Biomedical subjects
Publications and source records attributed to B Fisher.
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In this laboratory, it has been repeatedly demonstrated (using a murine mammary tumor model) that the combination of cyclophosphamide (CY) and Corynebacterium parvum (CP) is more effective than either agent alone in the control of tumor growth. This paper presents information obtained in our model comparing findings on the effects of CP with a Brucella abortus extract (Bru-Pel; BP) and glucan (GL) on tumor growth. In addition, the influence of those agents as well as bacillus Calmette-Guérin, tilorone, and levamisole on bone marrow macrophage colony production and cytotoxicity is presented. None of the nonspecific stimulating agents (NSSAs) inhibited tumor growth when administered systemically without CY, confirming our previous contention that such immunotherapy alone is likely to be an ineffectual form of treatment. Whereas tumor regression was observed following intratumor CP, neither GL nor BP had such an effect. When used with CY, neither BP nor GL administered ip or intratumorally inhibited tumor growth as effectively as did CP and CY. Inhibition of the growth of a distant tumor as well as the treated tumor occurred following intratumor CP and CY but not following intratumor BP and CY. All of the microbial NSSAs increased macrophage colony production to varying degrees in both normal and tumor-bearing mice. In the latter mice, CP had the most prolonged effect. Levamisole and tilorone failed to increase colony production in normal mice while in tumor-bearing mice the effect was inversely proportional to the amount of agent administered. To some extent, the stimulation of colony production by the NSSAs paralled the degree of tumor inhibition observed when those agents were combined with CY. The cytotoxicity of cultured macrophages could not be related to tumor growth inhibition.
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Nineteen individuals are reported who represent nine familial instances of various immunopathies. Multiple myeloma was diagnosed in 10 members of five families, lanthanic (idiopathic) paraproteinemia in five members of two families and either myeloma or lanthanic paraproteinemia in four members of the remaining two families. The parent-child relationship occurred in three instances, siblings were affected in three, and first cousins in three families. Immunochemical studies revealed IgG paraprotein in nine cases; IgA in three; IgMl type in three subjects belonging to the same family; Bence-Jones protein in one case and biclonal paraproteinemia, IgGk plus IgAl in one. Three individual cases of lanthanic paraproteinemia, discovered in a prospective study of 76 relatives of subjects with immunopathies, suggest that there may be a higher frequency of immunopathies among family members than observed in the general population of comparable age. The published reports on familial paraproteinemias are reviewed..
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Attention is directed to an apparently unique form of invasive breast cancer designated as tubulolobular invasive cancer. These neoplasms exhibit small tubules as well as cords of neoplastic cells in a lobular configuration reminiscent of lobular invasive carcinoma. The clinical and pathologic characteristics encountered in 24 examples were statistically compared with those of infiltrating ductal carcinomas without special specific features, pure tubular, and pure lobular invasive cancer. The results of these analyses as well as the morphologic characteristics of these lesions prompt the conclusion that this lesion represents a tubular variant of lobular invasive carcinoma. Short term treatment failure rates in patients with tubulolobular invasive carcinoma are intermediate between those of pure tubular cancer and lobular invasive carcinoma.
The biologic nature, diagnostic features and therapeutic management of patients with lobular carcinoma in its in situ and invasive forms are discussed. Although recorded studies emphasize that patients with lobular carcinoma in situ are "at risk" for the development of invasive cancer, it has not been unequivocally demonstrated whether such an event represents a persistence of cancer due to inadequate excision or a de novo lesion. In support of the latter is the contention that lobular carcinoma exhibits a propensity for multicentricity and bilaterality. The recognition that the histologic types of the subsequent invasive cancers are not universally lobular invasive might also be cited in this regard. This information also bears upon views purporting a stepwise development of lobular invasive carcinoma from its in situ analog. Analysis of our own material fails to confirm any significant association between invasive lobular carcinoma and multicentric lesions. The diagnostic difficulty in distinguishing lobular hyperplasia from in situ lobular carcinoma and the inadvisability of frozen sections for this purpose is noted. Although the results of some electron microscopic studies of the in situ lesion challenge the propriety of its "pure in situ" nature; this criticism does not appear valid from both a pathological as well as pragmatic standpoints. The various schemes have been proposed concerning the surgical management of patients with lobular carcinoma in situ are presented and discussed. Certain biologic principles prompt consideration of segmental mastectomy and axillary node sampling as an alternative, commodious form of treatment for such lesions. There does not appear to be any unique reason to invoke any different treatment regimen for lobular invasive carcinoma than has been utilized for other invasive breast cancers.
Although regional lymph nodes showed increased numbers of pyroninophilic cells for at least six weeks after the implantation of a C3H mammary tumor, a decrease in the number of these cells was noted four weeks after amputation of a tumor-bearing limb. These observations appear paradoxical, since such animals have repeatedly demonstrated so-called sinecomitant tumor immunity. However, the lack of pyroninophilia coincided with prior observations that cells obtained from the regional nodes after amputation of a tumor-bearing limb-showed decreased in vitro cytotoxicity. This suggested that the pyroninophilic elements, vis a vis immunoblasts, may have been more closely related to cytotoxicity rather than to tumor immunity per se. The possible importance of nodal lymph follicle formation in the latter was suggested by their increased presence in such regional nodes.
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There has been increasing interest regarding the use of Corynebacterium parvum (CP) with other modalities in the management of primary cancer. Due to the paucity of specific information available relative to CP toxicity, a Phase I study was carried out in patients with advanced disease. The purpose of the investigation was not to evaluate the effect of CP on tumor growth. from 273 injections of CP in 40 patients it was observed that following intravenous (i.v.) infusion of CP: a) a febrile response and chills of considerable severity occured in almost all patients and did not appreciably diminish in intensity following repetitive administrations; b) nausea, vomiting, headache, and confusion were not infrequent; c) a "flu-like" syndrome lasting 24 to 48 hours occurred following almost all courses of CP; d) blood pressure elevations occurred on occasion and were related to the severity of other-side-effects; hyper- or hypo- tension was not a problem; e) ther were no anaphalactic reactions. Pretreatment with a single administration of 100 mg of hydrocortisone prior to CP infusion markedly and in some instances dramatically diminished the toxicity and made acceptable the use of i.v. CP on an outpatient basis. The use of i.v. CP in patients with cerebral metasteses may be hazardous. Subcutaneously administered CP resulted in a significant number of undesirable local reactions. Evaluation of delayed cutaneous hypersensitivity response, immunoglobulins, complement, and E- and EAC-rosette-forming cells during CP administration failed to demonstrate significant change from injection values. Results were similar whether hydrocortisone pretreatment was or was not employed. From the standpoint of toxicity it now seems appropriate to use i.v. CP, particularly following pretreatment with hydrocortisone, in a controlled clinical trial to evaluate its therapeutic effectiveness in the management of primary cancer.
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