Colonic epithelial impedance analysis in a murine model of large-bowel cancer.

Death rates from large-bowel cancer have remained essentially unchanged over the past 40 years because the diagnosis is made late, after the tumor has spread to other sites. This study was undertaken to examine whether alterations in mucosal electrical capacitance precede the development of gross malignancy, since this parameter may reflect functional or structural changes in the colonocyte plasma membrane, which is of importance in the regulation of cell growth. Distal colonic mucosal capacitance was decreased at low frequencies after only four weeks of treatment with the carcinogen dimethylhydrazine in C1 mice. Alterations in electrical capacitance may be a useful marker in identifying patients with a propensity to develop large-bowel cancer.

Needle biopsies in breast cancer diagnosis: techniques in search of an audience.

Fine-needle aspiration cytology and Tru-cut needle biopsy have been described as excellent techniques in the diagnosis of breast cancer. Responses to questionnaires sent to 90 pathologists in San Diego County, however, proved that in only 2-10% of all new breast cancer cases are these techniques being used to make the initial diagnosis. This paradox appeared to be due mainly to a reluctance of clinicians to use these techniques. However, there also appeared to be a lack of confidence and training among pathologists in interpreting aspiration cytology specimens. In the authors' and other pathologists' opinion, reviewing breast aspiration cytology specimens requires special training and regular exposure to such material, whereas Tru-cut needle biopsy specimens can be interpreted accurately by almost any pathologist without special training. The results of our own series of needle biopsies and aspiration cytology in the diagnosis of breast cancer are presented and compared to those reported in several other published reports. These data indicate that approximately 90% (89% in our series) of all palpable breast cancers can be diagnosed by needle biopsy techniques.

Breast cancer treatment--current status. 2. Segmental mastectomy, alternative to total breast excision?

Loss of a breast to cancer can have a profound psychologic effect on a woman. Within the last few years, research in breast cancer has centered on trying to find procedures that are less mutilating than but just as effective as the conventional surgical procedures discussed in part 1 (page 126). In this second part by Dr Pilch, recent and ongoing studies of a newer promising method known as segmental mastectomy are reviewed. How simple excision with irradiation is being used in early disease is described in part 3 (page 151). Part 4 (page 161) considers adjuvant therapies in early and late disease.

Breast cancer treatment--current status. 1. Mastectomy, standard surgical approach.

For about three quarters of a century, radical mastectomy was considered standard initial treatment for invasive breast cancer. Within the past 15 years, modified radical mastectomy (total mastectomy with axillary dissection) has replaced radical mastectomy as standard treatment, even though superiority of the former has not been scientifically proven, with the exception of a single study. During the same period, total mastectomy with postoperative irradiation of axillary lymph nodes came into vogue, and debate centered on whether irradiation of nodes was as efficacious as surgical extirpation. Results of several prospective studies indicated that when used prophylactically, neither method enhanced survival but both prevented subsequent nodal disease, and when used therapeutically, both methods controlled cancer growth equally well. Today, modified radical mastectomy is still standard treatment for patients with operable breast cancer, since axillary dissection is now routinely performed for staging purposes, thereby being preferable to irradiation of nodes.

Aspiration cytology is superior to Tru-Cut needle biopsy in establishing the diagnosis of clinically suspicious breast masses.

Eighty-one consecutive patients with breast masses clinically suspicious for malignancy were evaluated prospectively. There were 31 benign lesions and 50 malignancies. Clinical diagnosis was correct in 85% (2.5% false negative, 12.5% false positive). Mammography was diagnostic in 52.8% (31.5% false negative, 15.7% false positive). Needle biopsy was accurate in 78.9% (21.1% false negative, 0% false positive). Aspiration cytology was diagnostic in 96.2% (3.8% false negative, 0% false positive). Statistical comparison of all four tests revealed that aspiration cytology was slightly more accurate than physical examination for all lesions (p = 0.07), but significantly more accurate for benign lesions (p = 0.005). Overall, aspiration cytology was significantly more accurate than mammography (p = 0.000001) and needle biopsy (p = 0.008). Only one minor complication, a superficial infection, occurred with aspiration cytology and needle biopsy. Thin-needle aspiration cytology is a benign procedure that appears to be superior to physical examination, mammography, and needle biopsy in establishing the diagnosis of clinically suspicious breast masses.

