Ruth Heimann

Combined effects of angiostatin and ionizing radiation in antitumour therapy

Angiogenesis, the formation of new capillaries from pre-existing vessels, is essential for tumour progression. Angiostatin, a proteolytic fragment of plasminogen that was first isolated from the serum and urine of tumour-bearing mice, inhibits angiogenesis and thereby growth of primary and metastatic,, tumours. Radiotherapy is important in the treatment of many human cancers, but is often unsuccessful because of tumour cell radiation resistance,. Here we combine radiation with angiostatin to target tumour vasculature that is genetically stable and therefore less likely to develop resistance. The results show an antitumour interaction between ionizing radiation and angiostatin for four distinct tumour types, at doses of radiation that are used in radiotherapy. The combination produced no increase in toxicity towards normal tissue. In vitro studies show that radiation and angiostatin have combined cytotoxic effects on endothelial cells, but not tumour cells. In vivo studies show that these agents, in combination, target the tumour vasculature. Our results provide support for combining ionizing radiation with angiostatin to improve tumour eradication without increasing deleterious effects.

Should internal mammary nodes be sampled in the sentinel lymph node era

BackgroundControversy exists regarding internal mammary lymph nodes (IMNs) in the staging and treatment of breast cancer. Sentinel lymph node identification with radiocolloid can map drainage to IMNs and directed biopsy can be performed with minimal morbidity. Furthermore, recent studies suggest that IMN drainage of breast tumors may be underestimated. To gain further insight into the prognostic value of IMNs, we reviewed the outcome of patients in whom the IMN status was routinely assessed.MethodsA retrospective review of 286 patients with breast cancer who underwent IMN dissection between 1956 and 1987 was conducted.ResultsMedian follow-up is 186 months, age was 52 years (range, 21–85 years), tumor size was 2.5 cm, and number of IMNs removed was 5 (range, 1–22); 44% received chemotherapy, 16% endocrine therapy, and 5% radiotherapy. Presence of IMN metastases correlated with primary tumor size (P<.0001) and number of positive axillary nodes (P<.0001) but did not correlate with primary tumor location or age. Overall, the 20-year disease-free survival is significantly worse for the 25% of patients with IMN metastases (P<.0001). In patients with positive axillary nodes and tumors smaller than 2 cm, there was a significantly worse survival (P<.0001) in the patients with IMN metastases. This difference in survival was not seen in women with tumors larger than 2 cm.ConclusionsPatients with IMN metastases, regardless of axillary node status, have a highly significant decrease in 20-year disease-free survival. Treatment strategies based on knowledge of sentinel IMN status may lead to improvement in survival, especially for patients with small tumors. At present, sentinel IMN biopsies should be performed in a clinical trial setting.

Clinical Progression of Breast Cancer Malignant Behavior: What to Expect and When to Expect it

PURPOSE Seemingly localized breast cancer is a heterogeneous mix of truly localized cancers and cancers with occult metastases. Our purpose is to determine the parameters of metastatic proclivity for the different clinical presentations of operable breast cancer and to present quantitative prognostic information useful to both doctors and patients. PATIENTS AND METHODS A series of regionally treated breast cancer patients was analyzed to determine the likelihood and time of the appearance of clinical metastases for different clinical subgroups. Patients operated on at the University of Chicago from 1927 to 1987 for clinically regionally localized breast cancer, who received no systemic therapy as a part of their initial treatment, were included. Overall survival and distant disease-free survival in this mature series are analyzed. RESULTS Metastagenicity, the metastatic proclivity of a tumor, increases with both tumor size and nodal involvement. This is also true for virulence, which is the rate at which these metastases appear. Each clinical group has a cured population, even those with extensive nodal involvement. A table provides a tool for determining the proportion of risk expended in each clinical group as a function of the distant disease-free survival. Whereas the likelihood of metastasis increases with tumor size and nodal involvement, the time to their appearance decreases. CONCLUSIONS Breast cancer metastagenicity and virulence are heterogeneous even within clinically similar groups of operable breast cancer patients. Tumor progression is correlated with increasing tumor size and nodal involvement. Markers are needed to identify individual tumor virulence and metastagenicity.

