Showing papers by "Bernard Fisher published in 1979"

Effect of Surgical Removal on the Growth and Kinetics of Residual Tumor

Abstract: Findings from this study using a transplantable C3H mammary tumor failed to indicate interaction relative to growth parameters between two foci present in the same host. Whether they were growing alone or in the presence of a second focus, tumor growth rates were similar until the combined mass of multiple tumors approached that which was incompatible with survival. Only then was a difference in growth observed. Cytokinetic parameters, i.e. , labeling index, primer-dependent DNA polymerase index or growth fraction, DNA synthesis time, tumor doubling time, and cell cycle time, were also similar whether tumors grew alone or in the presence of a second focus. Following removal of a tumor, changes were observed within 24 hr in the kinetics of the residual focus. There was an increase in labeling index (duration ⋍ 10 days) and primer-dependent DNA polymerase index with a decrease in the tumor doubling time. Minimal change was noted in DNA synthesis time and cell cycle time. The kinetic changes observed were reflected in a measurable increase in tumor size ⋍ a week following tumor removal. Absence of an alteration in DNA synthesis time and cell cycle time indicates that the increase in tumor growth was probably due to a conversion of noncycling cells in Go phase into proliferation. Relationship of the findings to the use of adjuvant chemotherapy is considered.

1‐Phenylalanine mustard (L‐PAM) in the management of premenopausal patients with primary breast cancer. Lack of association of disease‐free survival with depression of ovarian function

Abstract: Breast cancer patients participating in a prospective randomized clinical trial who were less than or equal to 49 years of age, had positive axillary nodes, and who received prolonged 1-phenylalanine mustard (L-PAM) as an adjuvant to mastectomy continue (after 4 years) to demonstrate a significantly greater disease-free survival (p = .007) than do patients who received placebo. Benefit was achieved in patients who were less than or equal to 39 years as well as those who were 40-49 years of age. Those in the younger age group showed a greater improvement in disease-free survival at 4 years relative to their controls (32% vs. 69%; p = .01) than did those in the older age group (48% vs. 61%; p = .09). When patients were examined relative to their nodal status, a highly favorable effect was found to have been achieved with L-PAM in those with 1-3 positive nodes (54% vs. 86%; p = .006). Results indicate that both age groups were benefited. When considered over time, they demonstrate that a relatively greater effect was achieved in the younger women. While L-PAM failed to significantly alter the disease-free survival of those with greater than or equal to 4 positive nodes a slightly better effect was achieved in the group less than or equal to 39 years. Since adjuvant chemotherapy has been found to be more effective in premenopausal than postmenopausal women, it has been presumed that decreased ovarian function, as a result of the chemotherapy, is responsible for the findings. To support or repudiate that concept, information regarding serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2), as well as menstrual function, has been obtained from women receiving L-PAM or L-PAM plus 5-FU therapy. In contrast to findings relative to disease-free survival, ovarian function and menses were most affected in patients 40-49 years of age. Amenorrhea occurred in 73% of patients in that age group and in only 22% of those less than or equal to 39 years (p less than .001). Similarly, a significant increase in LH and FSH and a decrease in E2, all indicative of ovarian suppression, was observed only in the older group of patients. Thus, it is concluded that while ovarian suppression may account for some of the adjuvant chemotherapeutic effect in premenopausal women, the dichotomy of findings in younger and older premenopausal women relative to therapeutic response and ovarian function indicates that other factors could be responsible.

Sounding board. Breast-cancer management: alternatives to radical mastectomy.

Abstract: The conclusions of the NIH consensus meeting on "The Treatment of Primary Breast Cancer" published in this issue of the Journal, deserve more consideration than mere acceptance or rejection depending on whether they support one's personal point of view. The report does not indicate the reasons for the conclusions, and they undoubtedly differed among the participants. I was a participant, and I should like to present my reasons for the recommendations and some personal thoughts about the meaning of the report. The recommendations that total mastectomy and axillary dissection should replace the Halsted radical mastectomy as the current treatment . . .

Further observations on the inhibition of tumor growth by C. parvum with cyclophosphamide. VII. Effect of treatment prior to primary tumor removal on the growth of distant tumor.

Abstract: The present investigations were directed toward determining whether primary tumor manipulation prior to its removal is advantageous for the control of metastases and survival. Studies were carried out to ascertain whether 1) there is justification for delaying surgical removal of a primary tumor to permit preoperative administration of cyclophosphamide (CY) and/or C. parvum (CP) and 2) there is an advantage to administering the immunotherapy directly into a primary tumor. After operation, in all investigations, systemic CP and CY was used. Despite the putative similarity of animals, tumors and treatment regimens there was marked variation in response of tumors to therapy. No benefit was derived from administering preoperative immunotherapy alone. When operation was delayed to employ systemic immuno-chemotherapy, a slight improvement in the control of distant tumor was noted. The employment of preoperative intratumor immunotherapy led to a greater prolongation of survival and more inhibition of distant tumor growth than did immediate primary tumor removal or the use of preoperative systemic immunotherapy. The results suggest that there may be an advantage to delaying removal of a primary tumor so that it may be employed in therapeutic strategies directed toward control of metastatic disease.

