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Recent analysis of relapse data from 1173 untreated early stage breast cancer patients with 16-20 year follow-up shows that frequency of relapse has a double peaked distribution. There is a sharp peak at 18 months, a nadir at 50 months and a broad peak at 60 months. Patients with larger tumors more frequently relapse in the first peak while those with smaller tumors relapse equally in both peaks. No existing theory of tumor growth predicts this effect. To help understand this phenomenon, a model of metastatic growth has been proposed consisting of three distinct phases: a single cell, an avascular growth, and a vascularized lesion. Computer simulation of this model shows that the second relapse peak can be explained by a steady stochastic progression from one phase to the next phase. However, to account for the first relapse peak, a sudden perturbation of the development at the time of surgery is necessary. Model simulations predict that patients who relapse in the second peak would have micrometastases in states of relatively low chemosensitivity when adjuvant therapy is normally administered. The simulation predicts that 15% of T1, 39% of T2, and 51% of T3 staged patients benefit from adjuvant chemotherapy, partially offsetting the advantage of early detection. This suggests that early detection and adjuvant chemotherapy may not be symbiotic strategies. New therapies are needed to benefit patients who would relapse in the second peak.

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BACKGROUND: The commonly accepted theory of breast cancer metastatic development assumes continuous tumor growth from tumor seeding until documentation of clinical recurrence. In particular, Gompertzian growth kinetics is currently the theoretical cornerstone of the natural history of breast cancer, and has been widely utilized for planning treatments. MATERIALS AND METHODS: To verify agreement between findings and the implications of the continuous growth model, several published papers about the natural history of breast cancer after removal of the primary tumor were reviewed. Also, findings from animal models concerning metastasis biology were considered. RESULTS: The continuous growth model failed in important ways upon this critical reappraisal. As an alternative, the tumor dormancy hypothesis was considered to provide a more reasonable description of tumor recurrence. Moreover, primary tumor removal was revealed as a potentially perturbing factor for metastasis development. CONCLUSIONS: A new general outline of metastatic development of breast cancer incorporating tumor dormancy in specific micrometastatic phases, stochastic transitions between them, and start signals from surgery for micrometastatic growth was designed. The proposed model suggests new views concerning scheduling of current chemotherapy, new treatment approaches aimed at keeping micrometastases in a dormant state for the patient's entire life, and the careful reappraisal of the timing of surgery within the multimodal treatment of operable breast cancer.

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The breast cancer treatment failure rate remains unacceptably high. The current breast cancer treatment paradigm, based primarily on Gompertzian kinetics and animal models, advocates short-course, intensive chemotherapy subsequent to tumor debulking, citing drug resistance and host toxicity as the primary reasons for treatment failure. To better understand treatment failure, we have studied breast cancer from the perspective of computer modeling. Our results demonstrate breast cancers grow in an irregular fashion; this differs from the Gompertzian mode of animal models and thus challenges the validity of the current paradigm. Clinical and laboratory data support the concept of irregular growth rather than the common claim that human tumors grow in a Gompertzian fashion. Treatment failure mechanisms for breast cancer appear to differ from those for animal models, and thus treatments optimize on animal models may not be optimal for breast cancer. A failure mechanism consistent with our results involves temporarily dormant tumor cells in anatomical or pharmacological sanctuary, which eventually result in aggressive metastatic disease.

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Since adjuvant chemotherapy and hormonal therapy generally extend disease free survival in breast cancer rather than provide a cure, we have examined the current breast cancer paradigm. Heterogeneity is a fundamental characteristic of breast cancer tissue and a well recognized aspect of the disease. There are variations in natural history, histopathology, biochemistry and endocrinology, and molecular biology of cancer tissues and cells within the tissues. A variety of data indicate that growth kinetics are also variable, not only from tumor to tumor, but also during the natural history of an individual's tumor. To better understand kinetic heterogeneity, a stochastic numeric computer model of the natural history of breast cancer has been developed. To be consistent with inter- and intratumor kinetic heterogeneity and with late relapse, the model predicts that tumors grow in an irregular fashion with alternating periods of growth and periods of dormancy rather than the generally accepted modified exponential, or Gompertzian fasion. The prediction of irregular growth has been compared to data relevant to growth characteristics of human breast cancer. Much data support the concept of irregular kinetics and temporary dormancy rather than steady, Gompertzian growth of human breast cancer. Thus, in addition to drug resistance, kinetic heterogeneity may help explain the limited impact that traditional chemotherpeutic treatment has had on mortality from breast cancer. Although the mechanisms underlying irregular growth need to be better understood, non-Gompertzian growth kinetics indicates that there may be alternative approaches for breast cancer treatment.