The natural history of breast carcinoma in the elderly: Implications for screening and treatment

The authors evaluated the two indicators of metastatic proclivity (namely, virulence [V; the rate of appearance of distant metastases] and metastagenicity [M; the ultimate likelihood of developing distant metastases]) of breast carcinoma in elderly women. The authors then compared these characteristics with the corresponding characteristics in a cohort of younger women to determine whether breast carcinoma was more indolent in women age > 70 years, as is commonly believed in the medical community.

Race and clinical outcome in breast cancer in a series with long-term follow-up evaluation.

PURPOSE To compare the outcome of African American (AA) and Caucasian (C) breast cancer patients who had equivalent disease extent and were similarly treated. PATIENTS AND METHODS We compared prognostic characteristics, treatment, and outcome of 1,037 C and 481 AA breast cancer patients treated with mastectomy between 1946 and 1987. The median follow-up duration was 15.6 years. RESULTS During the study period, there was a successive increase in the percent of patients who presented with early breast cancer. Between 1980 and 1987, 35.1% AA versus 47.6% C patients had < or = 2-cm tumors and 50.0% AA versus 61.9% C patients were node-negative, while between 1946 and 1959, 27.7% AA and 31.3% C had < or = 2-cm tumors and 41.5% AA versus 40.4% C patients were node-negative. The treatments were similar during the study period. The 20-year disease-free survival (DFS) rate of AA compared with C patients with node-negative < or = 2-cm, 2.1- to 4-cm, and greater than 4-cm tumors and of patients with one to three and > or = four positive nodes was not significantly different. Equal-size tumors had similar proportion of positive axillary nodes in AA compared with C patients. The DFS for AA patients compared with C patients was similar in the periods 1946 to 1959, 1960 to 1969, and 1970 to 1979, but was lower between 1980 and 1987 (P = .02). In multivariable analysis, race was not a significant variable. CONCLUSION In this large group of uniformly treated breast cancer patients, race was not an independent factor that influenced outcome. The racial differences seen between 1980 and 1987 are likely because of a larger percent of greater than 2-cm and node-positive tumors in AA patients. Education and access to early diagnosis should reduce or eliminate the racial differences seen.

Individual characterisation of the metastatic capacity of human breast carcinoma.

The clinical implications of understanding the invasive and metastatic proclivities of an individual patients tumour are substantial because the choice of systemic therapy needs to be guided by the likelihood of occult metastasis as well as by knowing when the metastases will become overt. Malignant potential is dynamic, progressing throughout the natural history of a tumour. Required of tumours is the development of critical phenotypic attributes: growth, angiogenesis, invasion and metastagenicity. Characterisation of the extent of tumour progression with regard to these major tumour phenotypes should allow the fashioning of individual therapy for each patient. To examine the clinical parameters and molecularly characterise the metastatic proclivity we have been studying a series of regionally treated breast cancer patients who received no systemic therapy and have long follow-up. Clinically we describe two parameters: metastagenicity - the metastatic proclivity of a tumour, and virulence--the rate at which these metastases appear. Both attributes increase with tumour size and nodal involvement. However, within each clinical group there is a cured population, even in those with extensive nodal involvement, underscoring the heterogeneity of breast cancers within each group and the need for further molecular characterisation. Using biomarkers that characterise the malignant phenotype we have determined that there is progression in the phenotypic changes. Angiogenesis and loss of nm23 are earlier events than the loss of E-cadherin, or abnormalities in TP53. The strongest biomarkers of poor prognosis are p53 and E-cadherin, but even when both are abnormal 42% of node-negative patients are cured indicating that other determinative steps need to occur before successful metastases are established. Identification of these critical later events will further increase the efficacy of determining the malignant capacities of individual tumours.

Aging, progression, and phenotype in breast cancer.

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 tumors 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.

