Inhibition of the immune response to experimental fresh osteoarticular allografts.

The immune response to osteoarticular allografts is capable of destroying the cartilage--a tissue that has antigens on its cells identical to those on the bone and marrow cells. Osteoarticular allografts of the distal femur were performed in rats using various methods to attempt to temporarily inhibit the antibody response. The temporary systemic immunosuppressant regimens investigated were cyclophosphamide, azathioprine and prednisolone, cyclosporine A, and total lymphoid irradiation. The most successful appeared to be cyclosporine A, but significant side effects were observed. To specifically inhibit the immune response in the allograft antigens without systemically inhibiting the entire immune system, passive enhancement and preadministration of donor blood were tried. Neither was as effective as coating the donor bone with biodegradable cements, a method previously found to be successful. Cyclosporine A was investigated in dogs in a preliminary study of medial compartmental knee allografts and was found to be successful in inhibiting the antibody response and in producing a more successful graft; however, some significant side effects were similarly observed.

Breast cancer treatment: evolving approaches but stable results.

This report describes the outcome of 530 women with breast cancer diagnosed from 1968 through 1983 and represents a demographic population rather than a referred selected one. The data represents the results of evolving breast cancer treatment approaches during the past 2 decades and is particularly useful as a measure of the total population denominator, free of selection factors that confound reports detailing a surgical, radiation, or chemotherapy experience. During the time interval reviewed, the standard treatment approach of the primary changed from radical mastectomy to biopsy and radiation therapy. Chemotherapy policy evolved from single agent treatment for relapse to multiple drug programs as adjuvant or for relapse. The major findings were: The 5-, 10-, and 15-year survival rates for the intervals 1972-75, 1976-79, and 1980-83 were slightly better than the earliest interval 1968-71, but with no statistically significant improvement. The frequency of favorable disease (Stages Tis, 1) increased from 16 to 31 percent during the interval but the mean age remained the same suggesting that patient education programs, availability of health insurance, or mammography may have lead to identifying patients with more favorable disease. Mastectomy has been replaced by breast conserving surgery and radiation as the most common treatment of the primary. Patients treated by surgery and biopsy/radiation had identical survival outcomes. It was not possible to detect improved survival that could be ascribed to the adoption of multiple agent chemotherapy but the magnitude of the effect is calculated to be on the order of 2% of the total patient population diagnosed. Death due to breast cancer decreases with time after diagnosis but is still 4% per year, 10 years after treatment. The findings suggest that progress has been made in detection, breast conservation, and palliation of symptoms in many subpopulations, but the end results for the total breast cancer population have remained stable during an era when the treatment approach evolved markedly.

Carcinoma of the larynx in childhood.

The unusual case of a 12-year-old boy with well differentiated in situ, and focally invasive squamous carcinoma of the larynx is reported, together with a review of the medical literature. In addition to this one, 54 cases of laryngeal carcinoma in children 15 years of age or younger have been reported since 1868. All were squamous except for one adenocarcinoma of a laryngeal minor salivary gland. Carcinoma of the larynx in children parallels that of adults in terms of squamous histology, predominantly vocal cord involvement, pattern of local spread, and response to treatment. However, the incidence of female patients is higher in childhood (40% of childhood cases vs. less than 10% of adult cases), and risk factors, except previous irradiation of papillomas, are rare. Although unusual, carcinoma of the larynx in children is probably more common than thought and the diagnosis should be considered in any case of a child with persistent hoarseness or cough.

Evidence for common and distinct determinants of colon carcinoembryonic antigen, colon carcinoma antigen-III, and molecules with carcinoembryonic antigen activity isolated from breast and ovarian cancer.

This study was designed to answer the question, do molecules with carcinoembryonic antigen (CEA) activity from colon, breast, and ovarian cancer differ? Extracts of two breast and three ovarian cancers with CEA activity were compared to three colon cancer CEA preparations and to the related antigen, colon carcinoma antigen-III, in terms of lectin- and antiserum-binding properties. With the use of Farr-type radioimmunoassays with the lectins, concanavalin A and wheat germ agglutinin, the iodinated colon CEA and CEA-like preparations from breast and ovarian cancer all showed distinctly different patterns of binding. Specificity of binding was confirmed by inhibition studies with the relevant monosaccharides. Similarly, with antisera prepared against colon CEA, colon carcinoma antigen-III, or breast CEA, it was shown that, although all preparations shared some antigens, unique antigenic determinants were also present on all preparations. These data are consistent with the concept of a series of closely related CEA and CEA-like molecules with distinct characteristics for each tissue source of CEA.

In vitro induction of tumor-specific immunity. III. Lack of requirement for H-2 compatibility in lysis of tumor targets by T cells activated in vitro to oncofetal and plasmacytoma antigens.

Many recent studies have demonstrated that cytotoxic T lymphocytes (CL) activated to various antigens other than those of the H-2 complex, will lyse target cells only when H-2 compatibility exists between the CL and target cell. From these observations, it has been inferred that T lymphocytes might only be capable of responding to H-2 antigen or antigens that become associated with H-2 region gene products. Our results suggest that this is not the case, and that in some situations, cytotoxic T lymphocytes can specifically lyse target cells of different H-2 types. Two in vitro systems are described where primary induction of cytotoxic T lymphocytes to oncofetal and plasmacytoma antigens results in CL capable of lysing suitable targets bearing these antigens, of either syngeneic or allogeneic derivation. Thus it is proposed that although interaction antigens involving H-2 components may preferentially activate T lymphocytes, this does not imply a restriction on the recognition potential of T lymphocytes.

