Showing papers by "Carlos Cordon-Cardo published in 1992"

Altered Expression of the Retinoblastoma Gene Product: Prognostic Indicator in Bladder Cancer

Abstract: Background It has been reported that 50%-70% of patients with bladder cancer experience recurrence after initial successful treatment and about 10%-20% of these patients die of the disease. Despite precise pathologic staging and grading, we are unable to predict clinical outcome in all patients. The retinoblastoma-susceptibility (RB) gene, a prototype of tumor suppressor genes, has recently been associated with development and/or progression of bladder cancer, as well as sarcoma and small-cell lung cancer. In transitional cell carcinomas of the bladder, we have observed altered expression of the Rb gene product--a nuclear phosphoprotein thought to function as a cell cycle regulator. Purpose The aim of this study was to investigate the hypothesis that altered patterns of Rb expression correlate with prognosis in bladder cancer. Methods Expression of the RB gene was evaluated in specimens from 48 primary bladder tumors obtained by cystectomy or transurethral resection. Rb protein expression was correlated with disease outcome in these patients. Rb expression was examined by immunohistochemistry, using the mouse monoclonal antibody Rb-PMG3-245 on frozen tissue sections. Computerized image analysis was used to quantify the level of Rb protein in individual tumor cells. Results The overall 5-year disease-free survival was 66%, with a median follow-up of 42 months. Normal levels of Rb protein expression were found in 34 patients (Rb-positive group). A spectrum of altered patterns of expression from undetectable levels to heterogeneous expression, however, was observed in 14 patients (altered Rb group). Of the 38 patients with muscle-invasive tumors, 13 were categorized as having altered expression of Rb protein. Only one of 10 patients with superficial carcinomas had altered expression of Rb protein. The 5-year survival was significantly decreased in patients with altered Rb protein compared with the survival in patients with positive Rb expression (P less than .001). Conclusions The results suggest that tumors exhibiting decreased expression of the RB gene-coded product (Rb protein) had a more aggressive biological behavior than those that expressed the Rb protein in the majority of their tumor cells. Implications This study demonstrates that altered patterns of Rb protein expression may be an important prognostic variable in patients presenting with invasive bladder cancer.

Expression of disialogangliosides GD2 and GD3 on human soft tissue sarcomas

Abstract: Methods. Fifty-six freshly frozen human sarcomas were studied for expression of disialogangliosides by avi-din-biotin immunohistochemical staining with purified monoclonal antibodies (MoAb) 3F8 (antidisialoganglioside GD2) and R24 (antidisialoganglioside GD3). Results. Ninety-three percent of the tumors tested by the immunohistochemical staining expressed GD2 and 88% expressed GD3. The intensity of expression varied among sarcomas of different histologic types. Lipo-sarcoma, fibrosarcoma, malignant fibrous histiocytoma, leiomyosarcoma, and spindle cell sarcoma reacted strongly with 3F8 and R24. Embryonal rhabdomyosarcoma and synovial sarcoma demonstrated substantially weaker staining by either MoAb. Weakly reactive or nonreactive tumors were, in general, high-grade or meta-static sarcomas. Ganglioside extraction and thin-layer chromatography/immunothin-layer chromatography of two liposarcomas confirmed the identities of these gangliosides. Conclusions. GD2 and GD3 may indicate sites for MoAb-targeted imaging and therapy for sarcomas. The association of a diminished stainability by 3F8 and R24 with aggressive sarcomas may indicate prognostic significance. Cancer 1992; 70:633–638.

P-glycoprotein expression in brain tumors.

Abstract: Overexpression of P-glycoprotein (P-gp) in cancer cells can result in resistance to several chemotherapy agents (multidrug resistance) including doxorubicin and vincristine. The drugs to which resistance develops also penetrate the blood brain barrier poorly. P-gp expression in brain capillary endothelial cells suggests that P-gp may restrict drug entry into brain tumors and thus be another mechanism of drug resistance. To seek evidence for either of these roles in the drug resistance of brain tumors, we examined the location of expression of P-gp in 49 brain tumors, using an anti-P-gp mouse monoclonal antibody and immunohistochemistry. P-gp expression was observed in tumor cells of two glioblastomas and a meningeal sarcoma but not in low-grade primary or metastatic tumors. In low-grade primary tumors, P-gp was present in all vascular endothelial cells. In the vascular endothelial cells of anaplastic primary brain tumors and brain metastases, P-gp expression was heterogeneous or absent. These findings are consistent with a role for P-gp in the resistance of some brain tumors to chemotherapy agents.

Expression of Her2/neu oncogene product p185 in correlation to clinicopathological and prognostic factors of gastric carcinoma.