Immunotherapy of a murine colon cancer with syngeneic spleen cells, immune RNA and tumor antigen.

In combination with xenogeneic immune RNA (l-RNA) and tumor antigen (TA), syngeneic spleen cells inhibited the growth of a N-methyl-N-nitrosourethane-induced colon carcinoma (CT-26) in BALB/c mice. The sequential administration of 1 X 10(7) spleen cells, l mg of anti-CT-26 l-RNA and 0.4 mg of CT-26 TA resulted in a 20% survival rate of mice bearing established CT-26 tumors. On the other hand, administration of the spleen cells only, l-RNA only or TA only was not effective in inhibiting tumor growth. Similarly, when any one of the three agents (l-RNA, TA and spleen cells) was omitted, no anti-tumor effect was obtained. A higher dose (1 X 10(8) and a lower dose(1 X 10(6) of spleen cells decreased the anti-tumor effect of this combination therapy. A higher dose (2 mg) and a lower dose (0.5 mg) of l-RNA, as well as a higher dose of TA (0.8 mg) had no influence on the anti-tumor effect. However, a lower dose of TA (0.2 mg) in combination with spleen cells and l-RNA decreased the anti-tumor effect. When all three agents were administered at higher or lower doses, no anti-tumor effect was obtained. When mice bearing CT-26 tumors were treated with spleen cells, plus l-RNA directed against a syngeneic but antigenically different tumor (BP/B/5) and BP/B/5/TA, with spleen cells plus CT 26 I-RNA and BP/B/5TA, or with spleen cells plus BP/B/5 l-RNA and CT-26 TA, no anti-tumor effect was observed. These results indicate that the anti-tumor responses observed were due to tumor-specific immune responses. In conclusion, in order to obtain growth retardation or regression of established CT-26 tumor transplants, the sequential administration of all three agents (spleen cells, l-RNA and TA) was required. The optimal doses of each agent were found to be 1 X 10(7) spleen cells, 0.5 mg or 1 mg of l-RNA and 0.4 mg of tumor antigen. Higher or lower doses decreased the anti-tumor effect. Tumor-specific immune reactions appeared to be involved.

Anti-tumor effect of syngeneic spleen cells treated with immune RNA and tumor antigen.

The anti-tumor effect of syngeneic spleen cells, xenogeneic immune RNA (l-RNA) and tumor antigen (TA) was studied in a chemically induced (N-methyl-N-nitro-sourethane) colon carcinoma model in BALB/c mice. When the mice were treated, sequentially, with these three elements by local injection under the tumor, complete tumor regression was observed in 25% of the animals. Complete tumor regression was observed in 17% of animals treated by injection of spleen cells pre-incubated with l-RNA in vitro followed by an injection of TA. When spleen cells were treated first with l-RNA and then with mitomycin-C, therapeutic benefit was obtained and the survival rate of mice treated with these spleen cells and TA was significantly higher than that of the control group (no treatment). The anti-tumor effect of this treatment was abrogated completely when spleen cells were treated with mitomycin-C prior to l-RNA incubation. When spleen cells were incubated with TA in vitro or after incubation with l-RNA and then injected into tumor-bearing mice, no anti-tumor effect was noted. These data suggest that DNA synthesis and/or lymphocyte proliferation is essential for the action of l-rna in sensitizing lymphocytes but not essential in the interaction of l-RNA-sensitized lymphocytes with TA. In addition it appeared that, under the conditions used, the participation of host factors was essential in the latter interaction, since treatment of l-RNA-sensitized lymphocytes with TA in vitro was ineffective.