In vitro induction of tumor-specific immunity. VI: analysis of specificity of immune response by cellular competitive inhibition: limitations and advantages of the technique.

The cellular competitive inhibition 51Cr-release assay makes two distinct contributions to the in vitro study of cell-mediated immunity. It allows target cells which are not amenable to isotopic labelling to be investigated for their antigenic specificity, and it provides a means, complementary to the direct cytotoxicity assay, of estimating qualitative and quantitative differences in antigen expression on intact normal and neoplastic cells. Various parameters of a micro-51Cr-release inhibition assay have been studied, and it was found that the assay conditions markedly influenced both the sensitivity and specificity. It is concluded that optimal assay conditions for specificity include: 1) moderate levels of lysis on the linear part of the CL/T titration curve, 2) avoidance of prolonged assay times, and 3) low ratios of blocker to target cells. When tumor cells with large cell volumes are used as competitive inhibitor (blocker) cells, non-specific blocking will occur; limits have been defined for this particular micro-inhibition assay which, in general, exclude these effects.

Analysis of murine oncofetal antigens as tumor-associated transplantation antigens.

In previous studies with in vitro activated cytotoxic T lymphocytes, we have demonstrated the presence of oncofetal antigens (OFA) on a range of murine tumor cells. The present studies with the same tumor lines attempt to determine whether these antigens are also capable of activating lymphocyte responses in vivo. Several experimental designs were followed, each being performed many times (1). Preimmunization of mice with irradiated fetal liver cells and followed by challenge with viable tumor cells did not consistently produce a state of tumor resistance. However, injection of live fetal cells frequently led to enhanced tumor growth (2). The growth of tumors in multiparous mice can be inhibited, in contrast to controls, but this effect was relatively short lived after parturition (3). Preimmunization with fetal cells in vivo did not result in augmented secondary cytotoxic T cell responses in vitro (4). Immunization of mice with irradiated tumor cells frequently led to a state of resistance to the clonal growth of hemopoietic fetal cells, although again the level of resistance was usually relatively weak. From the overall results, we conclude that OFA are relatively poor immunogens on tumor cells or fetal cells in vivo, and in contrast to in vitro responses, do not act as potent tumor transplantation antigens.

In vitro induction of tumor-specific immunity. II. Activation of cytotoxic lymphocytes to murine oncofetal antigens.

The presence of oncofetal antigens (OFA) on a wide variety of murine tumor cells was demonstrated to a totally in vitro system of cellular immunity. Nonimmune spleen lymphocytes were cocultivated with irradiated syngeneic fetal liver cells and, at various times after initiation of culture, were tested for the presence of cytotoxic lymphocytes (CL) by 51Cr-release assay with labeled tumor target cells. Significant cytotoxic activity was regularly detected after such culture, whereas only minor levels appeared in control cultures of spleen lymphocytes with irradiated syngeneic spleen cells. Specificity of the reaction was assessed by inhibition tests in which nonlabeled cells were admixed to the CL and 51Cr-labeled tumor targets. Fetal liver cells gave significant inhibition; however, no inhibition was found with adult spleen cells. Various tumor types gave inhibition, and fibrosarcomas were more effective than plasmacytomas or lymphomas. The results suggested that all tumor types tested possess such OFA, as well as their unique or virus-associated, tumor-associated transplantation antigens, and that the in vitro system permits a more active response to the tumor-associated OFA than that observed in in vivo studies.

Ly and Ia antigen phenotypes of T cells involved in delayed-type hypersensitivity and in suppression.

The Ly and Ia phenotypes of T lymphocytes involved in different functions were characterized by the use of specific antisera. T cells responsible for delayed-type hypersensitivity (DTH) and for helper functions were found to be Ly-1+,2- in contrast to cytotoxic T cells and T cells responsible for suppression of antibody responses which were Ly-1-,2+. Unlike some primed helper cells, T cells involved in DTH were Ia-. Suppressor cells in the system were Ia+.

Prospects for para-aortic irradiation in treatment of cancer of the cervix.

The incidence of para-aortic node metastasis in cancer of the cervix ranges from 5%to 50% in clinical Stages i-iv. Extended field irradiation is being administered more frequently because of high incidence of extrapelvic disease. The cancer of the cervix material at Walter Reed General Hospital has been analyzed as to site and time of failure to determine who might have benefited from extended field irradiation. Of patients who fail, the majority will have uncontrolled pelvic disease regardless of other involvement. Diagnostic procedures including staging laparotomy are unable to predict pelvic failure or the presence of occult distant disease in lung and bone. The maximum number of patients who could benefit from pari-aortic irradiation is lessthan 3% of a total series. It is concluded that the salvage of patients with para-aortic metastasis will be small, but for those few long-term survivors, the benefit will be great.

Carcinoma of the cervix: a time dose analysis of control and complications.

The use of 3 dose assessment systems is compared. The Manchester approach which measures a dose to Point A and Point B; the Paris approach using rads and mgh; and Ellis's NSD approach appear to have equal value in predicting probability of pelvic control and the likelihood of complication over the dose range employed at this hospital. Control increases with higher dose schemes, but complications appear to be influenced by other variables not accounted for in the 3 systems.