Abstract. Clinical and morphological characteristics of I39 naturally occurring and 20 bracken-fern-induced urinary bladder tumors of cows were studied. Hematuria was prominent and occurred as early as 60 days after bracken fern feeding began. Anemia and changes in leukocytes were late manifestations. Papillomas appeared as early as 1 year, whereas invasive carcinomas did not develop until 2.6 years after initiation of feeding. Twenty of 30 cows fed bracken fern developed bladder tumors within 5.3 years. None of eight untreated control cows that lived 4 years or six that lived 10 years developed neoplasms. Naturally occurring and fern-induced bladder tumors were epithelial (35%) or mixed epithelial and stromal (55%). Papillomas occurred in 24% and carcinomas in 61% of naturally occurring cases, whereas there were papillomas (40%) and carcinomas (50%) in fern-fed cows. Naturally occurring tumors were metastatic to regional lymph nodes and lung. N o metastases were detected in fern-fed cows.

A variable but often significant proportion of urinary bladder cancer in urban areas can be attributed to occupational and cultural (cigarette smoking) situations associated with exposures to various arylamines. The variable N-acetylation of carcinogenic arylamines by human hepatic enzyme systems, the known genetic regulation and polymorphic distribution of this enzyme activity in humans, and the known enhanced susceptibility of individuals with the genetically-distinct “slow acetylator” phenotype to various arylamine toxicities, has prompted examination of possible correlations between N-acetyltransferase phenotype and urinary bladder cancer risk in rural and urban populations. In this context, N-acetylation is viewed as a component of detoxication pathways with respect to arylamine bladder carcinogenesis. In preliminary utilizations of this approach, a population of urban urinary bladder cancer patients from Copenhagen, Denmark displayed a 13% excess (p = 0.065) of individuals with the slow acetylator phenotype (46/71 = 64.8%) when compared to a Danish control population (38/74 = 51.4%). These data are consistent with the possibility that arylamines may play an etiological role in bladder cancer in this locale and that slow acetylator individuals may be at higher relative risk (1.74) than rapid acetylator individuals. As 95% of patients reported histories of smoking, it was not possible to isolate and examine smoking factors. In contrast, a population of rural urinary bladder cancer patients from Lund, Sweden, where bladder cancer incidence (20/100,000) (1971) is lower than in Copenhagen (43.8/100,000) (1968-72), no difference in slow acetylator distribution was observed between bladder cancer (80/115 = 69.6%) and Swedish control (79/118 = 66.9%) populations, indicating a relative lack of involvement of arylamines in the etiology of rural bladder cancer. Populations of “spontaneous” bladder cancer patients would be expected to contain variable portions of disease related to arylamine exposure and would be less likely to display a detectable correlation than would an industrial population with documentable arylamine exposure. Consequently, confirmation of this hypothesis is being pursued by examination of industrial populations in an effort to obtain an empirical estimate of relative risk for slow and rapid acetylator phenotypes. These studies involve exposure-matched workmen both with and without bladder cancer.

A method for initiating rapidly growing cultures of normal human transitional cells from ureter and embryonic bladder specimens has been developed and quantified. A new microdissection technique was used to nonenzymatically separate the urothelium. The use of enriched medium containing 10 micrograms/ml insulin, 5 micrograms/ml transferrin, and 1 microgram/ml hydrocortisone resulted in improved growth. The use of thin collagen gel substrates (0.6 ml/60 mm petri dish) resulted in 97% attachment of explants compared to 77% attachment on plastic. Explants grown on thicker collagen (2 ml/60 mm petri dish) showed, in addition to better attachment, enhanced growth of cells as determined both by measurements of colony size and cell density. Cultures of transitional cells that were initiated using explants could be passed three to five times using 0.1% EDTA for dispersion. Autoradiography of [3H]thymidine-labeled cells showed an initial phase of rapid cell division in primary explant cultures and restimulation of cell division in passaged cultures. Transmission electron microscopy showed that the cells growing out from the explants were continuous with the stratified urothelium maintained in the original explant. Stratification of transitional cells occurred in cultures of both ureter and embryonic bladder cells. Surface cells were joined near their apices by junctional complexes. Desmosomes and Golgi vesicles were present in all cells. Passage in culture did not alter the morphological characteristics of cells.

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Since 1964, 200 patients were treated with intra‐arterial 5‐FU infusion. Of them, 127 failed with intravenously injected 5‐FU, and 27 were unsuitable for such treatment as their involvement was so far advanced as to have jaundice due to extensive parenchymal involvement. In all but 12 patients, the catheter was placed percutaneously through the brachial artery. The criteria for improvement included at least a 6‐cm decrease in distance of the liver edge from the xiphoid or costal margin, a 50% decrease in the abnormal enzyme studies, a return of elevated bilirubin levels to normal so that jaundice disappeared, and all these responses continued for at least 2 months. Inpatients were treated with 5‐FU, 25 mg/kg/day × 4, then 15 mg/kg/day for 7 or 8 days. If no toxicity appeared, the 5‐FU was then increased to 20 mg/kg/day until the total infusion period was 21 days, and the catheter was removed. Outpatients received 500 mg daily in 140 ml 5% dextrose and 2,500 units heparin daily for 90 days, and then the catheter was removed. Following the termination of the infusion, the patient was given weekly intravenous doses of 5‐FU at 15 mg/kg. After several months, with reactivation of the disease, the intra‐arterial infusion was repeated. Minimal toxicity occurred, and there was one death from the procedure. Morbidity in the forms of infection and hemorrhage did occur, but, in the last 100 patients, there were only 2 minor infections. Of 113 study patients, 69 (61%) met our criteria of improvement and had a median survival of 8.7 months. Forty‐four (39%) failed, and their median survival was 2.5 months. This demonstrates a significantly increased survival in the responders.