[Neoadjuvant chemotherapy MVAC in the treatment of infiltrating bladder carcinoma]. / Quimioterapia neoadyuvante MVAC en el tratamiento del carcinoma vesical infiltrante.

INTRODUCTION: Aiming to preserve the bladder in patients with infiltrative carcinoma of the bladder and to offer patients improved quality of life with no detriment for survival, a therapeutical protocol was set up. MATERIAL AND METHODS: Between August 1988 and January 1997 63 patients with stage T2 and T3a infiltrative carcinoma of the bladder, with no metastasis or node extension detectable with imaging techniques were treated in our unit. 45 of these patients met all protocol criteria and were given 3 neoadjuvant chemotherapy courses with MVAC (methotrexate, vincristine, adriamycin, cisplatin). INCLUSION CRITERIA: age under 75 years, Karnofsky greater than 50%, leucocytes greater than 2,500 cell/mL and platelet greater than 100,000/mL. Following chemotherapy, re-assessment was performed through lab tests, chest X-rays, abdomino-pelvic CT, bone scanning, cystoscopy, multiple randomized biopsies, tumoral bed scar resection and resection of relapsed urothelioma. Patients with complete remission were given radiotherapy. Those showing stabilisation of progression were proposed to undergo cystectomy. Fisher's test or chi 2 test were used for the comparison of qualitative variables. The survival analysis was performed using the Kaplan-Meier method. The curves comparison was done with Breslow's exact test. A Cox's proportional risk method allowed to calculate the relative risks together with their 95% confidence interval. RESULTS: 53.7% patients included in this protocol showed complete remission, 41.5% stable disease and 4.9% progression. 62.2% of patients were given radiotherapy versus 17.8% who underwent cystectomy. 20% received other therapies after rejecting both cystectomy or radiotherapy. Median follow-up was 43.38 months. Overall median survival was 96 months. The accumulate probability of survival at 4 years was 79%. 50% patients with complete clinical response relapsed during follow-up. Tumoral stage of those who relapsed was lower than the initial one in 63.7% cases, remained the same in 18.2%, and higher in 18.2%. With regards to grading, 66.7% patients had lower grading at relapse if tumour was initially grade 2. For those with initial tumour grade 3, only 20% had a lower grade. CONCLUSION: 64.4% patients retained their bladder. In 26.7% there was demonstrable metastatic disease. No differences were seen in the distribution or survival time based on the different treatment given after chemotherapy (p = 0.22). Patients with complete remission after chemotherapy have greater actuarial survival which is statistically significant (p = 0.04).

[Epidermal growth factor receptor (EGFR) in the prognosis of bladder carcinoma. Experience of 5 years]. / Receptor del factor de crecimiento epidérmico (EGFR) en el pronóstico del carcinoma vesical. Experiencia a 5 años.

METHODS: From November 1992 to November 1993, a prospective study was conducted on 20 controls and 61 patients with bladder carcinoma. EGFR expression was determined by radioimmunoassay and the correlation of the results of histological analysis and the clinical course was analyzed. The follow-up period was from November 1992 to July 1998. The association between qualitative variables and the x2 or Fisher exact test was compared using the hypothesis of the proportional ordinal trend for the ordinal variables, and the quantitative variables were analyzed using Student's t test and/or variance analysis (ANOVA). Survival was analyzed by the Kaplan-Meier method and comparison was performed using the Breslow exact test. The Cox proportional hazards regression model was utilized. The SPSS software for Windows 7.0 was used for the analysis. RESULTS: The EGFR values were higher for patients with bladder carcinoma than in controls (14.48 vs 2.54 fmol/mg of protein). EGFR values were higher in patients with superficial bladder tumor than in those with infiltrating tumors (27.03 fmol/mg vs. 10.05 fmol/mg of protein; p = 0.000). Poorly differentiated tumors showed higher values of EGFR (6.73, 14.48 and 17.07 fmol/mg of protein for grades I, II and III, respectively; p < 0.05). The EGFR values were higher in patients that died from cancer during follow-up (64.8) than in those who died from other causes (47.5) and those who are alive and on follow-up (42). An increase in EGFR values did not carry a risk of death from cancer (p = 0.1269; ns). Analysis of the grade of tumor differentiation showed that for the more aggressive tumor grade, a positive EGFR was a sign of reduced survival. Survival in patients with superficial and infiltrating tumor did not appear to change significantly according to the EGFR value. EGFR determination was not useful in predicting recurrence and increased EGFR values did not correlate with a higher risk of recurrence. CONCLUSIONS: 1) The normal pattern of EGFR could not be established. 2) EGFR was not useful in identifying subgroups at risk of death. 3) Knowledge about these proteins synthesized by oncogenes offers new possibilities in the treatment of cancer.

