ConclusionsThese data provide new insights into YKL-40 expression at the protein level in various tumor entities and its regulation in tumor models. Our data suggest that upregulation of YKL-40 expression is a common feature in vivo and is finely regulated by tumor cell-microenvironment interactions.

Assessment of Nutritional and Inflammatory Status to Determine the Prevalence of Malnutrition in Patients Undergoing Surgery for Colorectal Carcinoma.

Colorectal Cancer is the fourth most frequent cause of cancer death worldwide and its incidence increases from 50 years of age. It is often associated with protein-caloric malnutrition and 20% of cancer deaths occur due to this event. The aim of this study was to assess the prevalence of malnutrition and inflammatory status in 78 patients undergoing surgery for colorectal carcinoma. Nutritional Status was assessed by Mini Nutritional Assessment (MNA). Serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured by ELISA, while albumin, C-reactive protein (CRP) and transferrin (TRF) were tested using an immunometric assay. The mean MNA score in colorectal patients was 20.4±8.4, while 23/78 patients (29.4%) were well nourished, 36/78 (46.1%) were at risk of malnutrition and 19/78 (24.3%) were malnourished, reporting in the previous six months from the date of diagnosis a significant weight loss (>10 kg), muscle mass loss and severe reduction of food intake due to loss of appetite and altered taste perception. The serum means of IL-6, TNF-α and CRP, were significantly higher in colorectal patients compared to the control group (p<0.001, p<0.0001, p<0.0001, respectively) while lower TRF, albumin and HCT serum levels in cancer patients vs. healthy subjects (p<0.0001; p<0.0001 and p<0.0001) were found. more than 50% of colorectal cancer patients were malnourished or at risk of malnutrition and reported an imbalance between nutritional and inflammatory status. They, therefore, require a nutritional intervention before treatment in order to have a more effective response and improve quality of life.

Abstract 1273: A novel molecular target for lung cancer

Abstract The purpose of this study is to provide further evidence that Thymidine Kinase I (TK1) is selectively expressed on the surface of lung cancer cells, and therefore could be utilized as a potential molecular target. TK1 is an enzyme in the pyrimidine salvage pathway whose expression is closely correlated with cell proliferation and cell turnover. It has previously been shown that upregulation of TK1 is an early event in the development of most cancers. Additionally TK1 serum levels in cancer patients correlate with tumor progression and cancer aggressiveness. Moreover TK1 levels in the original tumors have also been shown to correlate directly with tumor recurrence thus making TK1 a useful prognostic marker in clinical oncology. Recent studies in our lab have provided evidence that TK1 is localized on the plasma membrane in lung cancer cells. Using scanning electron microscopy (SEM), flow cytometry, confocal microscopy and tissue staining, we confirmed the presence of TK1 on the cell surface of H460 cells. Using normal lymphocytes as a comparative control we found TK1 expression on lung cancer cells to be significantly increased compared to control cells. For this investigation, we used three custom designed monoclonal antibodies against human TK1 conjugated with FITC, namely CB1, A72 and A74. Using flow cytometry we confirmed the presence of TK1 on the cell surface, our data shows that H460 cells stained positive for TK1 (12% for A72, 19% for A74, and 29% for CB1). Furthermore, confocal microscopy indicated a positive fluorescent signal for A72, A74 and CB1, suggesting the presence of TK1 on the plasma membrane. SEM images of lung cancer cells and normal lymphocytes stained with TK1 antibodies and gold labeling reported a positive gold signal on H460 cells with relatively no signal from human lymphocytes. Immunohistochemistry staining of carcinoma tissue array panels compared with normal tissue array panels indicated a statistical significant difference of expression levels of TK1 between normal lung tissue and lung carcinoma (P value &amp;lt;0.05). Positive staining was considered if more than 5% of the cells were stained. There was negligible staining in normal lung tissue. Using these techniques we confirmed that TK1 is selectively expressed on the surface of H460 cells and not on normal cells. These results suggest that TK1 could be used as a possible molecular target in lung cancer therapy. Further studies are currently ongoing to monitor TK1 expression and progression to help to elucidate the mechanisms behind it's over expression in cancer cells and to track its progression and movement from the cytosol to the cell surface. Citation Format: Edwin J. Velazquez, Evita G. Weagel, Wei Meng, Michelle H. Townsend, Alex Cummonck, Craig Chandler, Michael R. Downey, Richard Robison, Kim L. O’Neill. A novel molecular target for lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1273.

