Kevin J. Harrington

ALTERED gamma-CATENIN EXPRESSION CORRELATES WITH POOR SURVIVAL IN PATIENTS WITH BLADDER CANCER

PURPOSEnWe studied the expression of alpha-, beta-, gamma- catenin and E-cadherin in transitional cell carcinoma (TCC) and normal bladder epithelium and correlated these results with pathological and clinical parameters.nnnMATERIALS AND METHODSnWe used an avidin-biotin immunoperoxidase technique to examine the cellular localization of alpha-catenin, beta-catenin, gamma-catenin and E-cadherin in 68 TCC and 14 normal bladder biopsies.nnnRESULTSnE-cadherin, alpha-catenin, beta-catenin and gamma-catenin were expressed in a normal membranous pattern in all normal bladder epithelium specimens. Loss of normal surface E-cadherin, alpha-catenin, beta-catenin and gamma-catenin expression was found in 52/68 (76.4%) tumors, 57/68 (83.8%) tumors, 54/68 (79.4%) tumors and 54/68 (79.4%) tumors (p <0.001). There was a significant correlation between the loss of normal membranous expression of catenins and E-cadherin and increased grade (p <0.05). A highly significant correlation was observed between the loss of expression of E-cadherin, alpha-catenin and gamma-catenin, but not beta-catenin, with increased TNM stage (p <0.05). The abnormal expression of gamma-catenin as well as E-cadherin was correlated with poor survival (p <0.05).nnnCONCLUSIONSnE-cadherin-gamma-catenin complex may be a useful prognostic marker in bladder cancer. Work is in progress to establish whether normal membranous catenin expression can be enhanced by gene transfer or biological therapy to induce a less invasive and metastatic phenotype.

Clinical significance of heat shock protein-70 expression in bladder cancer

OBJECTIVESnTo investigate the expression of heat shock protein-70 (HSP-70) in transitional cell bladder cancer and correlate it with normal and inflammatory bladder tissue samples.nnnMETHODSnWe used a three-step avidin-biotin method to examine the localization of a rabbit anti-HSP-70 polyclonal antibody in normal (n = 10), inflammatory (n = 10), and malignant (n = 67) bladder tissue samples.nnnRESULTSnFifty-eight percent of the bladder cancer samples and only 10% and 20% of the normal and inflammatory bladder tissue samples, respectively, expressed HSP-70. Localization of the antibody correlated with the grade (P <0.001), stage (P <0.001), and survival (P <0.05) of the patients with malignancy.nnnCONCLUSIONSnHSP-70 is frequently overexpressed by bladder cancer cells and could be used as biochemical marker in patients with bladder cancer.

Role of adhesion molecules in bladder cancer : An important part of the jigsaw

There is a growing body of evidence suggesting that alterations in the adhesion properties of neoplastic cells may play a pivotal role in the development and progression of bladder cancer. Loss of intercellular adhesion and the desquamation of cells from the underlying lamina propria allows malignant cells to escape from their site of origin, degrade the extracellular matrix, acquire a more motile and invasive phenotype, and finally invade and metastasize. In addition to participating in tumor invasiveness and metastasis, adhesion molecules regulate or significantly contribute to a variety of functions, including signal transduction, cell growth, differentiation, site-specific gene expression, morphogenesis, immunologic function, cell motility, wound healing, and inflammation. To date, a diverse system of transmembrane glycoproteins have been identified that mediate the cell-cell and the cell-extracellular matrix adhesion. The main families of adhesion molecules are the cadherins, integrins, members of the immunoglobulin superfamily, and selectins. We review the recent data regarding the role of selected adhesion molecules in the pathogenesis of bladder cancer and their clinical exploitation as biomarkers of this malignant disease.

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.

GENETIC ALTERATIONS IN BLADDER CANCER

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Prophylactic Cranial Irradiation in Patients with Small-Cell Lung Cancer

The meta-analysis performed by the Prophylactic Cranial Irradiation Overview Collaborative Group has provided clear evidence of the beneficial effects of this treatment in terms of survival and reduction of cerebral metastasis. Delivery of PCI results in a 5.4% improvement in overall survival at 3 years after the commencement of induction chemotherapy. PCI was also shown to yield a 54% proportional reduction in the incidence of cerebral metastases, from 59% to 33%, at 3 years. Subgroup analysis suggests a trend toward reduced incidence of cerebral metastasis with increased radiation dose and earlier introduction of PCI into the treatment regimen. Further studies will address the effect of different radiation doses and fractionation regimens (including twice-daily, hyperfractionated radiotherapy) and the optimal timing of PCI relative to induction chemotherapy. Evaluation of the data on the neuropsychiatric sequelae of PCI suggest that patients have significant abnormalities at baseline and that there is no demonstrable change after PCI. However, there is a suggestion that PCI delivered concomitantly with chemotherapy may be associated with a significant deterioration in cognitive function.

Management of Cerebral Metastasis in Patients with Non-Small-Cell Lung Cancer

The development of cerebral metastases represents a life-threatening condition in patients with NSCLC. The approach to management should be guided initially by consideration of the relevant prognostic factors. The RTOG RPA classification, which is based on age, the presence or absence of extracranial disease, and the Karnofsky performance status, functions as a useful means of dividing patients into groups with different outcomes. The RPA can be used to select patients for either aggressive management with potentially curative intent (for patients in RPA class 1), more palliative treatment (RPA class 2), or best supportive care (RPA class 3). Surgery, WBRT and radiosurgery may all have a role in treatment. There is a pressing need for appropriately controlled randomized trials to define more accurately the indications for each of these modalities.