Quimioterapia neoadyuvante MVAC en el tratamiento del carcinoma vesical infiltrante / Neoadjuvant chemotherapy with MVAC in the treatment of infiltrative carcinoma of the bladder

INTRODUCCIÓN: Se inició este protocolo de tratamiento con intención de conservar la vejiga en los pacientes con carcinoma vesical infiltrante y, con ello, dar al paciente una mejor calidad de vida sin detrimento de su supervivencia. MATERIAL Y MÉTODO: Desde Agosto de 1988 hasta Enero de 1997 hemos tratado a 63 pacientes portadores de carcinoma vesical infiltrante en estadio clínico T 2 y T 3a sin metástasis ni diseminación ganglionar objetivables por técnicas de imagen. De estos 45 cumplieron estrictamente el protocolo y recibieron 3 ciclos de quimioterapia neoadyuvante MVAC (metotrexate, vincristina, adriamicina y cisplatino). Los criterios de inclusión fueron : edad menor de 75 años, Karnofsky mayor del 50 por ciento, recuento leucocitario mayor de 2.500 células/ml y plaquetas superiores a 100.000/ml. Se realizó reevaluación tras la quimioterapia mediante estudios analíticos, radiografía de tórax, CT abdominopélvico, gammagrafía ósea, cistoscopia, biopsias múltiples randomizadas, resección de la cicatriz del lecho tumoral o resección de urotelioma recidivado. Los pacientes con remisión completa recibieron radioterapia. A los que presentaron estabilización o progresión se les propuso cistectomía. La comparación entre variables cualitativas se ha realizado con el test de la ??2 o test de Fisher. Se realizó un análisis de supervivencia con el método de Kaplan-Meier. La comparación de curvas se realizó con el test exacto de Breslow. Un modelo de riesgos proporcionales de Cox permitió el cálculo de los riesgos relativos junto a su intervalo de confianza al 95 por ciento. RESULTADOS: De los pacientes incluidos en este protocolo mostraron remisión completa el 53.7 por ciento, estabilización el 41.5 por ciento y progresión el 4.9 por ciento. El 62.2 por ciento de los sujetos recibieron radioterapia, frente al 17.8 por ciento a los que se realizó cistectomía. El 20 por ciento recibió otros tratamientos por negarse a cistectomía o radioterapia. La mediana de seguimiento fue de 43,38 meses. La supervivencia global mediana fue de 96 meses. La probabilidad acumulada de supervivencia a los 4 años fue del 79 por ciento. De los pacientes que tuvieron respuesta clínica completa recidivaron durante el seguimiento el 50 por ciento. De éstos el 63.7 por ciento lo hicieron en un estadio menor que el tumor inicial, un 18.2 por ciento repitieron estadio y un 18.2 por ciento presentaron un estadio superior. En cuanto al grado el 66.7 por ciento de los pacientes presentaron un grado menor en la recidiva si el tumor inicialmente era de grado 2. Aquellos que inicialmente presentaron un grado 3 solo disminuyeron el mismo en un 20 por ciento de los casos. CONCLUSIONES : El 64.4 por ciento de los pacientes conservaron su vejiga. La enfermedad metastásica demostrable apareció en el 26.7 por ciento. No se observaron diferencias en la distribución en el tiempo de la supervivencia según los diferentes tratamientos administrados tras la quimioterapia (p=0.22).Los pacientes que presentan remisión completa tras quimioterapia tienen una mayor supervivencia actuarial que es estadísticamente significativa (p=0.04) (AU)

[P185 (Neu) oncoprotein in the prognosis of bladder carcinoma. Experience of 5 years]. / Oncoproteína P185 (Neu) en el pronóstico del carcinoma vesical. Experiencia a 5 años.

OBJECTIVE: To determine the utility of p185 oncogene in the biological characterization of transitional cell carcinoma and in the prediction of recurrence, and to analyze survival at 5 years mean follow-up. METHODS: A prospective clinical cohort study was conducted on 81 patients. Tissue specimens were obtained between November 1992 and November 1993. The study comprised two groups: nontumoral bladder tissue specimens from 20 patients (group I) and tissue specimens from 61 patients with bladder carcinoma (group II). p185 expression was determined by enzyme immunoanalysis (EIA). A statistical analysis of the results was performed. RESULTS: p185 oncoprotein levels were higher in patients with recurrence (1098.97 HNU/mg protein vs. 924.54 HNU/mg). Although higher levels of p185 were found in the patients that had died vs those who are alive, the differences were not statistically significant for overall survival or stratification by tumor grade or infiltration (p = 0.556; ns). CONCLUSIONS: Determination of p185 oncoprotein was found to be useful in the prediction of tumor recurrence at 5 years mean follow-up.