Abstract: The expression of the Her2/neu gene product p185 was retrospectively analyzed in 58 patients with gastric carcinoma. The results were correlated to various clinicopathological and prognostic factors. Positive membrane staining for p185 could be detected in 38% of the patients (22/58). Membrane staining was significantly greater in well and moderately differentiated tumors of the intestinal type when compared with poorly differentiated lesions and carcinomas of the diffuse type (P less than 0.01). Positive membrane staining did not correlate with site and tumor stage, but T1 lesions had less membrane staining than more advanced primary tumors. Overall survival showed no difference between p185-positive and negative cases. Multivariate analysis defined a subgroup of curatively resected patients with stage III and IV disease that had a statistically significant poorer survival when p185 was overexpressed (P = 0.005). Overexpression of the Her2/neu product p185 appears to be associated with intestinal-type gastric carcinoma and may help in identifying a subset of patients at increased risk for shorter survival.

Treatment with high dose mouse monoclonal (anti-GD3) antibody R24 in patients with metastatic melanoma.

Abstract: R24 is a mouse IgG3 monoclonal antibody that reacts with the ganglioside GD3 expressed by melanoma cells and other cells of neuroectodermal origin (eg adrenal medulla) Antitumour activity of R24 was demonstrated in initial phase I and pilot trials, but treatment was limited by urticaria at cumulative doses of 400 mg/m2 A trial exploring intensification of the dose of R24 was conducted in eight patients Planned doses of R24 antibody were 800 and 1200 mg/m2 over 6-8 days by continuous iv infusion All patients received concomitant therapy with hydroxyzine hydrochloride and cimetidine to minimize urticaria One patient developed anaphylaxis, after which no further therapy was given All patients developed peripheral blood lymphopenia and marked decreases in serum complement values during treatment, suggesting depletion of two possible effector mechanisms of the antitumour effects of R24 A vascular leak syndrome, manifested by weight gain, oedema and hypotension, was evident in seven patients during the initial 24-36 h of treatment Serum sickness syndrome was observed in six of seven evaluable patients between days 5 and 8, coincident with the onset of the human anti-globulin response to R24 One patient given 1200 mg/m2 had a minor response (38% reduction in pelvic nodes) lasting 12 months There was no detectable increase (by immunohistochemical staining) in deposition of R24 within tumour sites at doses used in this trial compared to that observed at doses of 240 and 400 mg/m2 The maximum tolerated dose was 800 mg/m2 Dose-limiting toxicity was manifest as reversible hypertension with end-organ symptoms (chest pain or visual field defects) in patients treated with a dose of 1200 mg/m2(ABSTRACT TRUNCATED AT 250 WORDS)

Immunopathologic analysis of human urinary bladder cancer. Characterization of two new antigens associated with low-grade superficial bladder tumors.

Abstract: The authors have further characterized the normal human tissue distribution and tumor expression of two highly restricted tumor-associated antigens, detected by mouse monoclonal antibodies M344 and 19A211, which are primarily expressed on low-grade superficial urinary bladder tumors. This study was conducted using immunohistochemical staining of frozen and deparaffinized sections of human normal and tumor tissues. The antigens are stable and well preserved on deparaffinized tissue sections. M344 antibody identifies a high-molecular-weight determinant on a cytosolic protein component of over 300,000 Mr. This antigen was not detected on any normal tissue analyzed, including 14 specimens of normal urothelium and 22 cases of cystitis; however, M344 was positive in 74.5% of Ta-T1 tumors and 11% of T3-T4 tumors. 19A211 antibody identifies a sialylated epitope on a cytoplasmic protein complex of 100,000 to 200,000 Mr. This antigen also was expressed preferentially on low-grade superficial bladder tumors (77% Ta-T1) and less frequently on deeply infiltrating tumors (10% T3-4). 19A211 was negative on all normal cells tested, with the exception of umbrella cells, in approximately 25% of the normal urothelium and cystitis specimens studied. Either one or both of these tumor-associated antigens are detected in approximately 80% of low-grade papillary superficial tumors and carcinoma in situ of the urinary bladder. The expression of these antigens on a subset of low-grade bladder tumors, known to progress in only about 10% of cases, suggests that phenotypic differences may reflect biologic potential. Beyond their possible biologic significance, antibodies M344 and 19A211 may provide clinically useful probes for early detection and stratification of urinary bladder tumors.

Expression of blood group antigens in bladder cancer: current concepts.

Abstract: Blood group antigens are a group of carbohydrate structures bound to membrane lipids or proteins of erythrocytes and certain epithelial tissues including urothelium. The Lewis antigens are structures that are genetically and biochemically related to the ABO blood group. The ABO and Lewis blood group systems are differentially expressed in the normal urothelium of "secretors" versus "nonsector" individuals. The normal urothelium of "secretors" is rich ABH, Leb, and Ley antigens while the urothelium of "nonsecretors" does not express these antigens. Therefore, deletion of ABH antigens, commonly noted in TCC, can only be reliably ascertained in "secretor" individuals. Neoexpression of the Lewis X antigen (which is absent in normal urothelium) is noted in over 85% of TCC regardless of tumor stage and grade. Immunocytological detection of the Lewis X antigen on exfoliated bladder epithelial cells enhances the detection of urothelial tumor cells, particularly from low grade and low stage neoplasms.

