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Biomedical subjects

B Fisher

Publications and source records attributed to B Fisher.

At least 361 records · Page 20Linked to original sources
PubMed1976

Pathologic findings from the national surgical adjuvant breast project (protocol no. 4). II. The significance of regional node histology other than sinus histiocytosis in invasive mammary cancer.

The morphologic appearances of regional lymph nodes in radical mastectomy specimens obtained from 303 women entered into a prospective study of invasive breast cancer were categorized into patterns that have been considered to reflect immunologic function. An attempt was made to correlate these with 31 other histological and 8 clinical features, including short-term treatment failure (3 months to 4 years, average 24 months). No significant relationship to the latter was encountered. However, a lymphocyte predominance pattern was significantly associated with a stellate tumor border, absent cell reaction within the dominant tumor, absent sinus histocytosis of lymph nodes, combination tumor types, and a patient age of 55 years or more. A similar relationship between age of patient and sinus histiocytosis was found with the germinal center predominance pattern. In addition, this histologic appearance was associated with circumscribed tumors, severe cell reaction, and the infiltrating ductal carcinoma NOS and medullary types. Nodes with an unstimulated appearance were also found to be related to an absent cell reaction but marked sinus histiocytosis and a patient age of 45-54 years. Possible reasons for the differences between these findings and those of others relating prognostic value to such assessment of nodal histology is discussed, as are the findings of studies relevant to the identity of immunologic function with the morphologic appearance of nodal structure. The findings from this study fail to indicate any value of such nodal assessments as prognostic discriminants for breast cancer. Although longer periods of observation might alter this conclusion, such an event is regarded as unlikely.

Adenocarcinoma, Mucinous↗
PubMed1976

Pathologic findings from the national surgical adjuvant breast project. (Protocol no. 4). III. The significance of extranodal extension of axillary metastases.

One hundred fifty-eight patients with axillary nodal metastases recovered from radical mastectomy specimens for operable, invasive breast cancer were divided into those in whom such metastases were confined within the node and those in whom one or more nodes manifested extranodal extension. The relationships of these patterns to 33 pathologic and seven clinical features of these cases were investigated by contingency table analysis. Statistically significant associations (p less than .05) between extranodal extension of such metastases and short-term treatment failure, as well as the presence of four or more involved nodes, infiltrating ductal NOS histologic tumor type, stellate tumor border, and nipple involvement, were found. When the metastases were confined to the node there was a significantly greater likelihood that the cancers were either medullary or tubular histologic types. Associations with severe cell reaction and a nuclear grade of 1 were also found, but appeared to reflect the high frequency of medullary carcinomas in this group. The results suggest that evaluation of extranodal extension of axillary nodal metastases in patients with breast cancer may represent an important prognostic discriminant.

Breast Neoplasms↗
PubMed1976

Further observations on the inhibition of tumor growth by Corynebacterium parvum with cyclophosphamide. II. Effect of cortisone acetate.

Studies from this laboratory have demonstrated that the administration of cyclophosphamide (CY) and Corynebacterium parvum (CP) over a prolonged time to C3H mice with established measurable tumors resulted in complete arrest of tumor growth as well as partial and complete regressions in many instances. A study of the effect of two different doses of cortisone acetate (CA), administered two or five times weekly, on the tumor inhibitory properties of this chemoimmunotherapeutic regimen indicated that the addition of a corticosteroid to the CY-CP combination did not alter its tumor-inhibitory properties. There was no significant change when CA was administered with CP; however, tumor inhibition was enhanced to a degree approaching statistical significance when CA was added to CY at dose levels of 1.5 and 2.5 mg twice weekly. These results demonstrated that it may be possible in treatment of humans to administer a steroid in combination with a chemoimmunotherapeutic regimen without inhibition of the regimen's antitumor effects.

Animals↗
PubMed1976

Further observations on the inhibition of tumor growth by Corynebacterium parvum with cyclophosphamide. III. Effect of C. parvum on cyclophosphamide metabolism.

Results of investigations employing [14C]cyclophosphamide (CY) demonstrated that even though total plasma radioactivity was similar in female C3HeB/FeJ mice treated either with CY alone or Corynebacterium parvum and CY, the proportion of total activity due to nonmetabolized CY was greater when C. parvum was used. These findings indicated that the antitumor effect of C. parvum may not have been entirely due to its immunopotentiating properties but may also have been related to its effect on the metabolism of CY.