[Usefulness of p53 oncoprotein immunohistochemistry in the follow-up of bladder carcinoma: a 5-year study]. / Utilidad de la oncoproteína p53-IHQ en el seguimiento del carcinoma vesical: estudio a 5 años.

OBJECTIVE: Mutations in the TP53 gene are frequently detected in some types of malignant tumors (bladder, prostate, kidney, lungs, breast, colon and rectum). This study analyzed the utility of semi-quantitative determination of p53 in transitional cell carcinoma of the bladder by an immunohistochemical technique and evaluated the results at 5 years. METHODS/RESULTS: A prospective clinical cohort study was conducted on 81 patients. The study comprised two groups: nontumoral bladder tissue specimens from 20 patients (group I) and tissue specimens from 61 patients with bladder carcinoma (group II). In both groups the tissue specimens were obtained between November 1992 and November 1993, and during the follow-up period until July 1998. p53 expression was determined by a semi-quantitative method based on an immunohistochemical technique (NCL-p53-DO7, Novocastra). CONCLUSIONS: p53 oncoprotein was not found to be useful in the characterization of carcinoma of the urinary bladder.

[Quantification of p53 oncoprotein in bladder carcinoma: 5-year experience]. / Cuantificación de la oncoproteína p53 en el carcinoma vesical: experiencia a 5 años.

OBJECTIVE: Mutations in the p53 gene are frequently detected in some types of malignant tumors (bladder, prostate, kidney, lung, breast, colon and rectum). This study analyzed the utility of p53 quantitation in transitional cell carcinoma of the bladder and evaluated the results at 5 years. METHODS: A prospective clinical cohort study was conducted on 81 patients. The study comprised two groups: nontumoral bladder tissue specimens from 20 patients (group I) and tissue specimens from 61 patients with bladder carcinoma (group II). In both groups the tissue specimens were obtained between November 1992 and November 1993, including the follow-up period until July 1998. p53 expression was determined by a quantitative method based on immunoluminiscence (LIA-MAT p53). RESULTS: p53 expression was higher in bladder carcinoma than in healthy urothelial tissue; higher values of p53 were found for infiltrating and undifferentiated tumors. The p53 values were higher in patients with tumor recurrence than in those without (NS). The Bonferroni multiple comparisons test showed a higher mortality in patients with p53 > 0.9 than in patients who are alive or have died from other causes (p = 0.000). CONCLUSION: The results show that p53 LIA-MAT is an independent prognostic factor at a cutoff of 0.9 and permits identification of a subgroup of patients at high risk.

[Usefulness of P53 oncoprotein in urinary wash cytology: experience in patients with superficial bladder carcinoma]. / Utilidad de la oncoproteína p53 en citología urinaria de arrastre: experiencia en pacientes con carcinoma vesical superficial de vejiga.

OBJECTIVES: 1) To determine p53 expression in urinary wash cytology by immunohistochemistry in patients with superficial transitional cell carcinoma of the bladder and controls; 2) to correlate p53 in urinary wash cytology and anatomopathological characteristics of the bladder tumors analyzed; 3) to determine the utility of p53 expression in urinary wash cytology as a prognostic factor; and 4) to identify a subgroup of patients with superficial tumors of worse prognosis in order to improve control of the evolution of the tumor and treatment. METHODS: From 1993 to 1998, 141 cases were studied; 32 controls comprised group I and 109 (38 primary and 71 recurrence) patients with transitional cell carcinoma of the urinary bladder comprised group II. RESULTS: In group II, 29.5% were positive for p53 in urinary wash cytology, while no positive cases were found in group I. A total of 104 valid data were analyzed, which showed a higher percentage of p53-positive cases in grade III tumors (44.4%). Statistical analysis showed the percentage of p53-positive cases increased with tumor grade in a linear trend (p = 0.17). The recurrence rate in the p53-positive was 20% greater than in the p53-negative cases. Tumor progression was three times higher in the p53-positive than in the p53-negative patients. CONCLUSIONS: The application of biomolecular knowledge to cytology is a useful complement in follow-up of patients with superficial transitional cell carcinoma of the bladder and offers additional parameters to distinguish benign and malignant cells. Immunohistochemical determination of p53 in urinary wash cytology identifies patients with superficial tumors with a worse prognosis.

