Analysis of combination anti-angiogenesis therapy on markers of coagulation, platelet activation and angiogenesis in patients with advanced cancer

The effects of combination anti-angiogenesis therapy (marimastat, captopril and fragmin) on plasma levels of coagulation initiator tissue factor (TF), platelet marker soluble P-selectin and angiogenic vascular endothelial growth factor (VEGF) were tested in 25 patients with advanced cancer. They had higher soluble P-selectin (P<0.001) and TF (P<0.001), but not VEGF (P=0.066) than 25 age and sex-matched controls. VEGF and TF correlated significantly (r=0.8, P<0.001) in cancer patients. Soluble P-selectin, TF and VEGF did not change at 4- and 8-weeks whilst on treatment. We provide further evidence linking coagulation and angiogenesis but combination anti-angiogenesis therapy does not influence plasma soluble P-selectin, TF or VEGF.     

Systemic coagulation is activated in patients with meningioma and glioblastoma

Journal of Neuro-Oncology - WHO grade II meningiomas behave aggressively, with recurrence rates as high as 60%. Although complete resection in low-grade meningiomas is associated with a relatively...     

Circulating neuroendocrine markers in patients with prostate carcinoma

BACKGROUND: Circulating neuroendocrine markers were measured in patients with prostate carcinoma (PC), prostatic intraepithelial neoplasia (PIN), and benign prostatic hypertrophy (BPH) with the goal to: 1) evaluate the differences in the expression of these markers in patients with benign, premalignant, and primary or metastatic PC; 2) evaluate their prognostic significance; 3) compare values in patients with hormone-naive and hormone-refractory disease; and 4) assess changes after androgen deprivation or chemotherapy. METHODS: Serum neuron specific enolase (NSE) (immunoradiometric assay) and plasma chromogranin A (CgA) (enzyme-linked immunoadsorbent assay) were evaluated in 141 patients with BPH, 54 patients with PIN, and 159 patients with PC; 119 patients were bearing hormone-naive disease and 40 were bearing hormone-refractory disease. CgA was monitored in 31 patients submitted to androgen deprivation and in 24 patients receiving chemotherapy. RESULTS: Supranormal CgA was observed more frequently in patients with American Urologic Association (AUA) Stage D2 disease (45.5%) compared with those with Stage D1 disease (33.3%), Stage C disease (16.7%), Stage A/B disease (18.8%), PIN (25.9%), and BPH (17.0%) (P < 0.02). Supranormal NSE did not change in any of the patient subgroups. Elevated CgA was observed in 36.0% of patients with metastases who had hormone-naive disease and in 45.0% of patients with hormone-refractory disease (P value not significant). Supranormal NSE and CgA values were predictors for poor prognosis in patients with hormone-refractory disease. Elevated baseline CgA values decreased > 50% in 1 of 12 patients who received luteinizing hormone-releasing hormone analogs and in 2 of 12 patients who underwent chemotherapy. CONCLUSIONS: CgA appears to reflect the neuroendocrine activity of PC better than NSE. Elevated CgA values correlate with poor prognosis and are scarcely influenced by either endocrine therapy or chemotherapy.     

Interrelationship between angiogenesis,inflammation and oxidative stress in Indian patients with multiple myeloma

Background

Multiple myeloma (MM) is a B-cell malignancy characterized by the accumulation of clonal population of plasma cells in the bone marrow (BM). A variety of angiogenic factors, proteases, reactive oxygen species and inflammatory cytokines induce the formation of an extensive and suitable BM microenvironment. Previous studies have established the importance of angiogenic factors, inflammatory molecules and oxidative stress in MM but their interplay and effect on each other are not being taken together.

Methods

Circulatory levels of VEGF, angiopoietin-2 (Ang-2), IL-6 and TNF-α along with the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were investigated in 112 subjects including 62 MM patients and 50 healthy controls. Inter-stage analysis was done to evaluate the association of these molecules with the severity of disease. Pearson correlation was determined to find interrelationship, if any, between these molecules.

Results

We have observed elevated levels of VEGF, Ang-2, IL-6, TNF-α and decreased activity of SOD, GPx in MM patients in comparison to controls. All these molecules also showed a trend with the severity of disease. We have found strong association between these factors upon their correlation and regression analysis.