Animals↗
PubMed1976

Further observations on the inhibition of tumor growth by corynebacterium parvum with cyclophosphamide.

The cytotoxic macrophage was further characterized as an important effector cell in the inhibition of tumor growth. When we administered rifampin (a semisynthetic antibiotic that interferes with macrophage function but not viability) with Corynebacterium parvum and/or cyclophosphamide to tumor-bearing C3HeB/FeJ female mice, the tumor growth-inhibitory effects of the C. parvum were reduced. Moreover, when bone marrow cells from those animals were cultured, we found a marked decrease in the cytotoxicity of macrophages comprising clonies arising from colony-forming cells (CFC) in the bone marrow. Such findings supported our contentions that 1) the cytotoxic property of macrophages originates in ancestral stem cells or CFC in bone marrow, and 2) receptor sites of the CFC (or stem cells) that respond to a stimulus for self-replication probably differ from sites that when activated produce progeny with cytotoxic properties. Although the administration of rifampin resulted in macrophages virtually devoid of cytotoxic properties, both relative and absolute numbers of CFC increased.

Animals↗
PubMed1976

Characterization of mammotrophs separated from the human pituitary gland.

Human pituitary tissues from 27 patients and 7 persons post mortem were dissociated into single cell suspensions. On the average, 23% of the cells were mammotrophs. The concentration of prolactin in these suspensions averaged 3.8 ng/1,000 cells. After cell separation by velocity sedimentation at unit gravity, mammotrophs and other cell types were enriched twofold to threefold. The separated mammotrophs retained structural integrity at light and electron microscopic levels. In eight separation experiments, cells recovered from different gradient regions were assayed for intracellular prolactin levels. In cells from "normal" subjects, 8.5% of the prolactin recovered from the gradient was associated with large mammotrophs, whereas in patients with breast cancer, 28% of the hormone was associated with large mammotrophs. The number of mammotrophs recovered from this gradient region (beyond fraction 6) was doubled in breast cancer (2 expts). These mammotrophs showed areas of hypertrophied Golgi and endoplasmic reticulum. Culture of the separated cells from 1 patients with diabetes and 2 patients with breast cancer for 21 days showed that mammotrophs in the upper gradient fractions (diabetic) secreted seven times more hormone than those in the lower regions, whereas those mammotrophs from patients with breast cancer that fell to the lower gradient regions secreted 15 times more prolactin than did those in the upper regions. These data suggest that pituitaries of patients with breast cancer contain a small pool (10-20%) of hypertrophied mammotrophs that have the potential for significant secretory activity in vitro.

Adult↗
PubMed1976

Correlation of antitumor chemoimmunotherapy with bone marrow macrophage precursor cell stimulation and macrophage cytotoxicity.

The present investigations have assessed the effects of prolonged cyclophosphamide (CY) and Corynebacterium (CP) treatment on the production of bone marrow macrophage precursors [colony-forming cells (CFC)] and on the cytotoxicity of macrophages comprising colonies produced by the CFC. The findings have been correlated with tumor growth in animals receiving the immunochemotherapy. In addition, studies have been directed toward ascertaining whether the administration of CP with CY might lessen the myelosuppressive effects of the latter. Following each consecutive weekly dose of CY (even after as many as 11), there was a significant depression in the number of bone marrow cells (BMC's) but, by the next injection, marrow cellularity had returned to normal. When the number of BMC's was reduced, the proportion of the remaining cells, which consisted of CFC, was increased. Upon reconstitution of the marrow, the proportion of CFC returned to the level of the controls. The total number of CFC in marrow was at no time following CY therapy significantly less than the number in marrow of untreated mice. The addition of CP to the treatment regimen with CY resulted in an absolute as well as relative increase in CFC at all times during administration of the combined therapy, i.e., when there was a depression in total numbers of marrow cells, as well as when marrow restoration had occurred. Although CP stimulated the number of cells entering into differentiation, it failed to affect the total numbers of marrow cells, as well as when marrow restoration had occurred. Although CP stimulated the number of cells entering into differentiation, it failed to affect the total BMC's had been neither increased nor prevented from decreasing, by CP administration, indicating that the use of total cellularity as an index of the CP marrow-sparing effect is without merit. The present results relative to cytotoxicity of macrophages derived from the CFC concur with and extend our previous findings indicating that the cytotoxic property of macrophages originates in its ancestral stem cell or CFC and that factors responsible for increasing the CFC population do not selectively stimulate precursor cells responsible for production of the cytotoxic macrophage. Although the proportion of cytotoxic macrophages was not altered by CP when administered with CY, the absolute number of such cells was increased. Since the increase in macrophage colony production and, consequently, in cytotoxic macrophages correlates with increased inhibition of tumor growth when CP was used with CY, it is suggested that macrophage precursors are the cells of primacy in CP immunopotentiation. Their stimulation, resulting in enhanced cytotoxic macrophage formation, could be responsible for the inhibition of tumor growth observed in our model system. The findings also suggest that when myelosuppression is a limiting factor in the use of a chemotherapeutic agent, the concomitant use of CP may be advantageous.

