Organization of efferent neurons in area 19: the projection to extrastriate area 21a.

The organization of efferent neurons in area 19 of the cat was examined by bulk injections of retrograde tracers, WGA-HRP and CTX-Au, into extrastriate area 21a. In one case, the cortex was cut coronally and retrogradely labeled cells in area 19 were present in columnar register throughout layers 2 to 6, with the majority of labeled cells in layers 2/3. The number of columns per tissue section ranged from 0 to 4 and had a centre-to-centre spacing ranging from 0.6 to 0.9 mm. A few lightly labeled cells were found between the columns. In six other cases, the visual cortex was flattened, and cut in the tangential plane to reveal a pattern of irregular, widely spaced bands that were elongated in the mediolateral direction with a mean centre-to-centre spacing of 2.6 mm. The density of labeled cells within these bands fluctuated such that dense aggregates of cells were found, on average, at 0.9 mm intervals along the bands. This tangential heterogeneity in density, along with the patchy columnar staining witnessed in the coronal plane, suggests that the widely spaced efferent projection bands may have a patchy substructure with a spacing of approximately 1 mm. The pattern of efferent projection bands and its substructure in area 19 is reminiscent of the stripe-like organization of V2 found in primates.

The projection from V1 to extrastriate area 21a: a second patchy efferent pathway colocalizes with the CO blob columns in cat visual cortex.

The different patchy organizations of neurons projecting from primary visual cortex (area 17) to the various extrastriate areas may contribute to functional differences in the output to each of these areas. The pattern of neurons projecting to extrastriate area 21a was examined using large injections of retrograde tracers and compared to the pattern shown by neurons projecting to the lateral suprasylvian area (LS). Patches of neurons projecting to 21a showed a bimodal laminar distribution, with numerous labeled cells in the upper and lower third of layer 3 bracketing a sparsely labeled central third; LS-projecting neurons were confined to the lower and middle thirds of layer 3. The 21a projecting cells were relatively tighter in their clustering pattern than the LS projecting cells, i. e. the difference in labeling density between patch and interpatch zones was greater for 21a-projecting cells than for LS-projecting cells. As previously shown for the LS-projecting cells, patches of 21a-projecting cells colocalized with CO blob columns in area 17. Combined with our earlier results, this study shows that the CO blob compartments in area 17 give rise to at least two distinct efferent pathways, one projecting to LS and the other to 21a, and furthermore suggest that each pathway may carry unique information to its extrastriate target.

Breast cancer incidence highest in the range of one species of house mouse, Mus domesticus.

Incidence of human breast cancer (HBC) varies geographically, but to date no environmental factor has explained this variation. Previously, we reported a 44% reduction in the incidence of breast cancer in women fully immunosuppressed following organ transplantation (Stewart et al (1995) Lancet 346: 796-798). In mice infected with the mouse mammary tumour virus (MMTV), immunosuppression also reduces the incidence of mammary tumours. DNA with 95% identity to MMTV is detected in 40% of human breast tumours (Wang et al (1995) Cancer Res 55: 5173-5179). These findings led us to ask whether the incidence of HBC could be correlated with the natural ranges of different species of wild mice. We found that the highest incidence of HBC worldwide occurs in lands where Mus domesticus is the resident native or introduced species of house mouse. Given the similar responses of humans and mice to immunosuppression, the near identity between human and mouse MTV DNA sequences, and the close association between HBC incidence and mouse ranges, we propose that humans acquire MMTV from mice. This zoonotic theory for a mouse-viral cause of HBC allows testable predictions and has potential importance in prevention.

Immunological enhancement of breast cancer.

Breast cancer is a complex disease. Its aetiology is multifactorial, its period of development can span decades, and its clinical course is highly variable. Evaluation of the role of the immune response in either the development or control of breast cancer is also complex. Nevertheless, there is substantial information that in this disease, the immune response is not a host defence reaction and may even serve to facilitate cancer development. This evidence comes from a variety of sources including clinical-pathological investigations in women that show a correlation between the intensity of lymphocytic infiltration into the tumour mass with poor prognosis, studies in breast cancer patients that demonstrate a similar correlation between delayed hypersensitivity reactivity or in vitro assays of immune reactivity to tumour cell membranes or non-specific antigens and poor prognosis, and analyses of cancer incidence in chronically immunosuppressed, kidney transplant recipients who develop an unexpectedly low incidence of breast cancer. The overall conclusions from these human studies are corroborated by observations in mouse mammary tumour models that also demonstrate immune enhancement of breast cell proliferation in vitro and of breast cancer development in vivo. Potential mechanisms for these effects include production, by inflammatory cell infiltrates, of direct or indirect modulators of breast cell growth, e.g. cytokines, peptide or steroid hormones, enzymes involved in steroid metabolism, as well as of antibodies to growth factors or their receptors. These immune facilitatory mechanisms must be overcome if immune-based therapies are to be applied successfully in breast cancer.

Evidence for immune facilitation of breast cancer growth and for the immune promotion of oncogenesis in breast cancer.

