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Biomedical subjects

M N Harris

Publications and source records attributed to M N Harris.

At least 19 recordsLinked to original sources
PubMed1998

Irsogladine maleate inhibits angiogenesis in wild-type and plasminogen activator-deficient mice.

BACKGROUND: The activation of the zymogen plasminogen to the serine protease plasmin by urokinase-type (uPA) and tissue-type (tPA) plasminogen activators (PA) is an important event in a variety of physiologic and pathophysiologic processes in mammals. Enhanced PA activity occurs during angiogenesis and has been correlated in vitro and in vivo with increased tumor aggressiveness and is an indicator of poor prognosis in a variety of tumors in humans. Preliminary studies suggest that the antiulcer drug irsogladine maleate (IM) diminishes PA activity in vitro and may inhibit angiogenesis in vivo. To define the precise mechanism of angiogenesis inhibition by IM in vivo, we tested the ability of IM to blunt angiogenesis in a mouse cornea neovascularization model performed in wild-type and PA-knockout mice. METHODS: Three days prior to pellet implantation, groups of C57Bl/6 wild-type, uPA-deficient (upA-/-), and tPA-deficient (tPA-/-) mice received IM (300 mg/kg), IM (500 mg/kg), or vehicle (0.5% carboxymethylcellulose) via oral gavage. After 3 days of treatment, hydron polymer-coated pellets of sucrose aluminum sulfate containing 100 ng of basic fibroblast growth factor (bFGF) were inserted into surgically created pockets in the cornea of each mouse. On postoperative day 6, the neovascularization of each cornea was evaluated by a blinded observer using slit lamp microscopy and photographed. Angiogenesis was quantified by calculating vascular area (mm2) +/- SEM using a modified formula for a half ellipse that incorporates calibrated vessel measurements [Vessel length (mm) x Clock hours x pi x 0.2]. RESULTS: IM treatment (300 and 500 mg/kg/day) resulted in a dose-dependent reduction of angiogenesis in wild-type mice by 21 and 45.3% (P < 0.02, P < 0.001), in tPA-deficient mice by 42.6 and 46% (P < 0.001, P < 0.001), and in uPA-deficient mice by 27.2 and 46% (P < 0.05, p < 0.001), respectively. No quantitative differences in neovascularization were observed in either treatment group between transgenic mouse strains. No toxicity was noted in any group. CONCLUSION: IM inhibits bFGF-induced angiogenesis in wild-type, tPA-knockout, and uPA-knockout mice. The observation that IM significantly diminishes angiogenesis in both PA-deficient mice and wild-type mice suggests that the mechanism of action of IM may be independent of plasminogen activation.

Animals↗
PubMed1997

Poly(ADP-ribose) polymerase in human breast cancer: a case-control analysis.

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.

Aged↗
PubMed1997

Urokinase-type plasminogen activator-deficient mice are predisposed to staphylococcal botryomycosis, pleuritis, and effacement of lymphoid follicles.

Urokinase-type plasminogen activator (uPA) is thought to be an important mediator in the proteolytic degradation of extracellular matrix components observed in a wide variety of normal physiological and pathological conditions. However, the phenotype of a recently developed strain of urokinase-deficient (uPA-/-) mice appears to be normal when maintained under ideal nonstressful conditions. We report an outbreak of botryomycosis, an unusual staphylococcal infection, in a colony of uPA-deficient mice. A detailed histological examination of these uPA-deficient animals also revealed a variety of previously unreported phenotypic abnormalities such as pleuritis and the effacement of lymphoid follicles in the regional lymph nodes and spleen. Additional phenotypic abnormalities such as dystrophic calcifications and rectal prolapse were also observed in the uPA-deficient population. These abnormalities were also noted in ostensibly healthy uPA-deficient animals. Botryomycosis did not affect a colony of wild-type (uPA+/+) animals maintained concurrently under identical conditions in the same room. The peculiar predisposition of the uPA-deficient animals to this rare bacterial infection and the development of phenotypic abnormalities associated with the targeted disruption the uPA gene suggests that uPA contributes significantly to the cutaneous microenvironment and is additional evidence of the extensive involvement of the plasminogen activators in mammalian physiology.

Abscess↗
PubMed1996

Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient and wild-type mice: cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals.

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.

Animals↗
PubMed1996

Stereotactic fine-needle aspiration biopsy for the evaluation of nonpalpable breast lesions: report of an experience based on 2,988 cases.

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.

Adult↗
PubMed1996

The management of pigmented lesions of the nail bed.

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.