Animals↗
PubMed1976

The effect of a growing tumor and its removal on the cytotoxicity of macrophages from cultured bone marrow cells.

Previous investigations by us have demonstrated that there is a significant but transient (4 to 14 days) increase of colony-forming cells (CFC) in bone marrow following implanation of a syngeneic mammary tumor in C3H mice. Those CFC gave rise to enhanced macrophage colony production when cultured in semisolid medium. The present studies have for the first time demonstrated that macrophages from the colonies were cytotoxic to cells from the immunizing tumor, and they continued to possess that characteristic for as long as a tumor was present in the animal from which bone marrow was derived. By 21 days after tumor removal cytotoxicity was no longer evident. The findings provide evidence to suggest that the cytotoxicity displayed by the macrophage originates in its ancestral CFC or in the antecedent stem cell. They also suggest that receptor sites of the CFC (or stem cell) that respond to a stimulus for self-replication are probably different from those sites that, when activated, result in cytotoxic properties of their progeny. The present findings also indicate not only that quantitation of macrophage production is of relevance in determining the efficacy of a therapeutic regimen but also that knowledge concerning the specific properties, i.e., ctytotoxicity, of such cells is of equal or greater importance.

Animals↗
PubMed1976

The effect of Corynebacterium parvum in combination with 5-fluorouracil, L-phenylalanine mustard, or methotrexate on the inhibition of tumor growth.

Previous reports from this laboratory have demonstrated conclusively that cyclophosphamide administered asynchronously with Corynebacterium parvum (CP) results in greater C3H mammary tumor inhibition than that observed with either agent alone. An analysis of this combination has revelaed that the chemotherapeutic component contributes more significantly to tumor inhibition than does the immunotherapeutic one. This study was conducted to investigate the inhibition of C3H mammary tumors by other chemotherapeutic agents when used with CP. The results have demonstrated that 60 mg of cyclophosphamide per kg, 90 mg of 5-fluorouracil per kg, and 10 mg of L-phenylalanine mustard per kg administrated weekly have similar tumor-inhibiting properties. The addition of CP enhanced the tumor-inhibiting properties of each agent but to differing degrees. The effect of the immunopotentiator when used in combination with alkylating agents was greater than that seen when it was used with the antimetabolite 5-fluorouracil. The tumor inhibition observed when cyclophosphamide was administered asynchronously with CP was significantly greater than that observed when L-phenylalanine mustard was similarly used. Of particular interest was the finding that the addition of CP to a combination of chemotherapeutic agents resulted in no greater tumor growth inhibition than that which occurred when CP was used along with the most effective single agent in the combination. The data have indicated that, contrary to clinical impression, there is no evidence that CP through its toxicity-sparing effect permits the utilization of larger doses of chemotherapy. Consideration has been given to the mechanisms that might account for the differences in tumor growth inhibition encountered when CP was used with different chemotherapeutic agents.

Animals↗
PubMed1975

L-Phenylalanine mustard (L-PAM) in the management of primary breast cancer. A report of early findings.