Effect of Corynebacterium parvum on liver proliferation and regeneration.

Abstract: The observation that Corynebacterium parvum (CP) administration results in hepatomegaly prompted us to investigate the effect of that agent on hepatocyte proliferation in normal and partially hepatectomized rat livers. Its i.v. administration to normal rats with intact livers resulted in a significant increase in liver DNA synthesis (tritiated thymidine uptake), total liver DNA, and liver weight, which were maximal at 4, 7, and 9 days, respectively. Both weight and DNA content remained elevated for at least 56 days after CP injection. Autoradiography carried out at the time of maximal DNA synthesis indicated that hepatocyte proliferation contributed substantially to the increased tritiated thymidine uptake. Histological examination of livers from treated animals revealed an increased number of Kupffer cells, macrophage granuloma formation, and focal areas of hepatocyte necrosis. When smaller doses of CP, which resulted in less extensive histological changes, were used, increases in liver DNA synthesis, DNA content, and weight were similar to those occurring after use of a larger dose. The effect of CP was compared with that obtained when other immunomodulators were used. If a second injection of CP was administered at the time when DNA synthesis was maximal or when it had nearly returned to control values, further stimulation of DNA synthesis failed to occur. When CP was given 1 day before or after partial hepatectomy, liver regeneration was greater than it was in untreated hepatectomized controls. Liver remnants at the time of partial hepatectomy were larger when CP had been administered 7 days previously than were those in untreated controls. Consequently, although liver weights at time of sacrifice were similar in the two groups, the percentage of regeneration was less in CP-treated animals. Such a finding further indicates that the hepatomegaly following CP is related to increased numbers of hepatocytes since liver regeneration is inversely related to the liver remnant following partial hepatectomy. While liver damage resulting from CP administration may be responsible for the liver regeneration observed, other factors have been considered.

The significance of concordance in mammographic interpretations

Abstract: Twenty-eight women participating in a screening program had a breast cancer diagnosed subsequent to the report of a negative mammogram which was read by only one of a group of radiologists. Fourteen occurred prior to a scheduled routine screening visit (interval cancers) and 14 were detected during such an examination. The negative mammograms from the 28 cancer patients, together with those from 120 women without cancer (controls) were independently reviewed by each member of a panel of three radiologists. Forty-six percent of the cancer cases and 5.8% of the controls were interpreted as positive by two or more of the radiologists. These findings suggest that agreement among several independent reviewers enchances the value and accuracy of mamography by reducing the number of false negative interpretations.

Cellular Cytotoxicity and Serum Inhibition in Normal Mice following Transfer of Xenogeneic Tumor-sensitized Cells

Abstract: Findings from previously reported investigations revealed that lymphoid and myeloid cells from tumor-bearing mice, when transferred to normal syngeneic mice never exposed to a tumor, imparted “information” which resulted in the production of tumor-specific cytotoxic cells by recipients. The present studies determined the cytotoxicity of cells from normal mice which were recipients of cells obtained from rats (xenogeneic) sensitized to mouse tumor. Normal rat lymph node cells (LNC) or spleen cells (SPC), when evaluated prior to their transfer, were found to be noncytotoxic to tumor target cells. LNC or SPC from rats sensitized to mouse tissue, either normal or tumor, were highly cytotoxic. Subsequent to the transfer of LNC or SPC from normal rats or from those sensitized to H-2 antigen (normal mouse tissue), little or no cytotoxicity was identified in LNC, SPC, or macrophages cultured from bone marrow cells of normal recipient mice. When the transferred cells were derived from rats sensitized to both H-2 and tumor antigen, i.e. , tumor cells, and the target cells were from the same tumor used for sensitization, maximal cytotoxicity was demonstrated in cultured macrophages, LNC, and SPC of normal mouse recipients. An increase in cellularity of recipient nodes, spleen, and bone marrow occurred following transfer of tumor-sensitized xenogeneic cells, unsensitized rat cells, or those cells sensitized to normal mouse spleen, indicating an equivalent recruitment of host cells by all types of xenogeneic cells transferred. The behavior of the recruited cells, i.e. , tumor cytotoxicity, was entirely dependent upon the use of tumor for sensitization of donor cells. Findings similar to those in the syngeneic system indicate that sera from normal cell recipients inhibit the cytotoxicity of cells derived from tumor-bearing animals. The findings indicate that information has been transferred by tumor-sensitized xenogeneic cells to normal animals that have never been exposed to tumor cells, which results in their production of tumor-specific cytotoxic cells. H-2-sensitized xenogeneic cells failed to produce such an effect. The relation of these findings to the use of xenogeneic cells for passive tumor immunotherapy is commented upon.