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Biomedical subjects

P Vermeulen

Publications and source records attributed to P Vermeulen.

At least 19 recordsLinked to original sources
PubMed2004

Prognostic value of nonangiogenic and angiogenic growth patterns in non-small-cell lung cancer.

An essential prerequisite of nonangiogenic growth appears to be the ability of the tumour to preserve the parenchymal structures of the host tissue. This morphological feature is visible on a routine tissue section. Based on this feature, we classified haematoxylin and eosin-stained tissue sections from 279 patients with non-small-cell lung cancer into three growth patterns: destructive (angiogenic; n=196), papillary (intermediate; n=38) and alveolar (nonangiogenic; n=45). A Cox multiple regression model was used to test the prognostic value of growth patterns together with other relevant clinicopathological factors. For overall survival, growth pattern (P=0.007), N-status (P=0.001), age (P=0.020) and type of operation (P=0.056) were independent prognostic factors. For disease-free survival, only growth pattern (P=0.007) and N-status (P<0.001) had an independent prognostic value. Alveolar (hazard ratio=1.825, 95% confidence interval=1.117-2.980, P=0.016) and papillary (hazard ratio=1.977, 95% confidence interval=1.169-3.345, P=0.011) growth patterns were independent predictors of poor prognosis. The proposed classification has an independent prognostic value for overall survival as well as for disease-free survival, providing a possible explanation for survival differences of patients in the same disease stage.

Adult↗
PubMed2004

Circulating basic fibroblast growth factor is partly derived from the tumour in patients with colon, cervical and ovarian cancer.

In order to investigate whether the high bFGF serum levels encountered in cancer patients are derived from the tumour, we analysed serum bFGF levels in 18 untreated randomly selected patients with operable colorectal, cervical and ovarian cancer in the blood draining the tumour, i.e., in mesenteric and uterine veins, and compared these with arterial samples. No significantly elevated bFGF levels were found in the veins draining the tumours compared with arterial samples in our patient population. This suggests that, in contrast to what is generally presumed, serum bFGF levels might also be derived from other sources besides the tumour, e.g., platelets.

Aged↗
PubMed2002

Arterio-venous gradients of IL-6, plasma and serum VEGF and D-dimers in human cancer.

The circulating angiogenic factors vascular endothelial growth factor-A, interleukin-6 and the fibrin D-dimer fragment were measured in the mesenteric vein, the uterine vein, as well as in peripheral venous and arterial samples in 21 randomly selected patients with operable colorectal, ovarian and cervical carcinoma. In addition, immunohistochemistry for vascular endothelial growth factor-A and interleukin-6 was performed on colorectal tumours of such patients. Serum and plasma vascular endothelial growth factor-A were not significantly elevated in the vein draining the tumours, despite tumour cell expression of vascular endothelial growth factor-A. Serum vascular endothelial growth factor-A is therefore not all tumour-derived. In contrast, serum interleukin-6 was highly elevated in the draining veins in agreement with expression of interleukin-6 in the cytoplasm of tumour cells. In the megakaryoblastic cell line MEG-01, the expression of vascular endothelial growth factor-A was found to be regulated by interleukin-6. Thus, the higher platelet vascular endothelial growth factor-A load resulting in higher serum vascular endothelial growth factor levels in cancer patients may partly result from an interleukin-6 mediated up-regulation of the expression of vascular endothelial growth factor-A in the precursor of the platelet, i.e. the megakaryocyte. We also confirmed by immunohistochemistry that platelets adhere and aggregate on tumour endothelium. We propose that interleukin-6 indirectly promotes tumour angiogenesis through its up-regulation of the vascular endothelial growth factor-A load in platelets. In addition, the correlations found between peripheral venous interleukin-6 and peripheral venous fibrinogen and D-dimers levels, and the high D-dimer levels found in the draining vein of the tumour, in agreement with fibrin deposits found in the tumour stroma, suggest an important role for interleukin-6 in extra-vascular fibrinogen metabolism. Our results suggest a pivotal role for interleukin-6 in the intrinsic link between haemostasis and angiogenesis. This might be of importance in the development of anti-angiogenic agents based on interference with haemostasis.

Biomarkers, Tumor↗
PubMed2002

Plasma fibrin D-dimer levels correlate with tumour volume, progression rate and survival in patients with metastatic breast cancer.