Immune Tolerance to Tumor Antigens Occurs in a Specialized Environment of the Spleen

Peripheral tolerance to tumor antigens (Ags) is a major hurdle for antitumor immunity. Draining lymph nodes are considered the privileged sites for Ag presentation to T cells and for the onset of peripheral tolerance. Here, we show that the spleen is fundamentally important for tumor-induced tolerance. Splenectomy restores lymphocyte function and induces tumor regression when coupled with immunotherapy. Splenic CD11b(+)Gr-1(int)Ly6C(hi) cells, mostly comprising proliferating CCR2(+)-inflammatory monocytes with features of myeloid progenitors, expand in the marginal zone of the spleen. Here, they alter the normal tissue cytoarchitecture and closely associate with memory CD8(+) T cells, cross-presenting tumor Ags and causing their tolerization. Because of its high proliferative potential, this myeloid cell subset is also susceptible to low-dose chemotherapy, which can be exploited as an adjuvant to passive immunotherapy. CCL2 serum levels in cancer patients are directly related to the accumulation of immature myeloid cells and are predictive for overall survival in patients who develop a multipeptide response to cancer vaccines.

44 Vaccination of dendritic cells pulsed with tumor endothelial cells inhibits tumor growth

Peripheral tolerance to tumor antigens (Ags) is a major hurdle for antitumor immunity. Draining lymph nodes are considered the privileged sites for Ag presentation to T cells and for the onset of peripheral tolerance. Here, we show that the spleen is fundamentally important for tumor-induced tolerance. Splenectomy restores lymphocyte function and induces tumor regression when coupled with immunotherapy. Splenic CD11b+Gr-1intLy6Chi cells, mostly comprising proliferating CCR2+-inflammatory monocytes with features of myeloid progenitors, expand in the marginal zone of the spleen. Here, they alter the normal tissue cytoarchitecture and closely associate with memory CD8+ T cells, cross-presenting tumor Ags and causing their tolerization. Because of its high proliferative potential, this myeloid cell subset is also susceptible to low-dose chemotherapy, which can be exploited as an adjuvant to passive immunotherapy. CCL2 serum levels in cancer patients are directly related to the accumulation of immature myeloid cells and are predictive for overall survival in patients who develop a multipeptide response to cancer vaccines.

A Sandwich ELISA for Phosphoglycerate Kinase

Phosphoglycerate kinase (PGK1) is a key enzyme in glycolysis that can also be released from certain cells. In the extracellular milieu, PGK1 reportedly acts as a disulphide reductase to activate plasmin, resulting in the production of angiostatin, a potent angiogenesis inhibitor. Certain cancer cell lines secrete unusually large amounts of PGK1, raising the possibility that serum PGK1 levels can be used to screen for cancer. To facilitate the characterization of the PGK1 secretory pathway and to monitor serum levels of PGK1, we have developed a sensitive sandwich ELISA using an immuno-affinity-purified chicken polyclonal antibody for capturing PGK1 and an immuno-affinity-purified rabbit polyclonal antibody for detecting it. The assay is about 10-fold more sensitive than other reported PGK1 ELISAs. We used the ELISA to quantify the amount of PGK1 released from HeLa cells and PGK1 serum levels in cancer patients. Of 10 cancer patients whose serum was tested, 3 of 4 with pancreatic cancer had 65–900% higher levels of PGK1 than that found in normal serum.

Pharmacokinetics and pharmacodynamics of protein‐unbound docetaxel in cancer patients

