Late cardiac complications after radiotherapy for breast cancer was studied in 197 patients examined before, 6 months after, and 10 years after treatment. The 10-year follow-up was done by survey of the files of patients who had died and re-examination of patients who were alive and free of cancer. Among 95 patients who died, 3 died of cardiopulmonary diseases. Autopsy in 32 patients showed serious cardiac abnormalities in 3. Of 102 patients alive at follow-up, 3 reported heart symptoms. Sixty-nine patients participated in the re-examination. Electrocardiogram (ECG) abnormalities were found in 19% of these patients before treatment; in 45% at 6 months, essentially due to T-wave changes in patients who had received left-sided irradiation; and in 45% at 10 years, with fewer T-wave abnormalities but more ST depression and ectopic beats. Average working capacity was 83 W before, 81 W at 6 months, and 84 W at ten years. Average heart volume was 680 ml before, 689 ml at 6 months, and 718 ml (P less than 0.01) 10 years after treatment. In conclusion, there was a high incidence of ECG T-wave changes, but they were reversible, and the perimyocardial damage indicated was functionally insignificant. The incidence of serious cardiac complications was low.

The capacity of PWM (poke-weed mitogen) to stimulate Ig-secretion by blood lymphocytes was examined before and at various times after local radiation therapy (46.0 Gy) for breast cancer. It was observed that the secretion of IgM, IgA and IgG were significantly reduced at completion of radiation therapy. Secretion of IgM was reduced to the highest relative extent (approximately 10% of the pretreatment value). Thereafter there was a recovery of the Ig-secreting capacity which, however, remained below the pretreatment level, 12-18 months after completion of radiation therapy. The capacity of PWM-stimulated blood lymphocytes to secrete specific antibodies against morbilli and herpes simplex virus was also significantly impaired after radiation therapy. The reduction of Ig-synthesis in vitro was not correlated with the increase in the ratio between numbers of monocytes and lymphocytes in peripheral blood after radiation therapy. Possible explanations for these results are discussed.

Reduction of nitroblue tetrazolium by blood monocytes was significantly increased following post-operative radiation therapy for breast cancer. Attachment and ingestion of yeast particles by monocytes was not affected. Exposure of purified monocytes in vitro to 13 Gy did not significantly affect NBT reduction of yeast particle attachment, whereas ingestion of yeast particles was slightly increased.

The capacity of the blood lymphocyte population to spontaneously lyse K562 and Chang cell in vitro was examined in women who received local radiation therapy (45.0 Gy) for breast cancer. It was observed that cytotoxicity, on a cell-for-cell basis, was significantly reduced against K562 cells at completion of irradiation. This was followed by a recovery to the pretreatment level within 3–4 months and remained relatively constant for approximately 2 yr. The pattern of these changes were reasonably similar to that of the frequency of lymphocytes expressing Fc-receptors for IgG. In contrast, the relative cytotoxicity against Chang cells was unchanged at completion of irradiation. At 3–4 months, however, the relative cytotoxicity was increased above the pretreatment level and remained elevated for at least 2 yr. The results indicate that different effector cells are involved in the spontaneous destruction of K562 and Chang cells.

Radiation treatment of breast cancer patients (45.0 Gy) profoundly affected the peripheral blood lymphocytes. The number of these cells was markedly reduced with non-T-cells being more extensively depleted than T-cells immediately after radiation. The long-lasting lymphopenia, on the other hand, was mainly due to reduced number of T-cells. Antigen and mitogen stimulability, MLC reactivity, pokeweed (PWM)-induced immunoglobulin (Ig) production in vitro, and different cytotoxic functions decreased. Depletion of lymphocytes largely restored the radiation-depressed lymphocyte reactivity. The effects of in vitro exposure of blood lymphocytes to x-rays were similar to those seen after radiotherapy. Non-T-cells and T-cells with Fc-receptors for IgG were relatively radiosensitive. This latter observation agreed well with demonstrated increase of PWM-induced Ig synthesis after in vitro exposure to x-rays. T-suppressor cells defined by monoclonal antibodies were, however, radioresistant. The cytotoxic functions were reduced. No correlations were found between the pretreatment immunological status or the extent of radiation-induced immunological suppression, respectively, and prognosis.

The influence on the blood lymphocyte population of two types of postoperative adjuvant chemotherapy regimes given to patients with large breast tumors or involved axillary lymph nodes have been examined. Cyclic treatment with a combination of chlorambucil, methotrexate and 5-fluorouracil was more myelotoxic and required more extensive dose reductions than treatment with cyclophosphamide, methotrexate and 5-fluorouracil with the dosage used. Both treatments reduced the size of the blood lymphocyte population and changed its cellular composition, as defined by rosette tests, to approximately the same extent. Response of the lymphocytes to specific and non-specific mitogens were also affected to approximately the same extent. A comparison of the clinical value between the two treatments has not yet been performed.

Concanavalin a (Con A)-induced and Con A-inducible human suppressor lymphocytes were examined for their radiosensitivity (16 Gy). It was observed that X-ray exposure of Con A-induced suppressor cells abolished some of the suppressive activity. Exposure of lymphocyte preparations did not prevent the subsequent induction by Con A of suppressor cells capable of inhibiting mitogen responses of lymphocytes. The relative size of the Con A-inducible suppressor population in the blood was not changed in breast cancer patients after local radiation therapy.