Autoimmune diseases have been extensively studied in man and experimental animal models and salient points are reviewed, as a clear understanding of the immune mechanisms involved is essential if one is to understand the potential of immune interactions with established cancer cells or in the premalignant period of hyperplasia. Such reactions may be of benefit to the host, with down regulation of tumor growth, or unfavourable, with facilitation of oncogenesis and cancer growth. In particular, evidence is cited that supports a beneficial effect of the host response to non-small-cell lung cancer and the association of a poor prognosis in established breast cancer caused by a heightened immune response to the tumor. Histologic evidence supports these conclusions, as do studies of specific and nonspecific immune reactivity in breast cancer patients. The potential for cytokines to stimulate breast cancer growth, increase angiogenesis and decrease cell adhesion is reviewed, also recent evidence for autologous lymphocyte stimulation of breast cancer. Parallels between immune promotion of breast cancer in mice, caused by the mouse mammary tumor virus, and the development of breast cancer in women are also reviewed. If the mouse model has relevance for human breast cancer, one could predict that there would be a reduced incidence of breast cancer in a population of chronically immunosuppressed women following organ transplantation. Such is the case. This finding, plus the fact that all treatments that have shown efficacy in breast cancer have one thing in common, they are immunosuppressive, strongly support the role of immune facilitation of breast cancer growth and immune promotion of oncogenesis in breast cancer in a substantial number of growth.

Immune mechanisms and tumor dormancy.

The natural occurrence of tumor dormancy in man is reviewed based on observations made by a distinguished surgeon and two pathologists after a lifetime of practice. They concluded that dormancy is the result of immune mechanisms preventing the growth of microscopic metastases already present following curative surgery. Six cases of non-small-cell lung cancer are described in patients randomized to receive specific active immunotherapy in controlled clinical trials. Three patients had nonregional metastases at 11, 12 and 14 years. Two had regional recurrence after 9 years and in one patient a small hilar-node metastasis was found at necropsy after 7.6 years. In each case an immunodepressive event or drug treatment preceded resurgent growth. Animal models of tumor dormancy are reviewed and the evidence is clear that dormancy may be induced by manipulating immune mechanisms, resulting in cells remaining in mitotic arrest, or tumor cell proliferation is balanced by an equivalent rate of cell death. Based on these observations future clinical strategies should de developed to induce the dormant state in micrometastases in the adjuvant setting.

Dose response in the treatment of breast cancer.

We present evidence that drugs that are effective in causing regression of metastatic breast cancer in a dose-dependent fashion also cause a dose-dependent reduction of cytokines produced by the immune system. This may be an important factor in the occasional induction of a complete remission.

The possible role of stromal cell stimulation in worsening the prognosis of a subset of patients with breast cancer.

This review examines the evidence that a subset of patients with breast cancer have tumors that are stimulated to grow by host cells in the tumor stroma. The search for such a minority group was prompted by the following observations. Adjuvant chemotherapy which is immunosuppressive improves disease-free interval and survival, whereas non-specific immunostimulation worsens the prognosis. Intrinsic immune reactivity is associated with a poor prognosis. A subset of tumors with a bad prognosis has anaplastic cells, dermal lymphatic invasion and a moderate to intense lymphoplasmacytic stromal infiltrate. Evidence is reviewed that adjuvant chemotherapy may be beneficial by virtue of its immunosuppressive effects in addition to tumor kill of minimal residual disease.

Tumour dormancy: initiation, maintenance and termination in animals and humans.

The authors review the natural occurrence of tumour dormancy in man and animal models, which show the importance of cellular defence mechanisms in inducing and maintaining the state of tumour dormancy. Six cases of non-small-cell lung cancer are described. The patients exhibited moderate to very strong delayed hypersensitivity reactions to soluble lung-cancer antigen after specific immunotherapy. Three patients had nonregional metastases at 11, 12 and 14 years. Two had regional recurrence after 9 years, and in one patient a small hilar-node metastasis was found at autopsy after 7.6 years. In each case an immunodepressive event or drug treatment preceded resurgent growth. The effect of renal transplantation in patients with a history of surgery for cancer supports the conclusion that cellular defence mechanisms are crucial for the maintenance of tumour dormancy in man.

Adjuvant specific active lung cancer immunotherapy trials. Tumor-associated antigens.

The 10-year cumulative experiences of five year survivals of patients entered into a successful phase II specific active tumor-associated antigen (TAA) immunotherapy trial, a successful phase III specific active immunotherapy trial A and of patients from centers with acceptable protocol violation levels of an unsuccessful specific active immunotherapy trial B are evaluated. Here the authors report the efficacy of specific active TAA immunotherapy when the protocol is adhered to strictly, where the induction of cell-mediated immunity to TAA indicated a successful adherence to the protocol rather than the strategic result when centers from the third trial with major violations are included. The authors repeat here a summary of each of the three separate trials, each of the three trials having been reported elsewhere in their entirety, so that these total results may be compared to the present analysis. The survival experiences of a total of 234 lung cancer Stage I and Stage II patients, including all violations, from centers in northern New York, northern New Jersey, western Pennsylvania and eastern Canada show a statistically valid (P = 0.0002) 5-year survival difference between the control groups (receiving adjuvant alone or no treatment) at 49% survival and the specific active immunotherapy groups at 69% survival. The best promise of specific active immunotherapy alone in an adjunctive treatment setting is with early stage lung cancer. In addition to tests which monitor the effect of TAA immunotherapy induction of long-lasting cell-mediated immunity, tests (monoclonal antibody-derived epitope enzyme immunoassays) were developed to monitor specific, early antibody rises in the bloodstream (circulating humoral immunity).