Plasma levels of D-dimer are elevated in cancer patients. Activation of the extrinsic coagulation system and the fibrinolytic cascade within a tumour is thought to be related with growth, invasion and metastasis. We have investigated the relationship between these markers of fibrin metabolism, standard clinicopathological variables and serum levels of angiogenic cytokines in three cohorts: group A (n=30) consisted of 30 healthy female volunteers, group B (n=23) of consecutive patients with operable breast cancer and group C (n=84) of patients with untreated or progressive metastatic breast cancer. Plasma D-dimers, fibrinogen, IL-6, vascular endothelial growth factor and calculated vascular endothelial growth factor load in platelets are clearly increased in patients with breast cancer. D-dimers were increased in nearly 89% of patients with progressive metastatic disease. The level of D-dimers was positively correlated with tumour load (P<0.0001), number of metastatic sites (P=0.002), progression kinetics (P<0.0001) and the cytokines related to angiogenesis: serum vascular endothelial growth factor (P=0.0016, Spearman correlation=0.285), calculated vascular endothelial growth factor load in platelets (P<0.0001, Spearman correlation=0.37) and serum interleukin-6 (P<0.0001, Spearman correlation=0.59). Similarly increased D-dimer levels were positively correlated with increased fibrinogen levels (P<0.0001, Spearman correlation=0.38). The association between markers of fibrin degradation in patients with progressive breast cancer suggests that the D-dimer level is a clinically important marker for progression and points towards a relation between haemostasis and tumour progression. A role of interleukin-6, by influencing both angiogenesis and haemostasis, is suggested by these observations.

Antifibrinolytic Agents↗
PubMed2001

Early distant relapse in "node-negative" breast cancer patients is not predicted by occult axillary lymph node metastases, but by the features of the primary tumour.

Early distant relapse occurs in a minority of node-negative breast cancer patients. Whether this poor prognosis can be predicted by the features of the primary tumour, or by the presence of occult metastases in the "negative" lymph nodes (LNs), remains a matter of debate. One hundred and four T(1-2)N(0)M(0) breast carcinoma patients were divided into two groups: group 1 (44%) showing early distant relapse with a median disease-free survival of 25 months, and group 2 (56%) showing no evidence of disease after a median follow-up of 91.5 months. All patients had received locoregional treatment only. All tumours were evaluated for medial/lateral location, histological type, size, grade, mitotic activity, fibrotic focus, necrosis, angiogenesis, growth pattern, and lymphatic vessel permeation. The haematoxylin and eosin-stained slides of all axillary LNs were revised and two additional levels were cut from each paraffin block for cytokeratin immunohistochemistry. In 24 patients (23%), occult metastases were found. These consisted of single cells or small clusters (SCs) in the marginal sinus in 17 patients (16%) and of larger colonies of cells in seven patients (7%). All detected metastases were smaller than 2 mm in diameter (micrometastases). There was no significant correlation between the presence of occult LN metastases (SCs or colonies) and the prognostically important features of the primary tumour. Early metastatic disease was significantly correlated with larger tumour size (p=0.02), higher histological grade (p=0.0008), mitotic activity (p<0.0001), presence of necrosis (p=0.0004), presence of fibrotic foci (p=0.0005), angiogenesis (p=0.0009), and lymphatic vessel permeation (p=0.018). Multiple logistic regression analysis showed that histological grade and the presence of a fibrotic focus were the only independent prognostic factors and that the presence of occult LN metastases was inversely correlated with early distant relapse. Prospective prognostic studies of occult LN metastases should consider the features of the primary tumour in a multivariate analysis.

Adult↗
PubMed2001

Platelets and vascular endothelial growth factor (VEGF): a morphological and functional study.

The growth of primary tumours beyond a critical mass is dependent on angiogenesis. The switch to the angiogenic phenotype involves changes in the local equilibrium of cytokines with either pro- or anti-angiogenic properties. Vascular Endothelial Growth Factor (VEGF) is one of the major positive regulators of tumour angiogenesis. Serum VEGF is, in cancer patients, correlated with worse prognosis. Recent evidence suggests that platelets are the main contributors of serum VEGF. We demonstrate, ultrastructurally and with immunofluorescence techniques, the alpha granule and membranous localisation of VEGF and provide further evidence for the role of platelets, both in healthy individuals as in patients with locally and advanced breast cancer, in the storage of circulating VEGF. We also demonstrate that, linear with tumoural progression, platelets accumulate more VEGF. Enhanced production in bone marrow platelet progenitors as well as endocytosis of circulating VEGF by platelets and/or megakaryocytes could explain the higher VEGF load in platelets from advanced cancer patients. This study provides further evidence for a role of platelets in transporting VEGF.