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Mercury is released from dental amalgams, and therefore it is necessary to consider the biological and clinical consequences of such exposure. Intraorally, it would appear as though mercury can cause hypersensitivity/toxic reactions resulting in lichen planus lesions, and may play a major role in the pathogenesis of gingivitis, periodontitis and periodontal disease.

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Bone cell populations obtained by sequential digestion of newborn mouse calvariae remain morphologically heterogeneous despite well-documented biochemical differences. Fractionation of these populations on Percoll gradient reveal three major cell groups of low, intermediate, and high buoyant density (1.056, 1.070, and 1.095 g/ml) that are present in different ratios in early and late released populations. Cells of low and intermediate density dominate in early released populations. In contrast, late released populations contain mostly high-density cells. Basal levels of alkaline phosphatase are highest in cells of intermediate buoyant density. All cells respond to PTH with cAMP production and morphologic transformation, but biochemical responses to PTH, such as secretion of insulin-like growth factor I (IGF-I) and stimulation of alkaline phosphatase activity, occur mostly in cells of intermediate density. These data suggest that (1) subclasses of osteoblasts can be further separated by density and (2) PTH effects on alkaline phosphatase activity and IGF-I secretion are probably expressed by osteoblasts of a certain subclass and/or stage of development.

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It is generally accepted that human cancers grow in an exponential or Gompertzian manner. This assumption is based on analysis of the growth of transplantable animal tumors and on averages of tumor growth in human populations. A computer model of breast cancer in individual patients has raised some doubts about this assumption. The computer model predicts an irregular pattern of tumor growth that incorporates plateaus or dormant periods separated by Gompertzian growth spurts. Since growth patterns involving plateaus are not predicted by conventionally accepted exponential or Gompertzian kinetics, sufficient documentation of their existence may be regarded as some evidence that the computer model is correct. The literature has been surveyed to identify growth patterns specifically predicted by the model. The literature contains clinical evidence from individual patients of this growth pattern in primary breast, large intestine and rectum, and pulmonary cancers and metastatic pulmonary cancer. Much data, including the only breast data, are not consistent with exponential or Gompertzian kinetics but are explainable by irregular growth kinetics. Exponential growth is valid for some tumors and for short times, but there are many papers citing significant deviations from that growth. Exponential growth may accurately describe averages of human tumor growth and growth of multipassaged experimental tumors, but it is not valid for all individual tumors.

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A computer program which accepts clinically relevant information can be used to predict breast cancer growth, response to chemotherapy, and disease-free survival. The computer output is patient individualized because the program is highly iterative and simulates up to 2500 patients with exactly the same clinical presentation. Computer predictions have been compared to a broad spectrum of breast cancer data, and a high degree of correlation has been established. There are numerous significant clinical implications which can be derived from the computer model. Among these are the following. (a) Breast cancer tumors do not grow continuously but may have up to five growth plateaus each lasting from a small fraction of a year up to approximately 8 yr. (b) Adjuvant chemotherapy, such as 6-mo treatment with cyclophosphamide-methotrexate-5-fluorouracil, does not eradicate tumors but just reduces the number of viable cells by a factor of 10 to 100 and sets the eventual growth back by several years. This may partially explain why the age-adjusted death rate from breast cancer has not changed in the past 50 yr. (c) The computer model challenges the underlying principles in support of short-term intensive adjuvant chemotherapy, namely Gompertzian kinetics and genetically acquired tumor resistance to drugs. (d) The computer model questions the evidence opposing long-term maintenance chemotherapy protocols and suggests that maintenance protocols should be reexamined.

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An adenovirus type 2-transformed rat embryo brain cell line (F 17 A2AS) and two of its subclones (F 17 CI, F 17 C2) have been studied using chromosome banding and flow cytometric techniques. In determining the modal chromosome number, a bimodal distribution was observed in each of the cell lines. In each case the first numerical mode fell in the hypertriploid or hypotetraploid range while the second represented a mode in the hypertetraploid range. Analysis of Giemsa-banded karyotypes revealed the presence of several marker chromosomes. In most cases the origins of the markers could be established from their characteristics Giemsa-banding patterns. In particular, chromosome 2 was involved in the formation of several marker chromosomes. The DNA content analysis confirmed the bimodal chromosome distribution with values in the near tetraploid and near pentaploid range for each cell line.

