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Using uniform systematic random sampling, we tested whether a drop in mitoses and PCNA (proliferation cell nuclear antigen) positive cells following a delay in tissue fixation of up to five hours, would be unequivocally discernible at the well perfused periphery from 11 aggressive rat adenocarcinomas. No statistically significant difference (0.05 < P < 0.10; 95% Cl (-13.3, 1.3)) was found. We attributed this finding to the high proliferative heterogeneity of rapidly growing solid tumors because: (1) vascular perfusion is heterogeneous as rapidly proliferating epithelial tumors tend to outgrow their blood supply; (2) the ratio of perfused/ non-perfused tumor volumes may change as a solid tumor grows, altering to the same extent the ratio of proliferative vs. non proliferative regions in the tumor; and (3) the duration of mitoses is not constant. The consequences for accurate tumor grading are discussed.

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Serial sections on biopsies of 26 women with invasive breast carcinoma were stained for low molecular weight keratins (LKER), high molecular weight keratins (HKER), epithelial membrane antigen (EMA), vimentin (VIM), carcinoembryonic antigen (mCEA and pCEA), and nuclear estrogen (mER) and progesterone receptors (mPGR), using monoclonal and polyclonal sera. Specified areas were identified on serially sectioned slides and staining reactions were compared among areas as well as among patients. The study concludes: (1) LKER staining was positively related to (a) the percentage of tumor cells with densely stained nuclei, (b) a trabecular mode of stromal invasion, and (c) HKER and EMA staining, and inversely related to (d) VIM staining and gross tumor size. (2) HKER was also inversely related to gross tumor size. (3) VIM staining was positively related to pCEA staining. (4) VIM staining was inversely related to staining ER and PGR. (5) LKER, HKER, and EMA staining was stronger in areas of trabecular rather than confluent areas of stromal invasion within the same biopsy. (6) Staining for ER and PGR was not related to mode of stromal invasion, but showed a strong inverse relationship with mitotic index. Positive staining for LKER may be an indicator of better differentiation together with densely staining nuclei and trabecular mode of stromal invasion, whilst VIM and pCEA appear to be related to features indicative of lack of differentiation. Hormone receptor positivity seems to be strongly related to mitotic activity rather than differentiation.

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The algorithm described here identifies concave and convex segments of a closed contour by vector algebra, thereby defining the shape of a two-dimensional object in multiple ways: (1) as a ratio of total concave vs. total convex periphery length, (2) as the number of convexity changes per unit of perimeter length (or number of lobes per contour), (3) as the mean +/- SD of convex and/or concave segment lengths, and (4) as a measure of the discrete curvature from a finite number of points on the contour. The algorithm can be used, in its capacity to distinguish regularity and amplitude of indentations ("wrinkles" and "lobes"), in studies where the number, regularity and magnitude of surface fluctuations are important differentiating morphologic characteristics of the object. This short algorithm can easily be integrated among other classic algorithms measuring periphery, area, shortest and longest diameter, and form factors derived therefrom. The possibility of automating this method makes it possibly useful for the discrimination of shapes by artificial vision.

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Two methods are described which measure invasion in solid tumors: 1) average tumor extension, i.e. the distance between the edge of the primary tumor mass and the furthest extension of tumor nests in the adjacent stroma, and 2) total surface of tumor exposed to stroma, obtained by multiplying the volume within 1 mm of the outer margin of the primary tumor by the stereologically derived ratio of tumor surface to its volume. These techniques are applied to a retrospective review of 73 consecutive cases of female breast cancer with known lymph node status and without distant metastases at the time of the original diagnosis. The study explores how these parameters discriminate 10-year survivors from non-survivors and compares them with other known significant parameters of tumor aggressiveness, i.e. axillary lymph node status, mitotic count, tumor diameter, tumor/desmoplasia ratio, necrosis/tumor ratio, gland space/tumor ratio, nuclear volume (= nuclear grade), and age at diagnosis. This study concludes: 1) Each parameter of invasion, adjusted in the analysis for lymph node status and mitotic count, emerges as statistically significant with low invasion in the primary tumor conferring a better prognosis than high invasion. 2) The associations low mitoses/low invasion, high mitoses/low invasion and low mitoses/high invasion tend to indicate a favorable 10-year survival, while the combination high mitoses/high invasion results in poor survival. 3) There was a greater percentage of high invasion cases in the LN > 0 subgroup compared to the LN 0 subgroup, suggesting that high invasion in the primary tumor predisposes to metastases, but this trend did not always reach statistical significance. 4) The proposed methodology offers a practical approach for measuring invasion in solid tumors.