Alpha(1)-acid glycoprotein, a plasma protein that binds docetaxel, is a significant determinant of the clearance and activity of docetaxel, but its serum levels in cancer patients are variable. This emphasizes the importance of investigating the pharmacokinetics of unbound drug rather than total drug in the plasma. In the present study, the pharmacokinetics and pharmacodynamics of unbound docetaxel were investigated in cancer patients. Docetaxel was infused over a 1-h period in 69 patients. The concentration of unbound docetaxel was measured in the plasma ultrafiltrate at the end of infusion and the unbound fraction (fu) was calculated. The pharmacokinetics of total docetaxel in the plasma was investigated. The area under the concentration-time curve (AUC) of unbound docetaxel was calculated by multiplying fu by the AUC of total docetaxel. The peak concentration at the end of infusion (Cmax) and AUC of total and unbound drug were compared between patients who did or did not experience grade 4 neutropenia. The median of fu was 4.0%, ranging from 1.2 to 22.6% (5-95% percentile; 1.4-10.5%). Grade 4 neutropenia was observed in 24 patients. Although Cmax and AUC of total drug were not different in patients with or without grade 4 neutropenia, patients who experienced grade 4 neutropenia had significantly greater Cmax (92.3 vs 63.3 ng/mL, P=0.01) and AUC (0.137 vs 0.104 microgxh/mL, P=0.05) of unbound docetaxel. In a logistic regression analysis, the unbound Cmax and alpha1-acid glycoprotein were determinants of grade 4 neutropenia. Pharmacokinetics of unbound drug rather than total drug is a better predictor of neutropenia for docetaxel.

Elevated serum levels of interleukin-8 in advanced non-small cell lung cancer patients: relationship with prognosis.

Interleukin-8 (IL-8) is a pleiotropic cytokine that has also been shown to exert effects relevant to cancer growth and progression. Cancer progression is believed to be contributed to by the ability of this cytokine to promote angiogenesis and mitogenic effects. As IL-8 production at the tumor site may determine elevated serum levels of this cytokine because of hematogenous leakage, it is conceivable that patients with high IL-8 serum levels may have tumors actively producing this cytokine. The aim of this study was, therefore, to assess IL-8 serum levels in 60 non-small cell lung cancer (NSCLC) patients undergoing chemotherapy and to correlate them with prognosis. IL-8 serum levels were found to be significantly elevated in cancer patients with respect to controls. Moreover, IL-8 serum levels were shown to be significantly increased in stage IV patients compared with stage III patients. When basal IL-8 serum levels in cancer patients were analyzed according to response to chemotherapy, responders were shown to have significantly lower IL-8 serum levels than nonresponders. On univariate analysis, the IL-8 serum level was included among the variables capable of affecting both overall survival (OS) and time to treatment failure (TTF). However, multivariate analysis failed to demonstrate an independent prognostic significance for IL-8 serum levels. In conclusion, this study showed that IL-8 serum levels were elevated in advanced NSCLC patients and correlated with both OS and TTF, but they were shown not to be an independent prognostic factor.

Environmental factors, health-related habits, and serum selenium levels in cancer patients and healthy controls.

Previous studies conducted in Yugoslavia indicated that the concentration of selenium in soil, food items, and serum of the population is very low. The aim of the study was to investigate the possible relationship among environmental, health-related habits, nutrition, and selenium serum levels in cancer patients and the healthy population. The case-control study included a group of cancer patients and a matched group of healthy controls: 57 cancer patients and 41 healthy controls living in Stari Grad (an urban area of Belgrade), as well as 17 cancer patients and 13 healthy controls living in Barajevo (a rural community in the vicinity of Belgrade). The healthy controls were matched to cancer patients in sex and age; they were not blood related. The selenium serum levels were measured by atomic absorption spectrophotometry. Health-related habits and relevant dietary factors ("food frequency" method) that may influence the selenium serum levels were assessed by questionnaires. The differences in average values of selenium serum levels between the cancer patients and healthy controls were not significantly different, but both were below the lowest recorded in referential studies. A significant difference between the values obtained from urban and rural subgroups was noted. The most important factors that influenced the level of selenium included the residence place in the region with selenium deficiency (Barajevo), age, associated chronic diseases, and some dietary factors potentially related to the intake of selenium. The results obtained in this investigation pointed out that use of selenium supplementation in this area should be seriously considered.