Prolonged l-phenylalanine mustard (L-PAM) administration as an adjuvant to mastectomy in the management of patients with primary breast cancer and pathologically positive axillary nodes was evaluated by a prospective, randomized, clinical trial. Treatment failures occurred in 22 per cent of 108 patients receiving placebo and 9.7 per cent of 103 women given L-PAM (p = 0.01). A statistically significant difference (p = 0.02) existed in favor of L-PAM relative to disease-free interval. In premenopausal women, the difference with respect to disease-free interval of treated and control groups was highly significant (p = 0.008). A treatment failure occurred in 30 per cent of premenopausal patients receiving placebo and 3 per cent of those treated with L-PAM (p = 0.008). Whereas a similar trend was observed in postmenopausal patients, the difference is not statistically significant. Thus, L-PAM has been demonstrated to be effective in the treatment of women with primary breast cancer, particularly those who are premenopausal. Results were achieved with minimal undesirable side effects.

Bone Marrow↗
PubMed1975

Inhibitory effect of prolonged Corynebacterium parvum and cyclophosphamide administration on the growth of established tumors.

The present study was carried out to investigate the effects of prolonged administration of C. parvum alone and in combination with cyclophosphamide for the treatment of established, measurable C3H tumors. The continued weekly administration of C. parvum by itself provided a limited but significant inhibitory effect on tumor growth and significantly prolonged survival. Intraperitoneal and intravenous administration was found to be more effective than the subcutaneous route. When C. parvum was administered asynchronously in combination with cyclophosphamide at weekly intervals a tumor growth inhibitory effect was achieved which was greater than that resulting from either agent along. Such an effect was consistently obtained and was seemingly independent of the sequence of drug administration. When cyclophosphamide preceded the initial C. parvum administration, arrest in the rate of tumor growth occurred, resulting in infinite tumor doubling time for the duration of observation (greater than 90 days). The combination of C. parvum and cyclophosphamide produced a more effective inhibition of tumor growth than did BCG and cyclophosphamide similarly employed. The importance of these findings relative to clinical application is considered. While the significance and genesis of the marked desmoplastic reaction characterizing tumors from animals treated with C. parvum and cyclophosphamide is at present speculative, consideration is given to the possibility that this could signify a host response against tumor growth.

Animals↗
PubMed1975

Pathologic findings from the National Surgical Adjuvant Breast Project (protocol no. 4). I. Observations concerning the multicentricity of mammary cancer.

Microscopic foci of multicentric cancer were detected in 121 of 904 breasts surgically removed for a clinically overt, invasive cancer. This incidence of 13.4% is regarded as a conservative estimate since examples of such lesions occurring in the same quadrant as the dominant mass, except in those instances in which the latter was present within the tail of the breast or beneath the nipple, were excluded from the analysis. Further, this data was obtained from only one randomly selected block of the quadrants, and in 41% of the cases only one or two were available for study. Multiple multicentric cancers were found in the same breast in two and three quadrants in 11.6% and 5.8% of the cases respectively. In 9.3% of the cases the multicentric cancers were designated as noninvasive (lobular in situ and/or intraductal) and in 4.1% invasive. An attempt to correlate the occurrence of multicentric cancers with a large number of pathologic and some clinical features disclosed a statistically significant association between multicentricity and grossly nonencapsulated dominant cancers with maximum diameters greater than 5 cm, the presence of a moderate or marked intraductal component and noninvasive cancer in its vicinity, and tumor involvement of the nipple. In addition, it was noted that there was a greater likelihood that the primary tumor was of the lobular invasive type and that the overlying skin was involved when the multicentric cancer was invasive rather than noninvasive. Lymphatic tumor emboli were observed in quadrants in 18 or 2.0% of the cases. Although the number of examples is small, nevertheless positive associations were noted with the occurrence of primary tumors that were in the left breast or beneath the nipple and were not grossly circumscribed, but exhibited a nuclear grade of 1, intralymphatic and blood vessel invasion, calcium, and involvement of the overlying skin as well as nipple. In addition, patients with such intralymphatic extension were more likely to have clinically detectable lymph nodes of which four or more contained metastases. The relationship of these findings to the rationale of such procedures as segmental resection in the surgical treatment of breast cancer is discussed.

Age Factors↗
PubMed1975

The pathology of invasive breast cancer. A syllabus derived from findings of the National Surgical Adjuvant Breast Project (protocol no. 4).