Enhancement of metastasis development by BCG immunotherapy.

When BALB/c mice bearing growing transplants of a syngeneic colon carcinoma--Colon Tumor 26 (CT 26)--were treated with Bacillus Calmette-Guerin (BCG), no effect on tumor growth rate or survival time was observed compared to untreated controls. However, after excision of primary tumor transplants, enhanced development of lung metastases was noted in the BCG-treated mice, resulting in both as increased mortality rate (from metastatic disease) and a shorter survival time.

A continuous cell line derived from a human primary cutaneous melanoma: morphologic and karyologic properties.

A continuous tissue culture cell line, JD-MEL, derived from a primary cutaneous human malignant melanoma, is described. The cultured cells retain the characteristic epithelial morphology of the tumor of origin. The malignant nature of the cell line was demonstrated by the lack of contact inhibition, multilayered growth pattern and the ability to produce tumors in athymic BALB/c mice. Chromosome analysis revealed a near tetraploidy. Distinctive marker chromosomes and a female karyotype were present. No recognizable melanin pigment was identified in the cultured cells.

Immunogenicity of chemically induced murine colon cancers.

The antigenicity and immunogenicity of three colorectal carcinomas induced in BALB/c mice by 1,2-dimethylhydrazine or N-methyl-N-nitrosourethan were studied. All tumors were readily transplantable. Two of these tumors metastasized when transplants reached sufficient size. All tumors were found to be immunogenic in the strain of origin, and all tumors were shown to contain unique tumor-specific transplantation antigens in cross-protection experiments. The use of these tumors as an animal model for studies of adjuvant immunotherapy and chemoimmunotherapy is suggested.

Tumor-associated antigens of chemically-induced murine tumors; the emergence of MuLV and fetal antigens after serial passage in culture.

Using radioiodinated Staphylococcus aureus protein A [125I]SPA to measure syngeneic, allogeneic and heterogeneic IgG bound to murine tumor cells, we performed a serological analysis of surface antigens of 8 solid tumors and 2 leukemias of BALB/c mice (3 chemically-induced colon carcinomas, 3 chemically-induced sarcomas, 1 murine leukemia virus (MuLV) induced leukemia, 1 irradiation induced leukemia, 1 spontaneous melanoma and 1 spontaneous sarcoma). We were able to detect and distinguish between at least five separate antigenic specificities on these tumors. Unique tumor-associated antigens were found on 3 of the tumors, MuLV related antigens on 8 tumors, fetal antigens on 7 tumors and two distinct common antigens on 7 tumors (common antigen 1 (CA-1) on 5 tumors and common antigen 2 (CA-2) on 2 tumors). Neither of the common antigens was found to be sarcoma, carcinoma or tissue-tupe specific. A number of tumors which did not originally express either MuLV or fetal antigens in primary cultures expressed these antigens after several serial passages in vitro.

Human lymphoblastoid cells in culture replicate immune information carried by xenogeneic RNA.

Immune RNA is obtained from lymphoid organs of immunized animals and is reputed to transfer immunological information. Human lymphoblastoid cells in culture, after incubation with sheep Immune RNA produce RNA (Ic-RNA) which carries the same immunological information as the inducing sheep preparation. This Ic-RNA produced in tissue culture is capable of converting 'naive' human lymphocytes to cytotoxic effector cells against tumour target cells, to the same extent as the Is-RNA preparation used for induction of the cell line. The sheep Immune RNA information is present and can be recovered from the lymphoblastoid cells for at least ten weeks after the induction. It is suggested that xenogeneic Immune RNA information is incorporated in a stable fashion by cultured human lymphoblastoid cells, and also that it is replicated during their own replication. This system could be used for studying the incorporation of information carried by exogenous RNA and it might provide insight into some mechanisms underlying the transfer and processing of immunological information.