TNF-α and endotoxin serum levels in cancer patients undergoing intraperitoneal hyperthermic perfusion

Intraperitoneal hyperthermic perfusion (IPHP) is performed as one treatment for patients with advanced gastrointestinal cancer complicated by peritoneal dissemination or carcinomatous peritonitis. However, the anticancer mechanism of IPHP and its safety have not yet been fully elucidated. It has been experimentally known that endotoxinemia occurs by high body temperature, and that endotoxin stimulates the macrophage, monocyte and endothelial cell to induce the production of TNF-alpha. TNF-alpha is one of cytokines to be induced at the initial phase as a host immune response and play an important role to initiate the systemic inflammatory response syndrome (SIRS). We have tested whether the serum concentrations of TNF-alpha and endotoxin are elevated following IPHP. Eleven patients with gastro-intestinal cancer underwent surgery combined with IPHP. Mixed venous blood obtained from pulmonary artery (PA-blood) was collected at four sampling points. TNF-alpha and endotoxin levels in the PA-blood were measured by ELISA and a limulus amoebocyte lysate assay respectively. In all patients the serum TNF-alpha levels in PA-blood were temporarily elevated following IPHP from less than 10 pg/ml before IPHP to 42.8 +/- 26.6 pg/ml; endotoxin levels were not altered. This study shows that IPHP has the ability to induce endogenous TNF-alpha not mediated by endotoxin.

口腔癌におけるフィブロネクチンおよびフィブリノーゲンの動態に関する実験的研究

Fibronectin (FN), one of the glycoproteins existing in plasma and extracellular matrix, is found in the connective tissue stroma and basement membrane of cancer. It is also reported that fibrinogen (Fbg) cross-links to FN deposited in the tumor stroma and shows a high serum level in cancer patients. The purpose of this study was to examine the tissue localization and distribution of FN and Fbg with time lapse in experimentally induced carcinoma (VX2 carcinoma implanted in tongue) and its metastatic lesions in rabbits and to compare with those observed in wound healing process of normal oral mucosa in rabbits.Distribution of FN and Fbg was examined with direct imrnunoperoxidase technique. The plasma FN and Fbg levels in rabbits bearing VX2 carcinoma and foreign body granuloma were also quantitatively measured by a single radial immunodiffusion method.The results obtained were as follows:1) The tumor enlarged aggresively, and metastasized to cervical lymph nodes and lungs on 10 days after implantation.2) FN deposits were found in the tumor stroma on 7 days after implantation and in a capsulelike connective tissue around the tumor nest on 14 days after.3) Fbg was present as a fibrin nets surrounding the tumor nest on 7 days after implantation and it disappeared after 10-14 days.4) In the metastatic tissues (cervical lymph nodes' and lungs), FN and Fbg showed no marked deposits except around the tumor cells in the early stage of metastasis.5) In the experimentally induced wound of oral mucosa, FN and Fbg deposits were consistent with the distribution of fibroblast, collagen fiber, and histiocyte in immature granulation tissue. This reaction was similar to that observed in stroma of early VX2 carcinoma.6) The plasma FN level in rabbits bearing VX2 carcinoma increased gradually in 26% on 21 days after implantation comparing with the control value. The plasma Fbg also showed increased levels in 68% on 28 days after implantation comparing with the control value.The results suggested that the stromal fibroid production in malignant tumors might be one of the vital defense reactions against tumor growth similar to the case of wound healing reactions. It is also suggested that the tissue distribution of FN and Fbg as well as plasma FN and Fbg levels would be a good biological marker of tumor growth and metastatic process in oral cancers.

Serum vitamin level maintenance in cancer patients on total parenteral nutrition

The quantity of water and fat soluble vitamins required to maintain serum levels in cancer patients on total parenteral nutrition (TPN) has yet to be determined. A prospective evaluation of our current intravenous vitamin regimen during TPN was performed in order to define these requirements. Seventy-five patients receiving 97 TPN courses for seven to 60 days were studied. Serum levels of vitamins A (74 courses), B12 (85), folate (62), C (97), and 25-OH-cholecalciferol (25-OH-D) (9) were available for analysis. Daily vitamin intakes were recorded and serum levels were determined weekly. Restoration and maintenance of normal mean serum vitamin levels were achieved for all but 25-OH-D. However, analysis of individual courses in previously depleted patients revealed that serum levels were not restored in three patients (4%) for vitamin A and six patients (66%) for 25-OH-D. A TPN regimen designed to provide the following weekly vitamin quantities: A: 21,000 IU, D: 2100 IU, C: 3500 mg, B12: 126 micrograms, and folate: 7 mg will maintain mean serum vitamin levels for all but 25-OH-D. This regimen has the ability to uniformly restore and maintain vitamins B12, C, and folate in all patients but not in those patients previously deficient in vitamins A and D.