Conclusion

This study is a step toward understanding the indepth contribution of angiogenesis, inflammation and oxidative stress together in making BM microenvironment suitable for growth, survival and proliferation of malignant plasma cells in MM.

     

Circulating tumour markers can define patients with normal colons, benign polyps, and cancers

Background:

Early diagnosis represents the best opportunity for cure of colorectal cancer. Current screening programmes use faecal occult blood testing for screening, which has limited sensitivity and poor specificity.

Methods:

In this study we looked at a series of previously described diagnostic markers utilising circulating free DNA (cfDNA), with a preparation method allowing small DNA fragments to be isolated. The Circulating free DNA was isolated from samples obtained from 85 patients, including 35 patients without endoscopic abnormality, a group of 26 patients with benign colorectal adenomas, and 24 patients with colorectal carcinomas. In each case, polymerase chain reaction (PCR) was performed for Line1 79 bp, Line1 300 bp, Alu 115 bp, Alu 247 bp, and mitochondrial primers. In addition, carcinoembryonic antigen (CEA) was measured by ELISA. Each marker was analysed between normal, polyp, and cancer populations, and the best performing analysed in combination by logistic regression.

Results:

The best model was able to discriminate normal from populations with adenoma or carcinoma using three DNA markers and CEA, showing an area under the receiver operator characteristic (ROC) curve of 0.855 with a positive predictive value of 81.1% for polyps and cancer diagnosis.

Conclusion:

These circulating markers in combination with other markers offer the prospect of a simple blood test as a possible secondary screen for colorectal cancers and polyps in patients with positive faecal occult blood tests.     

原发性肝癌凝血及抗凝指标检测结果分析

 目的　探讨肝癌患者凝血及抗凝指标与肝癌病情及预后的关系。方法　对 4 9例肝癌患者 (其中 2 3例术后复查 )的部分凝血及抗凝指标进行检测。结果　肝癌合并肝硬化组PT、APTT、TT与正常组比较均显著延长 ;肝癌组术前FIB显著高于正常对照组 ,肝癌并肝硬化组FIB则显著降低 ;肝癌患者TF活性均显著高于正常对照组 ;各组肝癌患者AT III活性均显著降低。结论　肝癌患者明显存在凝血及抗凝血激活状态 ,TF和AT III可作为肝癌诊断和判断预后的指标     

Circulating myeloid-derived suppressor cells are increased and correlate to immune suppression, inflammation and hypoproteinemia in patients with cancer

Recent studies have identified myeloid-derived suppressor cells (MDSCs) that are potent suppressors of tumor immunity and therefore a significant impediment to cancer immunotherapy. It has been reported that MDSCs are generated by malignant diseases or inflammation. However, no systematic studies in patients have been described. In order to clinically characterize MDSCs, we tested PBMCs from patients with various types of cancer including cholangiocellular, hepatocellular and pancreatic carcinoma, esophageal, gastric and colorectal cancer, breast cancer and thyroid cancer, and GIST, and those from normal volunteers using flow cytometry analysis. A significant increase was seen in the percentages of MDSCs in PBMCs from patients compared with normal volunteers. Among these patients, MDSC level was higher in patients with cancer of the digestive system and patients with breast cancer compared with normal volunteers. MDSC level was significantly and inversely correlated to stimulation indices (SI) of PHA-blastogenesis of lymphocytes and serum concentration of total protein, and positively correlated to neutrophil count. MDSC percentage in patients with gastric and colorectal cancer was also significantly correlated to neutrophil count and inversely correlated with lymphocyte count, and showed highly significant correlation to neutrophil/lymphocyte rate (NLR). In patients with breast cancer, MDSC levels in preoperative patients was significantly increased compared to normal volunteers and significantly decreased in postoperative patients. Thus, it is clear that MDSCs are increased in patients with cancer and closely related to suppression of cell-mediated immune responses. These data also suggest that they are related to chronic inflammation and that their levels are increased further in the terminal stages of patients whose nutritional status is impaired as observed in hypoproteinemia. MDSC levels have also been shown to decrease after removal of tumors in patients with breast cancer.     

Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer

Introduction  

MicroRNAs (miRs) are interesting new diagnostic targets that may provide important insights into the molecular pathogenesis of breast cancer. Here we evaluated, for the first time, the feasibility and clinical utility of circulating miRs as biomarkers for the detection and staging of breast cancer.     

Circulating T regulatory cells migration and phenotype in glioblastoma patients: an in vitro study

Glioblastoma multiforme (GBM) is the most aggressive primary human brain tumor. The relatively high amount of T regulatory lymphocytes present in the tumor, contributes to the establishment of an immunosuppressive microenvironment. Samples of peripheral blood were collected from GBM patients and healthy controls and a purified population of Treg (CD4⁺/CD25^bright) was isolated using flow cytometric cell sorting. Treg migrating capacities toward human glioma cell line conditioned medium were evaluated through an in vitro migration test. Our data show that supernatants collected from GBM cell lines were more attractant to Treg when compared to complete standard medium. The addition of an anti-CCL2 antibody to conditioned medium decreased conditioned medium-depending Treg migration, suggesting that CCL2 (also known as Monocyte Chemoattractant Protein, MCP-1) is implicated in the process. The number of circulating CD4⁺/μL or Treg/μL was similar in GBM patients and controls. Specific Treg markers (FOXP3; CD127; Helios; GITR; CTLA4; CD95; CCR2, CCR4; CCR7) were screened in peripheral blood and no differences could be detected between the two populations. These data confirm that the tumor microenvironment is attractive to Treg, which tend to migrate toward the tumor region changing the immunological response. Though we provide evidence that CCL2 is implicated in Treg migration, other factors are needed as well to provide such effect.     

Hypoxia-inducible factor-1 alpha, in association with inflammation, angiogenesis and MYC, is a critical prognostic factor in patients with HCC after surgery

Background  

Despite well-studied tumor hypoxia in laboratory, little is known about the association with other pathophysiological events in the clinical view. We investigated the prognostic value of hypoxia-inducible factor-1 alpha (HIF-1alpha) in hepatocellular carcinoma (HCC), and its correlations with inflammation, angiogenesis and MYC oncogene.     

炎症介质与肿瘤血管生成

炎症介质不仅在肿瘤的发生发展过程中起到了重要的作用,在肿瘤的血管生成方面也扮演着重要的角色。炎症反应的调节通路和肿瘤血管生成调节通路存在较大的重叠。研究证实,包括COX-2、IL-1、IL-6等在内的众多炎症介质不仅能够促进肿瘤血管生成,在肿瘤血管拟态形成及肿瘤干细胞向血管内皮细胞定向分化过程中可能也起到积极的促进作用。     

循环内皮祖细胞与肿瘤血管生成

恶性肿瘤细胞可产生多种细胞因子,可使骨髓中的内皮祖细胞(EPC)动员至外周血,并将这些细胞募集到肿瘤组织的血管床,参与肿瘤的血管生成.EPC有望成为抗肿瘤血管生成的靶点或肿瘤基因治疗的载体.     

Distribution pattern of Tenascin-C in glioblastoma: Correlation with angiogenesis and tumor cell proliferation

Tenascin-C (TN-C) is an extracellular matrix protein which participates in different processes like normal fetal development, wound healing, inflammation, keloids and rheumatoid arthritis. Furthermore, the immunostaining for TN-C is seen in the stroma of various malignant tumors as in glioblastoma multiforme (GBM), however, the significance of these findings is still not clear. In this study 62 GBM samples were analyzed immunohistochemically for distribution patterns of TN-C and correlated with angiogenesis and tumor cell proliferation. Tenascin-C in GBM localizes in two compartments, perivascular and intercellular space. Intercellular tenascin-C (TN-C ic) showed focal distribution in 66%, and diffuse one in 34% of cases. Perivascular tenascin-C (TN-C pv) showed strong correlation with microvascular density (MVD) and vascular endothelial growth factor (VEGF) expression. Moreover, it seems that TN-C pv enhanced the effect of VEGF. Intercellular TN-C did not correlate with MVD and VEGF expression, but showed strong correlation with proliferation index. Furthermore, tumors with diffuse TN-C ic expression had higher proliferation indices than tumors with focal TN-C expression. Our results indicate that TN-C plays a role in angiogenesis and tumor cell proliferation, but beside the intensity of expression, the distribution patterns are also important in these processes. This study also suggests that perivascular and intercellular TN-C compartments have probably different sources and different roles in GBM.     