Defining negative margins in DCIS patients treated with breast conservation therapy: The University of Chicago experience

Abstract:  Management of ductal carcinoma in situ (DCIS) has been evolving and the majority of women are now being treated with breast‐conserving surgery and radiation therapy (i.e. breast conservation therapy [BCT]). Controversies still exist regarding the histologic features and margin status that are associated with local recurrence. The goal of this study was to review our institutions experience in patients diagnosed with DCIS and treated with BCT to determine pathologic features that can predict local recurrence, with particular emphasis on the final surgical margin status. We analyzed 103 consecutive patients with DCIS who were treated with BCT between 1986 and 2000. The slides were reviewed to determine the final margin status, type of DCIS, size of DCIS, nuclear grade, presence of necrosis and calcification, and volume of excised specimen. Margins were considered positive when DCIS touched or was transected at an inked margin. Negative margins were further categorized as close (less than 1 mm), 1–5 mm, and more than 5 mm. The size of the DCIS was determined based on either the maximal dimension on a slide or from the number of consecutive slides containing DCIS. Morphology and immunohistochemical profiles of the recurrent DCIS cases were compared with original DCIS. All patients were treated uniformly with external beam radiation therapy to the entire breast (median dose 46 Gy) with a boost to the tumor bed (median dose 14 Gy). The median follow‐up was 63 months (range 7–191 months). The actuarial 5‐year local control rate was 89%. The median time to local recurrence was 55 months. There were 13 local recurrences, of which 9 recurred as pure DCIS and 4 as invasive ductal carcinomas. Univariate analysis showed a significant association with local recurrence for positive margin (p = 0.008), high nuclear grade (p = 0.02), and young age at diagnosis (p = 0.03). If margins were negative, the 5‐year local control was 93%, as compared to 69% if margins were positive. A multivariate analysis showed that early age at diagnosis, positive margin status, and high nuclear grade were independently associated with local recurrence. The morphology and immunohistochemical stains of all nine recurrent DCIS were similar to those of the original DCIS. Breast conservation can be achieved with excellent local control by obtaining microscopically negative margins as strictly defined by DCIS not touching the inked surgical margins, and postoperative radiation that includes boost therapy to the tumor bed.

Volumetric visualization of anatomy for treatment planning

PURPOSE Delineation of volumes of interest for three-dimensional (3D) treatment planning is usually performed by contouring on two-dimensional sections. We explore the usage of segmentation-free volumetric rendering of the three-dimensional image data set for tumor and normal tissue visualization. METHODS AND MATERIALS Standard treatment planning computed tomography (CT) studies, with typically 5 to 10 mm slice thickness, and spiral CT studies with 3 mm slice thickness were used. The data were visualized using locally developed volume-rendering software. Similar to the method of Drebin et al., CT voxels are automatically assigned an opacity and other visual properties (e.g., color) based on a probabilistic classification into tissue types. Using volumetric compositing, a projection into the opacity-weighted volume is produced. Depth cueing, perspective, and gradient-based shading are incorporated to achieve realistic images. Unlike surface-rendered displays, no hand segmentation is required to produce detailed renditions of skin, muscle, or bony anatomy. By suitable manipulation of the opacity map, tissue classes can be made transparent, revealing muscle, vessels, or bone, for example. Manually supervised tissue masking allows irrelevant tissues overlying tumors or other structures of interest to be removed. RESULTS Very high-quality renditions are produced in from 5 s to 1 min on midrange computer workstations. In the pelvis, an anteroposterior (AP) volume rendered view from a typical planning CT scan clearly shows the skin and bony anatomy. A muscle opacity map permits clear visualization of the superficial thigh muscles, femoral veins, and arteries. Lymph nodes are seen in the femoral triangle. When overlying muscle and bone are cut away, the prostate, seminal vessels, bladder, and rectum are seen in 3D perspective. Similar results are obtained for thorax and for head and neck scans. CONCLUSION Volumetric visualization of anatomy is useful in treatment planning, because 3D views can be generated without the need for segmentation. When relationships among anatomical structures, rather than geometric models of them, are important, volume rendering presents advantages. The presented algorithm is readily adaptable to distributed parallel implementation on a network of heterogeneous workstations.

Does the number of lymph nodes examined in patients with lymph node-negative breast carcinoma have prognostic significance?

There are conflicting data on the prognostic significance of the number of lymph nodes examined in patients with lymph node‐negative breast carcinoma. Therefore, the authors analyzed the impact of the number of tumor‐free axillary lymph nodes on disease‐free survival (DFS) in two distinct patient populations.