[New quantitative method for determining p53 protein in bladder carcinomas]. / Nuevo método cuantitativo para determinar la proteina P53 en carcinomas vesicales.

OBJECTIVE: To continue a study protocol on the molecular biology of bladder tumors, analyze protein p53 expression using a new quantitative analytical method and the biological implications of the changes in p53 expression. METHOD: From January, 1993 to January, 1995, 74 patients were studied. These patients were divided into two groups: the first group comprised 14 controls of urothelial tissue and the second comprised 60 cases of transitional cell carcinoma of the bladder. A quantitative method of immunoluminescence (LIA-mat p53 method) was utilized to analyze p53 expression. RESULTS: Tissue oncoprotein p53 was higher in patients with bladder carcinoma than in healthy urothelial tissue. Higher values of protein p53 was found in infiltrating and undifferentiated tumors and in those patients who died than in those who are alive. CONCLUSION: Protein p53 determination using this new quantitative method permits identification of subgroups of patients with tumors that have a more aggressive biological behaviour.

[The molecular biology of bladder carcinoma]. / Biología molecular del carcinoma vesical.

OBJECTIVE: The clinical course of transitional cell carcinoma of the bladder can be difficult to predict due to its potential to invade the muscle layer and/or develop to a high grade lesion. Bladder carcinoma can arise from genetic changes that may activate the oncogenes (-c-erbB2, c-erbB1, c-myc, ras, etc.) and/or inactivate the suppressor genes (p53, Rb). The aim of the present study is to continue a study protocol on the molecular biology of bladder tumors. METHODS/RESULTS: From January, 1993 to January, 1995, 85 patients were studied. These patients were divided into two groups: the first group comprised 14 controls of urothelial tissue and the second comprised 65 cases of transitional cell carcinoma of the bladder. p53 expression was determined by an immunohistochemical method (NCL-p53-DO7 monoclonal antibody). Quantification of the p8 oncoprotein in cytosol and EGFR (epidermal growth factor receptor) in membrane was performed by ELISA (Oncogene Science) and RIA (Vienna Lab), respectively. A statistically significant relationship between the expression of p53 and EGFR with tumor stage and grade was found. Quantification of p185 and EGFR showed higher values in the tumor tissue than in the control samples, but a worse survival could not be determined. CONCLUSIONS: The present study shows that p53 expression can be considered to be a prognostic factor. It provides useful information on the aggressive behaviour of the tumor and has a direct relation with the survival rates.

[Serum and tissue quantification of tissue polypeptide antigen (TPA) in transitional cell carcinoma of the bladder]. / Cuantificación sérica y tisular de antígeno polipeptídico tisular (TPS) en el carcinoma transicional de vejiga.

Tissue polypeptide antigen (TPA) is a marker of proliferative cellular activity. The aim of this paper is to demonstrate the production of this marker in bladder carcinomas and to study the biological behaviour in this type of patients. From September, 1992 to June, 1993, we studied 50 patients divided into two groups. The first group comprised healthy subjects and the second one comprised 30 patients with bladder carcinoma. In both groups, we determined the TPS in blood and tumoral tissue by RIA (TPS-IRMA Beki-Diagnostic AB). Our results demonstrated higher levels of TPS in tumoral tissue and blood than in healthy subjects (1887.83 and 197.33 vs 231.5 and 58.23 IU/ml) and higher levels of tissular and blood TPS for the undifferentiated tumors (989.66 and 231.5, 1748.2 and 210, 1842.6 and 219, 2010.7 and 220 IU/ml for Broders' classification 1, 2, 3 and 4).

[Role of growth factors in the etiopathogenesis of benign prostatic hyperplasia]. / Implicaciones de los factores de crecimiento en la etiopatogenia de la hiperplasia prostática benigna.

A comment is made on the role growth factors play on the regulation of prostate growth. These factors require the mediation of an specific membrane receptor to which they have to bind in order to exercise their action correctly. The objective of the present job is to carry out a comprehensive review of each and every growth factor involved in prostate growth: family of the epidermal growth factor, family of the beta-transforming growth factor, and family of the fibroblast growth factor. As a final conclusion, it should be mentioned that the two prostate growth-regulating factors more extensively studied and with greater etiopathogenic relevance in benign prostate hyperplasia, are the epidermal growth factor and, more particularly, the fibroblast growth factor.

[Determination of serum SCC antigen in transitional cell carcinoma of the bladder]. / Dosificación sérica de antígeno SCC en el carcinoma vesical de células transicionales.