Blood Platelets↗
PubMed2001

Intratumoral hypoxia resulting in the presence of a fibrotic focus is an independent predictor of early distant relapse in lymph node-negative breast cancer patients.

AIMS: To examine the importance of a fibrotic focus-a scar-like area in a carcinoma-as a marker of intratumoral hypoxia that correlates with angiogenesis and with clinical outcome in node-negative breast cancer. METHODS AND RESULTS: One hundred and four T1-2N0M0 breast carcinoma patients were divided into two groups: group 1 (n=46) showing early distant relapse (median disease-free survival 25 months) and group 2 (n=58) showing no evidence of disease (median follow-up 91.5 months). All tumours were evaluated for medial/lateral location, size, histological grade, mitotic activity, necrosis, fibrotic focus, angiogenesis, vascular permeation and growth pattern. Multiple regression analysis showed that only histological grade and the presence of a fibrotic focus were independent predictors of early distant relapse. A fibrotic focus was present in 53% of the tumours. The relative size (fibrotic focus/tumour ratio) was significantly correlated with an unfavourable outcome. The presence of necrosis inside the fibrotic focus and the absolute and relative size of the fibrotic focus were significantly correlated with angiogenesis. A fibrotic focus was significantly associated with large, expansively growing tumours with high histological grade and numerous mitoses. CONCLUSION: A fibrotic focus can be used as a surrogate for quantifying angiogenesis and is an independent predictor of early metastasis in lymph node-negative breast cancer.

Adult↗
PubMed2001

Perforating oesophageal carcinoma presenting as necrotizing fasciitis of the neck.

A patient with a history of schizophrenia was admitted to our hospital in an already severe stage of necrotizing fasciitis of the neck, complicated with mediastinitis and gangrene. Later on, he also developed a vena cava superior syndrome and sepsis. In the few cases and small series described in the literature, necrotizing fasciitis of the neck is usually associated with surgery or trauma. Less frequently, an orodental or pharyngeal infection, often innocuous, is the underlying cause. None of these causes could be identified in our patient. Initially, on computer-assisted tomography (CT) scan, a tracheal rupture was suspected, but this diagnosis could not be confirmed on bronchoscopic examination. On gastroscopy, a stenotic oesophageal segment was discovered. Biopsy of this segment showed a poorly differentiated squamous cell carcinoma. The patient died in sepsis. Autopsy confirmed the presence of a large proximal oesophageal tumour with perforation. As far as we know, no case of a necrotizing fasciitis of the neck caused by perforation of a formerly unknown oesophageal carcinoma has been reported. Even mediastinitis, with or without gangrene, is rarely associated with oesophageal cancer, and in the few cases reported it is always due to fistulization after surgery.

Adult↗
PubMed2000

Biphasic sarcomatoid carcinoma (carcinosarcoma) of the renal pelvis with heterologous chondrogenic differentiation.

A case of a man with biphasic sarcomatoid carcinoma of the right kidney with chondrosarcomatous foci and with invasion of the pelvic mucosa and submucosa into the peripelvic adipose tissue is presented. In situ carcinoma of the urothelium of the right renal pelvis and proximal ureter was also noted. Comments on the nomenclature of malignant tumours with apparently mixed carcinomatous and sarcomatous phenotypes and a hypothesis on the histogenesis of these tumours are presented. Cytokeratin and p53 protein expression patterns, and the results of angiogenesis quantification are consistent with an epithelial-to-mesenchymal conversion induced by the stroma.

Aged↗
PubMed2000

Human plasma phospholipid transfer protein increases the antiatherogenic potential of high density lipoproteins in transgenic mice.

