Showing papers by "Samuel Hellman published in 1998"

Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin.

Abstract: Angiostatin, a proteolytic fragment of plasminogen, inhibits the growth of primary and metastatic tumors by suppressing angiogenesis. When used in combination with ionizing radiation (IR), angiostatin demonstrates potent antitumor synergism, largely caused by inhibition of the tumor microvasculature. We report here the temporal interaction of angiostatin and IR in Lewis lung carcinoma (LLC) tumors growing in the hind limbs of syngeneic mice. Tumors with an initial mean volume of 510 ± 151 mm 3 were treated with IR alone (20 Gy × 2 doses on days 0 and 1), angiostatin alone (25 mg/kg/day divided twice daily) on days 0 through 13, or a combination of the two as follows: ( a ) IR plus angiostatin (days 0 through 13); ( b ) IR plus angiostatin (days 0 and 1); and ( c ) IR followed by angiostatin beginning on the day after IR completion and given daily thereafter (days 2 through 13). By day 14, tumors in untreated control mice had grown to 6110 ± 582 mm 3 , whereas in mice treated with: ( a ) IR alone, tumors had grown to 2854 ± 338 mm 3 ( P b ) angiostatin alone, tumors had grown to 3666 ± 453 mm 3 ( P a ) IR plus longer-course angiostatin, tumors reached 2022 ± 282 mm 3 ( P = 0.036 compared with IR alone); ( b ) IR followed by angiostatin, tumors reached 2677 ± 469 mm 3 ( P > 0.05 compared with IR alone); and ( c ) IR plus short-course angiostatin, tumors reached 1032 ± 78 mm 3 ( P

Aging, progression, and phenotype in breast cancer.

Abstract: The malignant potential of cancer is dynamic, changing throughout the natural history of a tumor. For breast cancer, this is especially important because the clinical presentation has been altered by the increasing use of screening mammography. The varied outcomes of similarly staged patients is most consistent with breast cancer not being a homogeneous disease, but rather a spectrum of disease states that have varying capacities for growth and metastasis. Evolutionary pressures are at play in both tumor development and during the clinically apparent portion of the life of a tumor and are responsible for this spectrum of tumor heterogeneity. Required of tumors is the development of critical phenotypic attributes: growth, invasion, metastagenicity, and angiogenesis. The combination and permutation of genetic changes that result in the acquisition of these characteristics may vary, but they must result in some expression of each of these phenotypes. The expression of these attributes will differ as tumors evolve to become more adept at each of these characteristics. Recognizing tumor heterogeneity emphasizes the need to determine an individual tumor's place in the evolutionary spectrum. This may be accomplished using clinical features such as size, nuclear grade, and patient age, as well as by examining markers of angiogenesis, metastatic capacity, and proliferation. Identification of the extent of tumor progression with regard to these major tumor phenotypes should allow individual therapy to be fashioned for each patient.

Assessment of intratumoral vascularization (angiogenesis) in breast cancer prognosis.

Abstract: The search for prognostic markers is important both to identify those patients with occult metastases and also to spare chemotherapy in those patients whose tumors have not developed the capacity for distant spread. Angiogenesis, the formation of new blood vessels, is necessary for breast cancer growth and metastasis. Good correlation has been demonstrated between intratumoral vascularization and outcome in patients with breast cancer. Intratumoral vascularization in human breast cancer can be measured by using standard immunohistochemical methods. Strict guidelines for scoring need to be followed. Although attempts are being made to automate the reading, visual scoring remains superior. We studied a population of women with small node-negative breast cancer who received no adjuvant therapy and have a median follow-up of 15 years. We have found intratumoral vascularization, as measured by microvessel count, to be an independent prognostic factor for disease-free survival. Low microvessel count identifies a group of patients with a 20 year disease free survival of 93%. The proportion of women with low microvessel count decreases with increase in tumor size and increases with patient age. But even in mammographically detected nonpalpable breast cancer, that is, the smallest breast cancer we currently detect, the majority already have high microvessel count. Intratumoral vascularization appears to be an early event that is necessary but not sufficient for metastatic progression. Microvessel count seems to be an excellent marker to identify patients with good prognosis because those with low microvessel count have a 93% disease-free survival irrespective of size, grade, or estrogen receptor status, but is less good at predicting those at high risk since the 20-year disease-free survival is still 67-70% in those with high microvessel count. Thus, the higher risk group needs to be further stratified using additional prognostic factors.