The SCC antigen expresses in the squamous epithelium during the process of a neoplastic transformation. This paper's objective is to evaluate the biological behaviour of SCC antigen in surface, deep, localized and spread malignant vesical carcinoma. To this end, 100 patients divided in two groups were studied. The first group consisted in 30 healthy subjects strictly selected and the second group comprised 70 patients diagnosed with transitional cell vesical carcinoma. SCC Antigen measurement was made by Radioimmunoassay (RIA, Abbott). Our results suggest that this tumoral antigen has no use as a prognostic factor in patients diagnosed with transitional cells vesical carcinoma, since serum concentrations suffer no change in relation to size, extent and degree of tumoral differentiation.

[Usefulness of carcinoembryonic antigen in transitional cell carcinoma of the bladder]. / Utilidad del antígeno carcinoembrionario en los carcinomas vesicales de células transicionales.

Carcinoembryonic antigen (CEA), described by Gold and Freedman, was the first fetal tumor antigen isolated in tumor homogenates. The present study investigated the biological behaviour of CEA in superficial transitional cell carcinoma of the bladder, deep localized and disseminated. The study comprised 100 subjects; 30 carefully-selected healthy subjects comprised the first group and 70 patients with a diagnosed transitional cell carcinoma of the bladder comprised the second group. Serum CEA was determined by enzyme immunoassay (CEA, EIA, Roche). Our results suggest that serum CEA determination affords no diagnostic benefit in this type of malignant tumor.

[The usefulness of the carbohydrate antigen CA-50 in the prognosis of transitional-cell bladder carcinomas]. / Utilidad del antígeno carbohidratado CA 50 en el pronóstico en los carcinomas vesicales de células transicionales.

The carbohydrate antigen CA 50 is expressed in the epithelial tissue during the process of neoplastic transformation; i.e., transitional cell bladder carcinoma. The present study evaluated the biological behaviour of the CA 50 antigen in malignant superficial, deep localized and disseminated bladder tumors. One hundred subjects were entered into the study: 30 carefully selected healthy subjects comprised the first group and 70 patients with a diagnosed transitional cell bladder carcinoma comprised the second group. The serum CA 50 antigen was determined by immunofluorometric assay (Delfia CA 50 kit). Our results indicate that the carbohydrate CA 50 antigen can be utilized as a prognostic marker in patients with malignant bladder tumors. The serum antigen levels were higher for the more undifferentiated tumors and those in the advanced stages.

[Biologic behavior of human chorionic gonadotropin hormone (HCGH) in transitional cell carcinomas of the bladder]. / Comportamiento biológico de la hormona gonadotropina coriónica humana (HGCH) en los carcinomas vesicales de células transicionales.

Transitional cell carcinoma of the bladder carries a high rate of local recurrence and 15%-30% of the cases progress to advanced stages of the disease. The multiple forms of the tumor make it difficult to find reliable diagnostic elements of tumor evolution and some authors have advocated the use of tumor markers for the diagnosis and follow-up of malignant bladder tumors. This study was conducted to determine the biological behaviour of the HCG beta subunit it transitional cell carcinoma of the bladder. One hundred patients were entered into the study; the control group comprised 30 healthy subjects and the patient group comprised 70 cases of transitional cell carcinoma of the bladder. The results showed the HCG beta subunit increased with the size and degree of tumor infiltration, although the data were not statistically significant. Similarly, analysis of the degree of tumor differentiation/non differentiation provided no statistically significant data.

[Basic concepts in the use of tumor markers in the diagnosis and follow-up of malignant bladder neoplasms]. / Conceptos básicos en la utilización de los marcadores tumorales en el diagnóstico y seguimiento de las neoplasias vesicales malignas.

The absence of reliable diagnostic elements for the evaluation of malignant bladder tumors and the low sensitivity of the conventional diagnostic methods have prompted studies on the biological behaviour of this tumor type. The well known studies of Gold and Freedman and the recent investigations of Bates and Logo have proposed using tumor markers for early diagnosis and follow-up of different types of malignant tumors. However, the "ideal" tumor marker, one that is sufficiently sensitive and specific, has as yet to be discovered. We reviewed the tumor markers widely utilized to diagnose and follow-up malignant bladder tumors, and describe their main features. It must be pointed out that the lack of sensitivity and specificity of these tumor markers have led to the development of a new generation of tumor markers, such as cytogenetic markers, oncogenes, etc. Undoubtedly, this review of the literature will become obsolete with the advent of subsequent generations of tumor markers.