Plasma phospholipid transfer protein (PLTP) transfers phospholipids between lipoprotein particles and alters high density lipoprotein (HDL) subfraction patterns in vitro, but its physiological function is poorly understood. Transgenic mice that overexpress human PLTP were generated. Compared with wild-type mice, these mice show a 2.5- to 4.5-fold increase in PLTP activity in plasma. This results in a 30% to 40% decrease of plasma levels of HDL cholesterol. Incubation of plasma from transgenic animals at 37 degrees C reveals a 2- to 3-fold increase in the formation of pre-beta-HDL compared with plasma from wild-type mice. Although pre-beta-HDL is normally a minor subfraction of HDL, it is known to be a very efficient acceptor of peripheral cell cholesterol and a key mediator in reverse cholesterol transport. Further experiments show that plasma from transgenic animals is much more efficient in preventing the accumulation of intracellular cholesterol in macrophages than plasma from wild-type mice, despite lower total HDL concentrations. It is concluded that PLTP can act as an antiatherogenic factor preventing cellular cholesterol overload by generation of pre-beta-HDL.

Animals↗
PubMed1999

Experimental study of intraperitoneal suramin on the healing of colonic anastomoses.

INTRODUCTION: The effect of the antiangiogenic agent suramin on the healing of colonic anastomoses was studied in a rat model. METHODS: Rats underwent an end-to-end colonic anastomosis and its healing was tested by measuring bursting pressure, hydroxyproline content and number of newly formed vessels. For the bursting pressure experiment suramin was given intraperitoneally in a dose of 200 mg/kg (maximal tolerable dose) and 100 mg/kg. Hydroxyproline content and vessel density were only tested at 100 mg/kg since the toxicity at this dose was lower whereas bursting pressure was still diminished. RESULTS: There were no deaths. On the fourth day after operation bursting pressure in the control group was significantly higher than that in rats treated with suramin 200 mg/kg (P = 0.006) and 100 mg/kg (P = 0.002). Rupture occurred at the anastomotic line. On day 7, this difference was not statistically significant. Four days after the operation, the hydroxyproline content and vessel density were significantly below that in control segments (hydroxyproline: 10.3 versus 7.8 microg per mg dry weight; vessel content: 85.7 versus 49.6 vessels per x 100 field for control and suramin-treated rats respectively). On the seventh day no difference in hydroxyproline levels was seen but the vessel density was still diminished significantly (P = 0.04). CONCLUSION: Experimentally, suramin significantly inhibits and delays healing of colonic anastomoses. Presented in part to the XXXII Congress of the European Society for Surgical Research in Corfu, Greece, May 1997

Anastomosis, Surgical↗
PubMed1999

Effects of suramin on anastomotic colon tumors in a rat model.

BACKGROUND: The development of antiangiogenic drugs offers new promise in the treatment of malignancy. Suramin has been reported to inhibit tumor growth by blocking angiogenesis and has been used in clinical trials. The aim of the present study was to examine the effects of suramin on colonic anastomotic tumors in the rat. METHODS: (a) Colonic anastomotic tumor was induced in 120 WAG/RIJ rats. Half of the animals were given 100 mg/kg of suramin intraperitoneally at the time of tumor induction. Rats were sacrificed after 2, 4 and 8 weeks; tumor take and tumor weight were evaluated. (b) The number of red blood cell clusters per x 400 field was counted in each tumor. (c) A lymphocyte transformation test was performed in four groups of animals, 2 weeks before and 2 weeks after tumor implantation and/or suramin administration. RESULTS: (a) A significant enhancement of tumor growth was observed in the suramin-treated animals. (b) This was accompanied by a significant increase in functional blood vessels. (c) Suramin-treated rats had markedly decreased lymphocyte stimulation, pointing to a possible immunosuppressive effect. CONCLUSIONS: The growth of an anastomotic colon tumor is rather enhanced by a single intraperitoneal administration of 100 mg/kg suramin in the rat, possibly by an unexpected immunosuppressive effect.

Adenocarcinoma↗
PubMed1997

Soft tissue sarcoma in adults.

The importance of a multidisciplinary group in the treatment of soft tissue sarcomas is well established. This approach has led to a major shift in treatment from a single-modality radical surgery to a more sophisticated approach with limb-sparing resections integrated with external irradiation, interstitial irradiation, or both. The increasing knowledge of both the molecular mechanisms of sarcoma development and the biological characteristics (tumor cell proliferation, hypoxia, necrosis, angio-genesis) will enable us to predict prognosis on a more individual basis and thus allow for more selective treatment strategies. Studies relating these molecular markers and biological characteristics to treatment results obtained with surgery, radiotherapy, and chemotherapy are eagerly awaited.

Adult↗