Adolescent↗
PubMed1995

Malignant melanoma. Primary surgical management (excision and node dissection) based on pathology and staging.

The diagnosis of malignant melanoma is based on clinical grounds and a properly performed biopsy, preferably excision, so that the type of melanoma and the thickness can be assessed by methods described by Clark and Breslow. These facilitate clinical and pathologic staging. Excisions with conservative margins for thin lesions (less than 1.0 mm in thickness) and more extensive margins for thicker lesions are appropriate. The issue of elective lymph node dissection is controversial. Most authors agree it is not indicated for lesions less than 1.0 mm thick and may offer little advantage for lesions greater than 4.0 mm thick. Several retrospective studies show a survival advantage in patients with "intermediate" thickness melanomas who may have occult nodal metastases. However, there are prospective randomized clinical trials supporting the concept that positive lymph nodes are a manifestations of systemic disease, and survival is equivalent in patients who have subsequent therapeutic lymph node dissections. A procedure using intraoperative lymphatic mapping and selective lymphadenectomy may identify those patients who are likely to benefit from lymphadenectomy.

Biopsy↗
PubMed1995

Improved survival of patients with melanoma with an antibody response to immunization to a polyvalent melanoma vaccine.

BACKGROUND: Melanoma vaccine treatment appears to slow the progression of melanoma in some patients, particularly in patients in whom it stimulates cellular antimelanoma immune responses. The relationship of vaccine-induced antibody responses to clinical outcome is less clear. The purpose of this study was to investigate the clinical relevance of antibody responses to melanoma vaccine immunization. METHODS: Eighty-two evaluable patients with surgically resected American Joint Committee on Cancer Stage III malignant melanoma were immunized to a partially purified, polyvalent, melanoma antigen vaccine. Antimelanoma antibodies were measured by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis before vaccine treatment and 1 week after the fourth immunization. RESULTS: Vaccine treatment induced or augmented antibody responses to melanoma in 32 (39%) of the patients. The antibodies were directed to one or more antigens of 38-43, 75, 110, 150 and/or 210 kDs, which previously have been shown to be expressed preferentially in cultured human melanoma cells. The median disease free survival of patients with a vaccine-induced antibody response to one or more of these antigens was 5.4 years compared with 1.4 years for nonresponders (P = 0.06), and 5-year overall survival was 71% compared with 44%, respectively (P = < 0.01). As determined by Cox multivariate analysis, the difference in overall survival was independent of disease severity or of immunologic competence as evaluated by ability to be sensitized to dinitrochlorobenzene. The difference in survival between antibody responders and nonresponders improved with time. CONCLUSIONS: The antibody response to vaccine treatment is an immune marker of vaccine activity that appears to be predictive of a later reduction in the recurrence of melanoma and is unrelated to the vaccine's ability to induce cellular immune responses. This finding suggests that vaccine treatment may be effective in slowing the progression of melanoma in some patients and that the protective effect is mediated partly by vaccine-induced antimelanoma antibodies.

Antibody Formation↗
PubMed1995

Sinus histiocytosis mimicking metastatic melanoma in lymph nodes of a patient with a large joint prosthesis: case report and review of the literature.

Malignant melanoma metastases to regional lymph nodes may be mimicked by several non-neoplastic processes, including sinus histiocytosis induced by fragments shed from joint prostheses. A patient who had an elective lymph node dissection for malignant melanoma and was found to have "post-prosthesis lymph node histiocytosis" resembling metastatic disease is described. Knowledge of the patient's past history of a total shoulder joint replacement along with the use of polarized light microscopy to identify birefringent particles of prosthetic debris allows for an accurate histologic diagnosis.

Aged↗
PubMed1994

Stereotactic aspiration biopsy of nonpalpable nodules of the breast.

To evaluate the reliability of stereotactic aspiration biopsy (SAB) in assessing which nonpalpable nodules of the breast should be excised, SAB was performed upon 373 nodules. The nodules were classified as well-circumscribed or irregular and evaluated for the presence of microcalcifications. The cytologic diagnoses were classified as malignant, atypical or benign. Cytologically malignant and atypical nodules were excised. Benign nodules were excised if there was a family or past history of carcinoma of the breast or if they changed mammographically. Twenty-five nodules proved to be malignant. Of these, the diagnoses by stereotactic aspiration biopsy were adenocarcinoma in 20 patients, atypical in three, malignant hemangiopericytoma in one patient and benign in one. The borders of the malignant nodules were well-defined in eight patients and irregular in 17. Three malignant nodules with irregular borders had clustered microcalcifications. One false-positive instance was a sclerosing papilloma with atypical hyperplasia. Twenty-four nodules with benign cytologic diagnoses, which were excised, proved to be benign. An additional 132 nodules with benign cytologic diagnoses had six month interval mammograms for two years; 131 were without interval change and one increased in size and proved to be a carcinoma. SAB is reliable for diagnosing nonpalpable nodules. Nodules with malignant and atypical results must be excised. It is reasonable to have follow-up evaluation of well-defined nodules mammographically when the aspirate is benign.

