Anastasios J. Karayiannakis

Circulating VEGF levels in the serum of gastric cancer patients: Correlation with pathological variables, patient survival, and tumor surgery

ObjectiveTo evaluate the clinical usefulness of serum vascular endothelial growth factor (VEGF) levels in gastric cancer patients. Summary Background DataVascular endothelial growth factor plays an important role in the formation of new blood vessels involved in the growth and metastatic spread of solid tumors, but there is limited information regarding the clinical significance of serum VEGF levels in cancer patients. MethodsSerum VEGF concentrations were measured by an enzyme linked immunosorbent assay in 61 healthy controls and in 58 gastric cancer patients before surgery, and then again at 7 and 30 days after surgery. The association between preoperative serum VEGF levels, clinicopathological features and patient survival, and their changes following surgery were evaluated. ResultsSerum VEGF levels in gastric cancer patients were significantly higher than those in controls. There was a significant association between serum VEGF levels and disease stage, as well as invasion depth of the tumor and the presence of distant metastases. Serum VEGF levels decreased significantly after radical resection of the primary tumor and increased in patients with unresectable tumors. Multivariate regression analysis showed that serum VEGF level is an independent prognostic factor for survival. ConclusionsSerum VEGF levels in gastric patients are significantly higher compared with normal controls and correlate with local tumor extent, disease stage, and the presence of distant metastases. Preoperative serum VEGF concentration decreases significantly after radical resection of the primary tumor and is an independent prognostic factor for patient survival suggesting that determination of serum VEGF levels may be clinically useful.

E-Cadherin/catenin complex in benign and malignant melanocytic lesions

E‐cadherin is a calcium‐dependent cell–cell adhesion molecule expressed by melanocytes and responsible for their adhesion to keratinocytes in vitro. In this study, the expression of E‐cadherin and its associated cytoplasmic proteins α‐, β‐, and γ‐catenin was evaluated in melanocytic lesions by immunohistochemistry. E‐cadherin expression was evaluated in 70 malignant melanomas and the catenins in 35 of these specimens. Twenty benign melanocytic naevi were also evaluated for E‐cadherin and catenin expression. In normal epidermis, E‐cadherin/catenin immunostaining was localized at the intercellular borders. In melanomas, a differential loss of E‐cadherin expression was observed. Membranous E‐cadherin staining was absent in dermal nests of melanomas in their radial growth phase and in Clark level II and III lesions, whereas it was present in a high proportion of melanomas in their vertical growth phase, in Clark level IV and V lesions and in metastasizing melanomas. In contrast, superficial compartments of naevi showed membranous E‐cadherin immunoreactivity and junctional naevus cell nests displayed heterogeneous or diffuse cytoplasmic staining. Cytoplasmic α‐ and β‐catenin, but not γ‐catenin staining were detected in all benign and malignant lesions. These findings indicate that qualitative changes in the expression and cellular localization of E‐cadherin and of α‐, β‐, and γ‐catenin occur in melanocytic lesions and may reflect different stages in their progression. Copyright

Expression of catenins and E-cadherin during epithelial restitution in inflammatory bowel disease

Catenins are cytoplasmic proteins associated with E‐cadherin, the prime mediator of cell–cell adhesion. Perturbation in any of these molecules results in altered intercellular adhesion, cell differentiation, and increased migration. In this study, the expression and cellular localization of catenins and E‐cadherin in inflammatory bowel disease were examined. The expression of E‐cadherin; α‐, β‐, and γ‐catenin; and p120 was evaluated immunohistochemically in 31 paraffin‐embedded colonic specimens from 21 patients with ulcerative colitis and Crohns disease. Loss of normal membranous E‐cadherin and α‐catenin staining was detected at the mucosal edges around epithelial ulcerations in all cases of active ulcerative colitis and in 50 per cent of cases with active Crohns disease. Reduced expression of p120 protein was also found at the margins of ulcerated mucosa in all cases of active ulcerative colitis and in 75 per cent of those with active Crohns disease. There was a statistically significant correlation between the expression of E‐cadherin, α‐catenin and p120 and disease activity. There were no changes in β‐ and γ‐catenin expression in either ulcerative colitis on Crohns disease. These findings indicate that altered expression of E‐cadherin, α‐catenin, and p120 occurs during mucosal ulceration in inflammatory bowel disease. These changes may be involved in promoting cell migration during epithelial restitution of the gastrointestinal mucosa.

Abnormal expression of the E-cadherin-catenin complex in dysplastic Barrett's oesophagus.

It is now accepted that altered E-cadherin-catenin complex expression in oesophageal cancer correlates with clinical and pathological parameters, while abnormal E-cadherin expression occurs early in Barretts oesophagus. We evaluated immunohistochemically the expression and cellular localization of alpha-, beta-, and gamma-catenin, and E-cadherin in 5 dysplastic and 26 non-dysplastic cases of Barretts oesophagus. Usually all three catenins were localized at the cell membrane, as was E-cadherin. A similar staining pattern for E-cadherin and the catenins was observed in all cases of non-dysplastic Barretts syndrome. However, 60% (3/5) of cases with dysplasia showed loss of membranous beta-catenin staining and diffuse cytoplasmic distribution, with predominantly nuclear localization in two cases. Membranous staining and concomitant cytoplasmic localization of E-cadherin, alpha-catenin and gamma-catenin were seen in one case with abnormal beta-catenin immunoreactivity. Our results indicate that altered subcellular distribution of beta-catenin occurs frequently in dysplastic Barretts oesophagus and possibly reflects the signalling function of this molecule.

