The PTEN/MMAC1 gene on chromosome 10q23 encodes a lipid phosphatase with tumor-suppressive properties. Germline PTEN/MMAC1 mutations have been implicated as the predisposing factor in Cowden disease and other hamartoma syndromes, and somatic mutations and deletions have been identified in a wide range of human cancers, including 30-40% of metastatic melanoma cell lines. To study further the possible role of PTEN/MMAC1 in the pathogenesis and progression of malignant melanoma, we examined uncultured specimens from 16 primary and 61 metastatic tumors from 67 patients. Denaturing gradient gel electrophoresis was used to analyze systematically the coding region of PTEN/MMAC1 and revealed mutations in four of the metastatic samples (7%). Sequence analysis of the mutants identified a 1 bp frameshift insertion, a 2 bp frameshift deletion, an 11 bp frameshift deletion, and a single base substitution resulting in the generation of a premature stop codon. Analysis of two intragenic polymorphisms showed allelic loss in three of eight informative primary tumors (38%) and in 18 of 31 metastatic tumors (58%). One of the mutant cases showed allelic loss, suggesting that both PTEN/MMAC1 alleles were inactivated in this tumor. Altogether, these results suggest that mutation and deletion of PTEN/MMAC1 may contribute to the development and progression of malignant melanoma.

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The presence and distribution of Factor VIII related antigen (FVIIR:Ag) in formation fixed, paraffin embedded tissue were studied in benign and malignant vascular tumors, inflammatory vascular diseases, normal tissue from various organs and a number of malignant tumors. The unlabeled peroxidase-anti-peroxidase method was utilized. Immunostaining was observed only in endothelial cells, in tumor cells of endothelial cell origin and in megakaryocytes and platelets. The staining method gave a distinct picture of the vascular pattern in all types of tissue examined. The demonstration of FVIIIR:Ag by means of the immunoperoxidase technique is considered a valuable method in diagnosing tumors of vascular origin. The method also facilitates detection of vascular invasion of malignant tumors in small caliber vessels.

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We observed nine cases of transitional-cell carcinoma of the urinary bladder among patients who had had long-term treatment of other cancers with cyclophosphamide. Seven of the bladder carcinomas occurred within a cohort of 471 patients treated for non-Hodgkin's lymphomas. In this cohort the relative risk of bladder cancer was 6.8 (95 percent confidence interval, 3.2 to 14.2). The cumulative risk (mean +/- SE) was 3.5 +/- 1.8 percent 8 years after the start of treatment with cyclophosphamide and 10.7 +/- 4.9 percent after 12 years. Three of the nine patients were 50 years of age or younger; seven died with progressive bladder cancer. Subsequently, an additional patient had acute nonlymphocytic leukemia. Hemorrhagic cystitis was observed in 33 patients (cumulative risk, 11.8 +/- 2.1 percent after five years). Development of carcinoma of the urinary bladder was not related to previous hemorrhagic cystitis. The results caution against long-term treatment with cyclophosphamide for diseases with a favorable prognosis.