Adenocarcinoma↗
PubMed1993

The use of esmolol to attenuate the haemodynamic response when extubating patients following cardiac surgery--a double-blind controlled study.

We have assessed the cardiovascular changes associated with emergence from anaesthesia, reversal of neuromuscular blockade and extubation in a group of 14 patients immediately after coronary artery bypass graft surgery had been completed. Patients were randomly allocated to receive either esmolol 500 micrograms.kg-1 over 1 min followed by 100 micrograms.kg-1.min-1 or placebo starting prior to reversal. Significant hypertension and tachycardia occurred in the placebo group, whilst these changes were prevented by the administration of esmolol.

Adrenergic beta-Antagonists↗
PubMed1993

Fine needle aspiration biopsy in patients with augmentation prostheses and a palpable mass.

Six patients with augmentation prostheses presented with a firm, painless, breast mass that could not be visualized by mammography. One lesion was demonstrated to be solid by ultrasound, and the remaining sonograms were nondiagnostic. The lesions were indistinguishable from carcinoma, by physical examination. All of the patients had fine needle aspiration biopsy despite close proximity to the implant. The patients all had silicone granulomas related to silicone leakage. Our experience suggests that fine needle aspiration biopsy is a useful technique to evaluate palpable breast masses that are not visualized by mammography in patients with augmentation prostheses.

Biopsy, Needle↗
PubMed1993

Distinction between postsurgical changes and carcinoma by means of stereotaxic fine-needle aspiration biopsy after reduction mammaplasty.

Stereotaxic fine-needle aspiration biopsy (SFNAB) was performed to evaluate suspicious mammographic findings (31 stellate lesions, 20 regions of grouped calcifications, two nodules, and one area of prominent trabecular markings) in 54 patients who had undergone reduction mammaplasty. SFNAB findings were correlated with findings in histologic specimens whenever possible; the cytologic samples were classified as malignant, atypical, or benign. In 22 lesions, the abnormalities on mammograms were considered highly suspicious for malignancy. In the 32 others, the degree of suspicion was lower, but these lesions had a change in appearance since acquisition of the first postoperative mammogram. SFNAB enabled diagnosis of adenocarcinoma in five women. Patients who have undergone mastectomy with reconstruction of one breast and mammaplasty in the other are at higher risk for development of contralateral breast cancer, as are all patients who have had such cancer. SFNAB is reliable for evaluation of suspicious mammographic abnormalities that develop after mammaplasty and findings that change after acquisition of the first postoperative mammogram.

Adult↗
PubMed1992

Stereotactic localization for fine needle aspiration biopsy in patients with augmentation prostheses.

Fifteen patients with augmentation mammoplasties had mammography demonstrating nonpalpable breast lesions. Of the 15 patients, three (20%) had adenocarcinoma confirmed by open biopsy and histopathology. All patients underwent stereotactic localization for fine needle aspiration biopsy. Four of the 15 patients had benign cysts (26%). None of the cysts could be diagnosed by ultrasound. The remaining eight patients had mammary dysplasia of a proliferative or nonproliferative type of fibroadenoma. These benign entities were followed with interval mammography demonstrating no change. The data suggest that fine needle aspiration biopsy is an effective technique to assess nonpalpable breast lesions in patients who have had augmentation mammoplasties.

Adenocarcinoma↗
PubMed1992

Recurrent breast cancer: stereotaxic localization for fine-needle aspiration biopsy. Work in progress.

The efficacy of stereotaxic localization for fine-needle aspiration biopsy in the detection of recurrent cancer manifested as calcifications on mammograms was evaluated in 43 patients that had been treated with local resection and radiation therapy. Six patients had malignant aspirates and one had an atypical aspirate; examination of the surgical specimens revealed all seven of these to be malignant. Thirteen patients underwent surgical biopsies, the results of which were malignant in seven and benign in six. The remaining 30 patients were followed up with mammography. The follow-up mammograms were obtained at 6-month intervals and demonstrated no change in appearance. On the basis of this initial experience, stereotaxic localization for aspiration biopsy offers the potential to accurately distinguish benign from malignant lesions.

Adenocarcinoma↗