The inter-relationships of 32 pathologic and 7 clinical parameters encountered in the study of 1000 examples of invasive breast carcinoma have been presented. In some instances the biological significance of these associations is at present unclear. In others it is to be noted that there is no information provided as to the rank of their significance. Nevertheless, the associations that were encountered not only help further characterize the various forms of breast cancer but also provide information regarding the possible biological significance of some of their features. Although it is not our intention to minimize the possible significance of the inter-relationships of pathologic parameters, most emphasis in the summarizing statements which follow has been placed upon those correlations which may relate to prognosis. In this regard reference has been made to short-term treatment failure, vis a vis local recurrence and/or metastases, which may not necessarily accurately reflect patient survival, although generally such a relationship exists. Information in this regard as well as to the rank of the significance of these pathologic features shall be forthcoming when sufficient time has elapsed since the inception of this study to allow for such conclusions, i.e. survival or long-term treatment failure rates. Lastly, it becomes evident that the guidelines followed in the examination of these specimens appear to represent at least the minimum requirements necessary for a meaningful pathologic evaluation of breast carcinoma.

Adenocarcinoma, Mucinous↗
PubMed1975

Studies concerning the regional lymph node in cancer. VIII. Effect of two asynchronous tumor foci on lymph node cell cytotoxicity.

Results suggest that cytotoxicity by cells from nodes regional to a primary tumor is unique. While a primary tumor was present, A) cytotoxicity was displayed by cells from lymph nodes (RLNs) to that tumor, B) cells from nonregional lymph nodes regional (NRLNs) possessed lesser cytotoxicity which failed to increase in response to a second tumor focus in an area drained by those nodes, and C) the second focus attenuated cytotoxicity of cells from LNs regional to the primary tumor. Following removal of the primary tumor, cells from RLNs rapidly lost cytotoxicity and with passage of time were unable to regain that function in response to a second tumor focus. In contrast, cells from NRLNs demonstrated increased cytotoxicity at any time following removal of the primary tumor when exposed to a second focus. These observations suggest that nodes regional to a distant metastatic focus may be unable to react to it and thus contribute little to the host response generated by the primary tumor. In addition, since nodes regional to a primary tumor manifest diminished cytotoxicity in the presence of a distant tumor focus, tumor cells gaining access and lodging in those nodes subsequent to the development of other metastatic foci are likely to proliferate, resulting in the "positive" lymph node. The findings are in keeping with our contention that host factors responsible for metastases, and perhaps metastases themselves, are at least in part responsible for growth of tumor in RLNs. They also have relevance to the site of administration of specific immunotherapeutic agents and to the significance of the removal of RLNs with a primary tumor.

Amputation, Surgical↗
PubMed1975

Further observations on the inhibition of tumor growth by Corynebacterium parvum with cyclophosphamide. I. Variation in administration of both agents.

Studies from this laboratory have indicated that the administration of cyclophosphamide (CY) and Corynebacterium parvum (CP) over a prolonged time to C3H mice with established measurable tumors resulted in complete arrest of tumor growth as well as partial and complete regressions in many instances. The present investigations on optimal dosage, route, frequency, and sequence of administration of CY and CP in the model system were performed to obtain information that could be useful in the design of chemotherapeutic and immunotherapeutic regimens for the treatment of human tumors. Findings have suggested the need for administration of CP in more than one instance. Although a single dose of CP in combination with weekly injections of CY had a significantly prolonged inhibitory effect, weekly doses of CP and CY were more effective. We also concluded that the time between doses of an immunostimulating agent (I-I interval) as well as between administration of chemotherapy (C-C interval) may be critical for an optimal result. In this model system, C-C and I-I intervals of 7 days inhibited tumor growth most effectively. The time between administration of chemotherapy and immunotherapy (C-I interval) has been considered critical. Whereas slightly better results were achieved in these studies when the immunotherapy was administered 4 days after the CY or when the C-I interval was +4 days, almost equally good results were obtained when both agents were given on the same day, which signified that the C-I interval may not be as critical as other investigators have reported. The present findings confirmed and extended our prior observations and indicated that the iv and ip routes of administration were superior to the im and sc routes in our model. The observed tumor growth inhibition was a result of both chemotherapeutic and immunotherapeutic modalities; also, the inhibitory properties of the regimen were more related to the chemotherapeutic component. Finally, almost identical tumor growth inhibition was observed when CP obtained from two different laboratories was used in conjunction with CY.

Animals↗