Expression of P-glycoprotein in normal muscle cells and myogenic tumors.

Abstract: We have analyzed the expression of the multidrug resistance (mdr-1) gene product, P-glycoprotein, by immunohistochemical staining of frozen tissue sections of human normal muscle fibers and 31 tissue specimens of cases of myogenic sarcomas. The objective of this study was to further characterize what appears to be a variety of responses to therapy in like-appearing but distinct tumors. We have used two mouse monoclonal antibodies that recognize two different epitopes of P-glycoprotein. Mouse monoclonal antibody HYB-241 detects an extracellular epitope of P-glycoprotein, whereas C219 detects a carboxy-terminal intracellular epitope and has recently been reported to cross-react with the mdr-3 gene product. Differential epitope expression was observed among normal muscle fibers with the two antibodies used. Smooth-muscle cells were unreactive for the two antibodies, whereas cardiac and a subgroup of skeletal muscle fibers were intensely stained by C219, but not by HYB-241. P-glycoprotein expression was observed in 23% of the 31 myogenic sarcomas analyzed. Our study was conducted mainly using adult myogenic sarcomas (28 out of 31 cases), with a few cases (three out of 31 cases) of childhood sarcomas. Nineteen tumors were leiomyosarcomas, seven cases were embryonal rhabdomyosarcomas, and five cases were rhabdomyosarcomas. We have considered expression of the mdr-1-coded P-glycoprotein when we observed either HYB-241 and C219 staining, or just HYB-241 immunoreactivities. Although P-glycoprotein expression can now be detected in human sarcomas, further studies are needed, mainly comparing tumor samples before, during, and after therapy, to establish the possible significance of the P-glycoprotein expression in clinical drug resistance.

Blood group antigens in normal and neoplastic urothelium.

Abstract: The ABO and Lewis blood group antigens are cell surface carbohydrate determinants formed by the sequential addition of saccharides to precursor backbone structures of membrane lipids and proteins. Suppression of normally active glycosyltransferases results in the absence of antigens that are normally expressed. ABH antigen deletion in malignant and premalignant urothelium has been extensively evaluated; it appears to correlate with significantly higher rates of tumor recurrence and disease progression. However, we have recently shown that the ABH blood group system is differentially expressed in the normal urothelium of secretors in contrast to nonsecretor individuals. The normal urothelium of nonsecretors does not express A, B or H determinants; therefore, deletion of ABH antigens can only be ascertained in secretor individuals. Although nonsecretors only comprise 22–24% of the population, this observation mandates a reevaluation of earlier studies. Deletion of A, B or H antigens is noted in carcinoma in situ (CIS), and in invasive and metastatic transitional cell carcinoma (TCC) of secretor individuals. Increased synthesis or activation of normally quiescent glycosyltransferases in bladder tumors can result in the expression of aberrant tumor-associated blood group antigens. Immunohistochemical analysis has demonstrated that Lewis X (Lex) is not detected in normal adult urothelium except for occasional umbrella cells. However, papillomas, CIS and TCC expressed Lex in 84% of cases, regardless of grade, stage, blood type or secretor status of the individual. The presence of Lex positive cells in bladder lavage specimens enhanced the detection of urothelial tumor cells, correctly identifying bladder tumors in 253/293 (86%) cases compared to a 63% sensitivity for cytology alone. The specificity of Lex immunocytology was 87%; 57 of 65 control subjects were negative for the Lex antigen. Furthermore, the detection of the Lex antigen in exfoliated bladder cells is a useful marker for predicting bladder tumor relapse in high risk, disease-free patients. All 17 Lex-positive patients recurred with clinical evidence of disease between 2 and 33 months (mean 8.4 month), while only 8 of 39 Lex-negative patients recurred; 31 patients remain NED (2–40 months, mean 16.2 months). © 1992 Wiley-Liss, Inc.

Cell surface differentiation antigens of normal urothelium and bladder tumors.

Abstract: Bladder cancer ranks as the third most common malignancy among men and tenth among women Superficial transitional cell carcinomas (stage Ta, Tis, and T1) account for approximately 70–40% of these tumors, while the remaining 20–30% are invasive (T2, T3, and T4) Approximately 70% of superficial tumors will have one or more recurrences, with 25% of these expressing a higher histologic grade and 10–15% subsequently developing invasive and/or metastatic disease The detection and prediction of tumor recurrence and/or tumor progression is crucially important if timely and appropriate therapy is to be instituted Conventional histopathologic evaluation usually provides definitive diagnosis upon which therapeutic planning is based However, at present there are no more reliable morphologic indicator to identify which individuals will have recurrent disease or who will progress to invasive and/or metastatic cancer Recent advances in tumor biology have identified markers that are good candidates for clinical applications in early tumor detection, as well as for the stratification of patients with like-appearing morphological lesions with different biological and clinical behavior The ultimate goal is to develop predictive assays that would segregate patients with high probability of failures versus patients who would be cured by localized modes of therapy