The effect of specific and nonspecific immunotherapy on natural killer cell activity in patients with non-small-cell lung cancer.

Fourteen patients with stages I and II non-small-cell lung carcinoma receiving adjuvant immunotherapy after surgery were studied serially for natural killer (NK) cell cytotoxicity assays. Seven patients received active nonspecific immunotherapy with Freund's complete adjuvant alone and seven patients received active specific immunotherapy with tumor-associated antigen plus Freund's complete adjuvant. Both groups were analyzed as a single group in view of the lack of any difference in the results. The results indicated that NK-cell cytotoxicity v K562 was lower in untreated patients than in normal controls, but the difference was not significant. There was no evidence of specific cytotoxicity v the lung cell line A549 in untreated patients when compared with normal controls. Compared with pretreatment values, elevated cytotoxicity v both K562 and A549 was observed at every post-treatment time point tested, and this was statistically significant at several time points by a paired t test. No specific effect was noted after immunization with lung antigen on cytotoxicity against the lung cell line A549. Other correlations studied did not show any relationship between delayed hypersensitivity skin testing or serum carcinoembryonic antigen levels and NK-cell cytotoxicity. It is concluded that NK-cell reactivity was increased nonspecifically by active specific and nonspecific immunotherapy. This increase seems to peak at the 12-month period and was significant when compared with pretreatment levels.

Lung tumor-associated antigens: thin layer immunoassay.

Six hundred eighty-four rapid, sensitive thin layer immunoassays (TLI) were performed using an adapted visualization of condensation on plastic surface (VCS) method, for testing squamous cell and adenocarcinoma monospecific (TAA) and monoclonal antibody derived lung tumor-associated antigens (TAA epitopes) against small amounts of coded human test sera. The TAA epitopes selected for VCS-TLI were more specific, but both forms of TAA gave positive tests in 94% of lung cancer test sera of the appropriate histological types. The four antigens (adeno TAA and TAA epitope, squamous TAA and TAA epitope) did not react in VCS-TLI with coded sera from preselected normal individuals with known medical histories. With both TAA epitopes, 5% of non-lung cancer test sera were positive. There were indications that such tests may be useful in aiding pathological evaluations and in detecting precancerous conditions in patients with asbestosis. Cross-reacting (with other non-lung cancers) and specific peptide sequences of TAA were indicated in the comparative tests with the corresponding TAA epitopes, suggesting the tests for probing and analyzing portions of the antigens. Of immediate use is VCS-TLI for monitoring patients on specific active TAA immunotherapy.

Specific and nonspecific immunotherapy as an adjunct to curative surgery for cancer of the lung.

Attempts to improve survival following curative surgery for non-small-cell lung cancer are reviewed. Most of these approaches have been designed to stimulate the resistance of lung cancer patients in a non-specific fashion. Living bacteria or products of dead bacteria have been given as adjunctive treatment. Various routes have been used; oral, intradermal, subdermal, or intrapleural, with either BCG or Corynebacterium parvum. No reproducible benefit has been observed. Levamisole has not been proven to be useful. Trials have yet to be completed to confirm the use of thymosin fraction V for small cell carcinoma in improving the effectiveness of chemotherapy. A pilot trial using specific active immunotherapy is described. Prolongation of survival four years after closure of the trial in those patients immunized, compared with non-immunized patients, has prompted two further clinical trials. A small trial has confirmed the effectiveness of specific immunotherapy as adjunctive therapy for squamous cell carcinoma. A large multicenter trial in Canada and the United States should be completed and open to analysis in 1984 and may shed light on the role of tumor-associated antigens in stimulating specific resistance to lung cancer.

Ulcerative enterocolitis in dogs induced by drugs.

An ulcerative enterocolitis was induced in dogs by two drugs; cinchophen given intravenously or indomethacin given orally. Ulcers were closely associated with Peyer's patches with either drug. Granulomata were occasionally seen in the mucosa and adjacent mesenteric nodes of dogs who received cinchophen. Transmural inflammation was seen only in some dogs who received indomethacin. A skip-like distribution of mucosal lesions was seen, induced by either drug and corresponding to the skip-like collections of lymphoid follicles. An explanation of the pathogenesis of these lesions is offered in the light of recent advances in the understanding of the immune response of gut-associated lymphoid tissue.

[HL-A antigens in bronchogenic carcinoma]. / HLA-Antigene beim Bronchuskarzinom.

A decrease in the frequency of HLA-A2 was noticed in 37 bronchogenic carcinoma patients studied. HLA-B8 was found to be increased in the prolonged survivors of bronchogenic carcinoma.