Faculty Bibliography

The importance of a genetic polymorphism (A/B allele) of poly(ADP-ribose) polymerase (PARP) pseudogene on chromosome 13q34-qter, and PARP enzyme activities in the development of human breast cancer were evaluated in a cancer case-control study. A total of 309 Caucasian women (> or = 50 years old) were evaluated for the PARP genotype, 70 of whom had histologically confirmed breast cancer, 128 women with benign breast diseases as study controls, and 111 reference controls. Age was significantly associated with case-control status (p < 0.0001), but family history of breast cancer, age at menarche, age at first live birth and parity were not. The frequency of the PARP B allele was similar in breast cancer cases (0.14), study controls (0.13), and reference controls (0.15). In a subset of 14 breast cancer cases and 32 study controls, the mean PARP enzyme activities (induced by H2O2 or oligonucleotide) were observed to be lower in cancer cases; an age-adjusted odds ratio of 3.40 (95% confidence interval = 0.70-19.54) for the below-median oligonucleotide-induced PARP was suggestive of an association. In subjects with the AB or BB genotype, the mean H2O2-induced PARP enzyme activity was significantly higher (p = 0.02, adjusted for case-control status and age) compared with that in subjects with the AA genotype. These findings indicate that: (a) the genetic polymorphism of the PARP pseudogene on chromosome 13 is not associated with the development of breast cancer in our study population; (b) oligonucleotide-induced PARP activity may be useful for identifying postmenopausal women at increased risk for breast cancer; and (c) there is a possible functional link between the genotype of the PARP pseudogene and enzyme activation

A critical requirement to use tumor antigens as vaccines is that they stimulate CD8+ T cell responses. In this study, we tested the ability of a shed, polyvalent, melanoma antigen vaccine to induce such responses to the melanoma-associated antigens, MAGE-3 and MART-1/Melan-A. Fifteen HLA-A2+ patients with resected malignant melanoma were immunized to the vaccine sc every 2-3 weeks x 4, and monthly thereafter. CD8+ T cells in peripheral blood reacting to HLA-A2 restricted epitopes on MAGE-3 (FLWGPRALV) and/or MART-1/Melan-A (AAGIGILTV) were quantitated directly using a filter spot assay at baseline and following 4 immunizations. Vaccine immunization induced CD8+ T cells reacting specifically to one or both of these antigens in 9 (60%) patients. These cells were CD8+ and HLA-A2 restricted, as reactivity was abrogated by monoclonal antibodies to CD8 and to class I HLA, but not by anti-CD4. The CD8+ T cells were specifically directed to these antigens, as they did not react to the same targets pulsed with a control HLA-A2 restricted peptide recognized by T cells. All responding patients remained recurrence-free during a follow-up of 12-21 months, whereas melanoma recurred within 3-5 months in non-responders. The differences in outcome were unrelated to differences in disease-severity or overall immunological competence between CD8+ T cell responders and non-responders. These results demonstrate that a polyvalent vaccine can stimulate a CD8+ T cell response to MAGE-3 and MART-1/Melan-A in humans, and suggest that the responses are protective and surrogate markers of vaccine efficacy. (C) American Society of Clinical Oncology 1997

Evidence suggests that the plasminogen activators (PAs), in particular urokinase-type PA (uPA), play a pivotal role in tumor invasion and metastasis. We studied the contribution of the PAs to the malignant phenotype through the chemical induction of melanocytic neoplasms in uPA-deficient mice. Primary tumors were induced and promoted concurrently in 35 uPA-/- deficient and 35 uPA+/+ wild-type mice using a single application of 7,12-dimethylbenz(a)anthracene followed by repetitive applications of croton oil. Animals were sacrificed at 60-day intervals for 1 year. At necropsy, the four largest pigmented lesions in each animal were excised, characterized histologically, and evaluated microscopically for evidence of invasion. The regional lymph nodes, lungs, and solid abdominal visceral organs were sectioned and examined microscopically for evidence of metastatic disease. Cellular blue nevi were induced in 100% of uPA-/- and uPA+/+ promoted animals. Although a reduction in the radial and vertical progression of these lesions was noted in the uPA-deficient mice compared with the wild-type group, more than 95% of cellular blue nevi induced in both groups of animals invaded the underlying tissues. These lesions did not metastasize to the regional lymph nodes. Malignant melanoma arose in 5 of 35 (14.3%) of promoted wild-type mice. These tumors were locally aggressive, produced tissue-type PA, but were not metastatic to the regional nodes, lungs, or abdominal viscera. These results indicate that the invasive capability of melanocytic lesions may depend more on tissue-type PA than uPA activity. No melanomas were induced in the uPA-/- mice. The resistance of the uPA -/- strain to melanoma induction suggests that uPA contributes to malignant progression. We propose that the absence of uPA negatively affects tumorigenesis by decreasing the liberation and availability of growth factors such as basic fibroblast growth factor

BACKGROUND: The increasing use of mammography has led to a significant increase in the detection of clinically occult lesions, the majority of which prove to be benign. SFNB has been suggested as a means of expediting a diagnosis for lesions that are malignant while limiting surgical biopsies for those that are benign. METHODS: Clinically occult mammographic lesions were assessed by SFNB in 2,988 patients. Definitive histologic diagnoses were made on surgical specimens in all instances in which the cytologic diagnosis was malignant, suspicious, or atypical. Patients with benign cytology were either followed with interval mammograms or underwent surgical biopsy. RESULTS: Two hundred ninety-one of the 295 lesions (99%) diagnosed as cancer via SFNB were confirmed by histopathology. Twenty-two of the 22 lesions (100%) that were diagnosed as suspicious were diagnosed on histopathology as malignant. Forty-three of the 70 lesions (61%) with cytologic atypia were diagnosed on histopathology to be malignant. CONCLUSIONS: SFNB is an accurate means of diagnosing carcinoma, but must be followed by surgical biopsy when the cytology shows atypia. For lesions diagnosed as benign by SFNB, close interval mammography is essential

Pigmented lesions of the nail bed, especially without a history of trauma, represent a diagnostic challenge to the clinician. These lesions are often categorized as melanonychia striata (MS), which refers to any linear tan-brown-black pigmentation of the nail bed. The differential diagnosis of MS includes subungual hematomas, onchomycosis nigricans, junctional nevi, melanoma in situ (MIS), and malignant melanoma (MM). Our algorithm at the New York University (NYU) Medical Center for the treatment of pigmented lesions of the nail bed is presented. A histopathologic diagnosis with any evidence of melanocytic atypia, however subtle, requires absolute confirmation by complete excision. The absence of a clear margin or recurrence requires total nail bed excision and reconstruction using a full-thickness graft. The diagnosis of MIS is similarly treated. The surgical management of subungual MM is discussed. All cases of MM of the hand treated at NYU were reviewed. In all, 30 patients were treated from 1982 to 1995. Follow-up ranged from 6 months to 13 years. In our series, there were 8 cutaneous and 22 subungual melanomas. There was a marked delay in treatment of both groups, with subungual melanomas more often erroneously treated as other pathology prior to correct diagnosis. The 5-year survival rate was 100% for patients with cutaneous lesions, but only 80% for those with the subungual variety. There was a statistical difference in the depths of the lesions (subungual, 3.68 mm; cutaneous, 1.36 mm) with a p-value of 0.008. The role of elective lymph node dissection in the absence of clinical metastases as well as intraoperative sentinel lymphatic mapping remains controversial and is discussed