Circulating nucleosomes and immunogenic cell death markers HMGB1, sRAGE and DNAse in patients with advanced pancreatic cancer undergoing chemotherapy

Serum biomarkers are urgently needed for patient stratification and efficient treatment monitoring in pancreatic cancer (PC). Within a prospective diagnostic observation study, blood samples were obtained from 78 patients with advanced PC before and weekly during the course of palliative chemotherapy. Circulating nucleosomes and immunogenic cell death markers, high‐mobility group box 1 (HMGB1), soluble receptors of advanced glycation end products (sRAGE) and DNAse activity, were measured by enzyme‐linked immunosorbent assay and correlated with results of radiological staging after 2 months of treatment, with time to progression (TTP) and overall survival (OS). Median TTP and OS of PC patients were 3.9 and 7.7 months, respectively. Pretherapeutic baseline biomarker levels did not correlate with objective response; however, nucleosome levels on day (d) 28 were higher (p = 0.048) and sRAGE levels at time of staging (d56) were lower in progressive patients (p = 0.046). Concerning estimation of prognosis, high nucleosome levels (d7, d14, d21 and d56), low sRAGE levels (d56) and DNAse activity courses (d0–d7) correlated with TTP, whereas high nucleosomes (d7, d14 and d56), high HMGB1 (d21 and d56) and DNAse (d0–d7) were associated with OS. After adjustment to Karnofsky performance score, nucleosomes and HMGB1 (both d56) and DNAse (d0–d7) remained independent prognostic factors. Thus, courses of circulating nucleosomes and immunogenic cell death markers HMGB1 and sRAGE show prognostic relevance in PC patients undergoing chemotherapy.     

凝血指标异常与非小细胞肺癌转移及预后的关系

目的:探讨非小细胞肺癌（NSCLC）患者凝血指标异常与一般临床病理特征、转移及生存期的关系。方法:对128例NSCLC患者进行凝血指标测定,采用SPSS 17.0统计软件进行统计学处理,组间比较采用方差分析,两样本均数比较采用t检验,凝血指标与生存期关系采用线性相关分析。结果:各凝血指标与NSCLC患者的年龄、性别无相关性。腺癌组APTT值明显低于鳞癌组,D-D水平明显高于鳞癌组,PT、FIB、PLT水平与病理类型无相关性。有转移组D-D水平明显高于无转移组,APTT、PT、FIB、PLT水平与有无转移无相关性。血小板水平与生存期呈负相关（r=-0.373 9,t=3.56,P<0.01）。结论:NSCLC患者普遍存在凝血指标异常,可能与病理类型及转移有关,凝血异常可影响患者的生存期。深入研究凝血异常状态,有利于估计病情变化及判断预后,对延长患者生存期有重要意义。     

Circulating tumor markers in cervical cancer

Serum levels of CA 19-9, CA 125 and CA 15-3 were measured in 91 patients with cervical cancer (16 with intraepithelial neoplasia and 75 with invasive cancer). In 35 patients with locally advanced cervical cancer, serum marker levels were measured at monthly intervals during neo-adjuvant chemotherapy. CA 19-9 was found to be abnormally high only in advanced stages with an overall sensitivity of 7.3%. CA 125 and CA 15-3 were elevated in 31.9 and 23.1% of the patients, respectively, with a combined sensitivity of about 40%. The mean values of CA 125 and CA 15-3 were positively related to clinical stage and tumor differentiation. CA 125 and CA 15-3 values were correlated with response to chemotherapy in more than 80% of the cases. These findings suggest that CA 125 and CA 15-3 could be usefully employed in the management of cervical cancer.     

Circulating tumor markers in breast cancer

A list of tumor markers evaluated in breast cancer patients is included as well as their relative value for a patient with metastatic breast cancer. Variations in the levels of circulating markers correlated well with disease course; however, the accuracy of these variations is not total.