The Relationship between nm23, Angiogenesis, and the Metastatic Proclivity of Node-negative Breast Cancer

Abstract: Distant metastases are the major cause of morbidity and mortality in women with breast cancer. The prediction of this metastatic proclivity is essential in determining prognosis and should allow an appropriate choice of therapy. A critical look at the metastatic process and its phenotypic expression offers an opportunity to identify some of the important events in the process that may relate to prognosis, with the goal of identifying those patients with occult metastases and also sparing systemic treatment in those patients whose tumors have not developed the capacity for distant spread. To evaluate the significance of nm23 and angiogenesis in the metastatic cascade, we used archival material from 163 node-negative breast cancer patients who had a median follow-up of 14 years. All patients underwent mastectomy and received no adjuvant chemotherapy or hormone or radiation therapy. Immunohistochemistry was used to detect nm23-H1 expression, whereas angiogenesis was determined by microvessel count (MVC). We found the 15-year disease-free survival (DFS) to be significantly better in patients with high nm23 compared with low nm23 (91% compared with 70%, P = 0.008). Low MVC is associated with excellent (92%) long-term DFS. In those patients with high MVC, high nm23 allows the identification of a subgroup with significantly higher DFS (90% compared with 66%, P = 0.02). Among high nuclear grade tumors, if nm23 is high, the DFS is significantly better (89% compared with 68%, P = 0.03). Thus, nm23 is still associated with excellent survival, even when there is unfavorable angiogenesis or nuclear grade. Multivariate analysis confirms that nm23 and MVC are important prognostic factors. High MVC appears necessary but not sufficient for metastasis to occur, whereas low nm23 may further contribute to metastatic progression. Both nm23 and MVC contribute valuable information in characterizing the malignant phenotype.

Race and the Will Rogers phenomenon in prostate cancer.

Abstract: PURPOSE: With the introduction of prostate-specific antigen testing, the "Will Rogers phenomenon"--stage migration associated with more sensitive diagnostic and staging procedures--seemed likely to occur. MATERIALS AND METHODS: Yearly values of prostate-specific antigen from 1988 to 1995 were determined for whites (n = 34) and African-Americans (n = 321). Pretreatment levels were used as objective surrogates of tumor cell burden. Changes in clinical stage and pathological grade by calendar year also were determined. RESULTS: There was a statistically significant yearly decline in levels of prostate-specific antigen for African-Americans (12.2% per year). There was no significant decline among whites. Similar trends were seen on multivariate analysis that adjusted for stage and grade. There was clinical stage migration for whites and African-Americans. There was also a shift in tumor grade for both whites and African-Americans. DISCUSSION: Over the past decade, African-Americans have shown a decline in tumor cell burden at the time of diagnosis as reflected by a decline in mean levels of prostate-specific antigen. For whites and African-Americans, there has been a shift to early clinical stages. The Will Rogers phenomenon, as demonstrated in African-Americans by decline in prostate-specific antigen and in whites and African-Americans by clinical stage migration, indicates lead-time and length biases, resulting in a more favorable disease profile at diagnosis for both groups. The decline in prostate-specific antigen among African-Americans indicates that the initial higher tumor cell burden seen in the past was caused by socioeconomic factors rather than inherited differences, and is likely to be ameliorated with widespread prostate-specific-antigen screening.

The benefits of mammography are not limited to women of ages older than 50 years.

Abstract: BACKGROUND Although the benefits of mammography are established in women age ≥ 50 years, its use in women age < 50 years is controversial. It is the purpose of this study to determine whether the better outcome in mammographically detected breast carcinoma compared with clinically detected breast carcinoma observed in women age ≥ 50 years also is observed in women age < 50 years. METHODS The authors analyzed 869 cases of Stage I and II breast carcinoma in women treated with breast-conserving therapy between 1984-1994. The median follow-up was 43 months (range, 3-128 months). Three hundred and eighteen patients (37%) presented with mammographic abnormalities without clinical signs of disease and 551 patients (63%) presented with clinical signs of disease. The median age of the patients was 56 years (range, 22-88 years). Three hundred and four patients (35%) were age < 50 years. RESULTS Mammographically detected tumors in women age < 50 years were of similar size to those in women age ≥ 50 years (median 1.1 cm vs. 1.0 cm). Axillary lymph node involvement and tumor grade were not significantly different between these two groups. However, in women age < 50 years the clinically detected tumors were found to be significantly larger, more likely to be axillary lymph node positive, and of higher grade compared with tumors in older women. Consequently, in patients with mammographically detected tumors, there was no significant difference in recurrence free survival (RFS) between women age < 50 years compared with women age ≥ 50 years (90% and 92%, respectively; P = 0.4), whereas in patients with clinically detected tumors there was a significant difference in 5-year RFS (77% vs. 87%, respectively; P = 0.02). CONCLUSIONS Mammography results in the diagnosis of smaller and lower grade breast carcinoma. If mammographically detected, there appears to be no difference in RFS between women age < 50 years and those women age ≥ 50 but there is a difference if the tumors are clinically detected. If left to grow to the size necessary for clinical detectability, the disease appears to be more aggressive in younger women. Cancer 1998;82:2221-2226. © 1998 American Cancer Society.