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Murine fibrosarcoma cells can be separated into subpopulations by centrifugation through 10 to 35% Renografin density gradients. Previous work has shown that the heavier cell populations are rich in chronically hypoxic cells. In this study, each subpopulation was characterized for thymidine incorporation, thymidine transport, thymidine triphosphate pool sizes, and thymidine triphosphate specific activities. The heavier cell populations have less accessibility to exogenous thymidine, and they have lower endogenous pools of thymidine triphosphate and synthesize lower levels of DNA than do the lighter cell populations. However, if the cells are removed from the tumors and labeled with [3H]thymidine in vitro, all subpopulations synthesize DNA at similar rates. Two-parameter flow cytometry using acridine orange staining following partial acid denaturation of chromatin identified a small quiescent population in the most dense cell fraction, but the small number of these cells cannot account for the results of the biochemical studies. It appears that the hypoxic cells in the fibrosarcoma tumors are noncycling or slowly cycling, are in all phases of the cell cycle, and recover their ability to synthesize DNA when cultured under in vitro conditions.

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In order of decreasing potency, CdCl2 greater than HgCl2 greater than CoCl2 greater than CuSO4 greater than NiCl2 greater than ZnCl2 and PbSO4 slowed cell growth at concentrations ranging from 1 microM to 60 microM. Flow cytometry analysis of cell cycle position indicated that cell growth was selectively blocked in S phase by these concentrations. Water insoluble metals such as As, Ni, crystalline Ni3S2, crystalline NiS, crystalline Ni3Se2 and NiO also resulted in an S phase blockage of cells at concentrations of 1 to 10 micrograms/ml. The crystalline nickel sulfide and selenide compounds as well as As metal were the most potent of these. At higher concentrations blockage of cells in mitosis was also evident with a number of the water insoluble metal compounds. The potency of the metal compounds in blocking cells in S phase was related to their chemical reactivity and their uptake into cells. The S phase specific blockage produced by the metals examined was consistent with their genotoxic or carcinogenic activity since such activity indicated a selective interaction with DNA metabolism.

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Cultured mouse cells were tested for tumorigenicity in nude mice with both a conventional assay (injection of cell suspensions) and a new test involving implantation of cells grown on gelatin sponges. Sublines of Balb/3T3 cells, obtained from different sources, varied in their tumorigenic potential with either assay. One subline (A) formed distinctive precancerous nodules only in the sponge assay; these nodules often became progressive after a latent period of 3-4 months. However, suspensions of cells of this subline also caused tumors after a similar latent period, but no nodular phase preceded tumor formation. Another subline of Balb/3T3 (M) has failed to form tumors in either assay. The Balb/3T3 sublines did not differ in vitro properties, such as low saturation density, failure to grow in methylcellulose, and monolayer morphology. A second experimental approach involved tests on nude BALB/c mouse-embryo fibroblasts at various passage levels. The cells were passaged from primary culture, through crisis, to heteroploid, established cell lines. Tumorigenicity was demonstrable earlier in the sponge assay, at which time in vitro parameters putatively associated with malignant behavior were unchanged. Possible relationships with the in vivo phenomenon of solid-surface sarcomagenesis are discussed.

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Ploidy and cell cycle compartment distribution were measured by DNA flow cytometry in 261 patients with a variety of different tumors. Eighty-one percent of all tumors were aneuploid, and 72% were hyperdiploid. Ploidy levels spanned a wide range from hypodiploid (maximum 30% less than diploid controls) to hyperoctaploid (440% in excess of diploid controls) with a mean and median values coinciding at a near-triploid DNA content. The proportion of cells with G1 DNA content decreased with increasing hyperdiploid abnormality. While unrelated to biopsy site and to a number of host factors such as age, sex and race, both ploidy and cytokinetic parameters were markedly affected by histopathologic diagnosis. Patients with metastatic lung, breast and GI cancer had higher ploidy levels than individuals with the corresponding primary tumors. Ploidy (except for one patient) remained constant, and G1/100 proportions showed only minor variation by disease site and over a median observation time of 6 months. Prognostic factor analysis was performed in the subgroup of patients studied within 6 months from diagnosis. The adverse impact of low tumor G1/100 proportion on survival was lost as the proportional hazard analysis was extended to include diagnostic subgroups. Accounting for histopathologic diagnosis, stage of disease, ploidy, and the proportion of tumor G1/100 cells, the following sequence of adverse prognostic factors in order of their relative ranks was established: (1) absence of breast cancer (p=0.0001), (2) hypertriploid DNA index (p=0.049), and (3) presence of metastatic disease (p=0.079). Our study demonstrates that DNA content-derived information on instrinsic tumor cell features pertaining to cytogenetics and cytokinetics may provide an objective means of biologically relevant cancer classification.

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