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In a retrospective review of 76 consecutive cases of female breast cancer with no distant metastases at the time of the original biopsy, we compared how efficiently three different counting methods--mitoses/10,000 cells, mitoses/mm2 of tumor, and mitoses/10 high power fields (x 400)--would discriminate survivors from nonsurvivors 10 years after the original diagnosis. The effect was compared in subgroups of patients with different axillary lymph node status. The conclusions are that: (a) the methodology for counting mitoses is not trivial. Indeed, only mitoses/mm2 of tumor permitted prognostic predictions approaching overall statistical significance, at the exclusion of mitoses/10,000 cells, and mitoses/10 high power fields. (b) In each subgroup based on lymph node status, a low mitotic index in the primary tumor confers a better prognosis than a high mitotic index. (c) When comparing subgroups defined by increasing number of metastatic lymph nodes, one observes a gradually increasing proportion of patients whose primary tumor displays a high mitotic index, thus suggesting that a high mitotic index in the primary tumor predisposes to metastases. (d) A combination of lymph node status and mitotic counts offer a more refined ranking for risk of tumor recurrence than predictions based on lymph node status alone. (e) Although mitotic activity has a measurable impact on disease outcome of a patient population, it is paradoxical that counting mitoses is of disappointing prognostic value as a clinical tool. This is so because the method is not helpful in predicting outcome in those individuals whose disease will evolve contrary to the expectations conferred by their lymph node status.

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In an individual sensitized to an antigen, Withdrawal of the corresponding antibody and of the accompanying antigen-antibody complexes stimulates antibody production: the end result is thus not unlike the effect of a booster dose of that antigen. Conversely, a sufficient concentration of antigen-antibody complexes will eventually shut off the antibody production to that antigen. The body is able to regulate through this mechanism the amplitude of the immune response, using the feed-back interaction of antigen-antibody complexes with the immune system. Without such a control system any antigenic stimulation would result in an uncontrolled out-pouring of antibodies, as is observed in myeloma. The regulation of cell mediated immunity is also indirectly affected by the concentration of circulating antigen-antibody complexes. Other mechanisms of immunoregulation are also at work, using the mediation of so-called suppressor cells, identified as sub-populations of T and B cells acting both specifically and non-specifically on immune effectors cells. It is likely that a major factor contributing to the pathogenesis of some persistent chronic infections such as syphilis, brucellosis, chronic viral hepatitis, leprosy, vaccinia, congenital cytomegalovirus infection persisting in childhood, and so on, and in conditions such as cancer, is an inadequate initial production of antibodies, further aggravated by the ensuing immunosuppression brought about by the formation of antigen-antibody complexes. Antigen-antibody complexes have indeed been identified as playing a prominent role in some of these diseases. It is also suggested that the magnitude of the initial antigenic dose may influence the ensuing immune response: while a large antigen dose could induce a "classic" and efficient immune response, a low antigen dose, such as an incipient neoplasm, could result in a minimal antibody response, further suppressed by the appearance of antigen-antibody complexes. Through this mechanism, a premature failure to eradicate the disease would follow. I suggest that a significant and sudden lowering of the concentration of relevant entibodies and antigen-antibody complexes through exchange plasmapheresis, would trigger a fully adequate and therapeutic immune response. This possibility is discussed.

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