Abnormal expression of p120 correlates with poor survival in patients with bladder cancer

p120 is a cytoplasmic molecule closely associated with the Ca(2+)-dependent cell-cell adhesion molecule E-cadherin, by forming complexes between the cytoplasmic domain of E-cadherin and the cytoskeleton. Although it has been shown that loss or downregulation of E-cadherin is associated with an invasive and poorly differentiated phenotype in several tumours, there is very little information available concerning p120 expression in malignant disease. We used an avidin-biotin immunoperoxidase technique to examine the immunoreactivity and cellular localisation of p120 and E-cadherin in 68 transitional cell carcinomas (TCC) and 14 normal bladder biopsies and correlated these results with pathological and clinical parameters. E-cadherin and p120 were expressed in a normal membranous pattern in all normal bladder epithelium specimens. Loss of normal surface E-cadherin and p120 expression was found in 52/68 (76%) and 57/68 (84%) tumours, respectively. There was a significant correlation between the loss of normal membranous expression of p120 and increased grade (P < 0.001) and T stage (P < 0.001). The abnormal expression of p120 was correlated with poor survival (P < 0.05). Our data indicate that the E-cadherin-p120 complex may be a useful prognostic marker in bladder cancer.

Adhesion molecules as targets for the treatment of neoplastic diseases.

The quest for therapeutic specificity is implicit in all branches of medicine. In cancer treatment, cytotoxic agents, such as chemotherapy and radiotherapy, comprise the current therapeutic modality. Unfortunately, when used against most solid malignancies, their therapeutic indices are relatively low due to the significant damage they inflict on normal tissues. Furthermore, cure rates have remained essentially static over the last two decades. Specificity in killing neoplastic cells, while sparing healthy ones is therefore the only alternative approach, with several molecules qualifying as candidates for targeting therapy. Reduction of cell-cell and cell-matrix adhesion are, early tumorigenesis events also implicated in the invasive and metastatic process. The fact that abnormal adhesive marker expression is a feature commonly shared by most malignancies, along with its tendency to occur as both an early and late event in neoplastic development, makes these molecules potential candidates for antineoplastic targeted therapies. This review presents the perspectives of specific anti-adhesion molecule targeting as a possible therapeutic approach in neoplastic diseases.

Splenectomy for Massive Splenic Infarction Unmasks Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder characterized by pancytopenia, hemolysis, and thrombosis. Abdominal vein thrombosis is a life-threatening manifestation of this disease. We present a patient with complete spleen necrosis due to thrombosis of the splenic vessels. After splenectomy, other causes of thrombophilia were excluded and the diagnosis of PNH was established. The patient was put on anticoagulation but despite the prophylactic international normalized ratio maintained over the last 18 months of follow-up, he had another episode of intrahepatic thrombosis which was treated with tissue plasminogen activator thrombolysis.

Enhancement of medical images using a fuzzy model for segment dependent local equalization

A novel model for fuzzy equalization of medical images is proposed. The method requires a preprocessing step which accomplishes a fuzzy segmentation of the image into N segments with overlapping fuzzy boundaries. Histogram equalization is performed according to individual equalization functions derived from each segment of the image. A fuzzy membership function is associated with each segment. Enhancement results compare well against histogram equalization techniques that derive the equalization transform function from the global histogram of the image.

Epithelial mucin expression in bladder cancer: correlation with pathological and clinical parameters

Abstract Recently, attention has been drawn to the role of polymorphic epithelial mucin (PEM) as a possible target for cancer immunotherapy. To investigate the expression of this molecule in bladder tissue, we used two mouse monoclonal antibodies (HMFG1 and HMFG2) raised against the core protein of the PEM. The localization of these two anti-PEM antibodies was examined in normal (n=10), inflammatory (n=10) and malignant (n=67) bladder tissue samples with the use of a three-step avidin-biotin method. For HMFG1 and HMFG2 localization was successful in 78% and 60% of the bladder cancer samples, respectively, where as they were localized only in 30% and 40% of normal bladder tissue samples, respectively. Staining of either antibodies did not correlate with the grade, stage, or survival of bladder cancer patients. We conclude that PEM is frequently overexpressed by bladder cancer cells and HMFG1 is the antibody of choice to be used as a carrier of a cytotoxic agent for application of intravesical targeted therapy of bladder cancer.

Commentary on Chapter 19

Mucosal immunology is still poorly understood. Within gut-associated lymphoid tissues the mucosal barrier balances appropriate responsiveness to cognate antigen with physiological tolerance directed towards innocuous haptens and foreign peptides. Immune activity is controlled by the local cytokine microenvironment and by the production of large quantities of surface IgA (sIgA) designed to exclude antigen in the mucus layer.