In a controlled clinical trial preoperative radiotherapy was compared to modified radical mastectomy followed either by no further treatment or by postoperative radiotherapy. The total number of patients was 960; 654 of these had a follow-up time of more than five years. The patients who were irradiated preoperatively, had a significantly better survival rate than the patients who were treated with surgery only (p = 0.05); however, this was not true for those irradiated postoperatively. The radiation dose in the ipsilateral internal mammary nodes was, on the average, lower with the postoperative treatment technique than with the preoperative technique. This difference in dose-distribution in the internal mammary nodes is analyzed. The result of the study indicates that adequate local treatment may increase survival in a subgroup of patients.

Peripheral lymphocyte subpopulations were examined in 37 women with breast carcinoma who were postoperatively randomized to adjuvant local radiation therapy or cyclic treatment with 5-Fluorouracil, Methotrexate and Chlorambucil. Both T and non-T lymphocyte counts were reduced but the latter subpopulation was reduced to the highest relative extent in both groups of patients. Following radiation therapy the non-T cells repopulated more rapidly than the T cells, whereas the repopulation seemed to be the reverse in patients treated with chemotherapy.

A group of 17 patients, having undergone modified radical mastectomy for breast cancer, received 12 cycles of chemotherapy with methotrexate, 5-fluorouracil, and chlorambucil during 17 months. The number of circulating T and non T lymphocytes, as defined by E, EAC, and ME rosette formation, were reduced during treatment. The Non-T lymphocytes, however, were reduced to the highest relative extent. Relative phytohemagglutinin and mixed lymphocyte culture responses of the cells decreased, whereas purified protein derivative responses were unchanged. Serum concentrations of IgM were reduced, but IgA and IgG concentrations were unchanged or slightly increased. Antibody titres to morbilli and herpes simplex were not changed, whereas the antibody activity against cytomegalovirus (CMV) increased in several seropositive patients. None of these patients, however, developed signs of a CMV infection.

The blood lymphocyte population was monitored in 6 patients with advanced malignant tumors who were treated with large doses of a new cytotoxic drug termed pepleomycin. It was observed that the size of the cell population, its cellular composition, mitogen stimulations and natural killer activity did not change in any consistent ways during or after treatment. It is concluded that pepleomycin does not directly affect the lymphocytic population.

The yield and the prognostic significance of initially performed bone scintigraphy in 387 patients with operable mammary carcinoma are reported. The mean follow-up time was 52 months. In 12 patients (3.1%) the scintigraphy was considered to indicate bone metastases but in only 3 of these bone metastases later developed. The low information obtained has resulted in exclusion of bone scintigraphy in the initial assessment of clinically operable patients with mammary carcinoma.

Bestatin, a substance produced by Streptomyces olivoreticuli, inhibits certain cell-membrane-associated enzymes and has been shown to augment immune responses in experimental animals. We have determined whether bestatin medication changed the peripheral lymphocyte population in 15 advanced cancer patients. After 2 weeks of daily, 30 mg oral bestatin medication, the lymphocyte counts remained essentially unchanged, but the frequency of E-rosette-forming lymphocytes increased. In vitro stimulation of the lymphocytes with PHA or PPD remained essentially unchanged while the natural-killer activity of the lymphocyte population increased in most patients. Bestatin treatment caused no detectable side effects.

The natural killer (NK) activity of peripheral lymphocytes against 51Cr-labelled Chang or K562 cells was tested using a 4 h release assay before and after postoperative radiation therapy for mammary carcinoma. NK activity against K562 was significantly reduced at completion of therapy (a total target dose of 45.0 Gy) and restituted 3 to 4 months later. NK activity against Change cells exhibited a slight but non-significant decline at completion of therapy followed by an overshoot 3 to 4 months later. The frequency of Fc-IgG receptor bearing lymphocytes was decreased at completion of therapy and largely restored after 3 to 4 months.

Twenty one patients with advanced metastatic cancer of various types received 30 mg of Bestatin daily per os as a single treatment for several weeks. It was observed that the blood lymphocyte counts remained unchanged but the frequency of SRBC rosette forming cells increased and the frequency of lymphocytes possessing receptors for the Fc-part of IgG became normalized after two weeks of treatment. The frequency of lymphocytes possessing receptors for C'3 was not changed. The natural killer activity of peripheral lymphocytes for K562 and Chang cells increased but the PPD stimulation of the lymphocytes was not altered. A slight, but significant increase of the PHA stimulation of lymphocytes was observed after 4-7 weeks of Bestatin treatment. It is concluded that Bestatin is a nontoxic drug which changes the cellular composition as well as certain immunological functions of human lymphocytes.

The peripheral lymphocyte population was examined in sixty-five randomized breast cancer patients before and after post-operative adjuvant cyclic chemotherapy or local radiation therapy. During 10 months of chemotherapy total lymphocyte and T cell counts were reduced to 70% and non-T cells to about 50% of pretreatment values. The population of T cells was unaltered whereas the proportion of non-T cells was significantly reduced at the end of the period. Immediately after radiotherapy total lymphocyte and T cell counts were reduced to 30%, and non-T cells to 15% of pretreatment values. During 10 months' observation total lymphocyte and T cell counts increased to 70%, and non-T cells to 50--60% of pretreatment values.