New perspectives on use of thymic factors in immune deficiency.

Current knowledge on the role of thymic factors in the immune response is inadequate and remains relatively primitive when compared with present technical possibilities for assessing lymphocyte subsets or cytokine interaction. New studies support the potential importance of thymic factors as regulators of immune interactions. Indirect evidence supports the concept that thymic factors may work at the level of IL-2. The functional identity of cells responsive to thymic factors and the relation of observed effects to cytokine network interactions need to be established. The use of thymic factors in the future will depend on the development of criteria to identify appropriate settings in which to use such factors and the implementation of appropriate measures of immune functional response.

Serum levels of immunoreactive thymosin alpha 1 and thymosin beta 4 in large cohorts of healthy adults.

Enzyme linked immunosorbent assays were used to measure serum levels of immunoreactive thymosin alpha 1 and thymosin beta 4 in 681 healthy adults (range 18 yr-101 yr). Immunoreactive thymosin alpha 1 was found to occur at a geometric mean of 540 pg/ml with a range from 252 to 1158 pg/ml. There were no differences in the levels when analyzed according to race, sex or age. Immunoreactive thymosin beta 4 was measured at a geometric mean of 12.6 ng/ml with a range from 6.9 to 23.0 ng/ml. There were no differences in the levels when analyzed according to race or sex, however, there was a slight upward trend with increasing age. This data may be useful as a reference when monitoring clinical studies, determining the kinetics of drug metabolism and distinguishing patient groups with elevated levels of either of these peptides.

Suppression of cellular immunity by head and neck irradiation. Precipitating factors and reparative mechanisms in an experimental model.

A model was developed in C3H mice to investigate the immunosuppressive effects of head and neck irradiation and to explore mechanisms for repair of the defects. Mice receiving 1200 rad (12 Gy) of head and neck irradiation showed significant depression of delayed-type hypersensitivity, peripheral blood lymphocyte counts, spleen cell counts, and spleen cell production of interleukin-2. Treatment with optimal dosages of thymosin alpha 1 (T alpha-1) produced significant increases in all of these values, in some instances to levels higher than in the nonirradiated controls. In identical experiments with mice irradiated to a portal limited to the pelvic region, T alpha-1 induced only partial remission of the abnormalities. The dose response of T alpha-1 with head and neck irradiation showed a relatively limited dose range for immune restoration, a finding that warrants similar determinations in clinical trials with immunomodulating agents. The results suggest a potential clinical usefulness of T alpha-1 and also interleukin-2 in restoring cellular immunity after irradiation for head and neck cancers. The model appears to be useful for investigating immunomodulating agents before they are clinically evaluated as adjuvants with head and neck irradiation regimens.

Effects of radiation therapy on T-lymphocyte subpopulations in patients with head and neck cancer.

Cellular immunity was assessed in 85 patients with head and neck cancer with monoclonal antibodies to lymphocyte surface antigens that identify total T cells, helper cells, and suppressor cells. The control group consisted of 22 healthy volunteers. Nine patients who had surgical procedures for benign diseases were also studied. Compared with the controls, the patients with cancer who received radiation therapy had a significant decrease in total lymphocytes, T cells, helper cells, suppressor cells, and decreased helper/suppressor cell ratio. Significant decreases in lymphocyte subpopulations were not detected in patients tested before treatment or in patients treated with surgery alone. The immune deficits observed were prolonged in duration, with some present in the patients studied up to 11 years after radiation therapy. This long-lasting immune depression may have relevance to tumor recurrences and second primaries in patients with head and neck cancer treated by radiation therapy and to attempts at increasing cure rates with adjuvant agents that improve immune reactivity.

Experimental autoimmune thyroiditis: modulation of the disease level in high and low responder mice by thymosin.

Experimental autoimmune thyroiditis (EAT) in mice is characterized by production of anti-thyroglobulin autoantibodies and lymphoid infiltration of the thyroid gland. The pathogenesis of EAT is genetically controlled, but its mechanism is not yet clear. To investigate the mode of the expression of genetic control in the development of the disease, we attempted to modulate immune responses with thymosin fraction 5 (T-5) in mice which are either high or low responders to thyroglobulin. Severe thyroid lesions in high responder mice appear 2-3 weeks after immunization, while low responders develop very mild or no lesions. High responder mice have also higher antibody titer than the low responder strain. T-5 administered in five daily injections before or simultaneously with immunization, was strongly suppressive to EAT development in the high responder strain while there was no effect on thyroiditis level in low responder mice. T-5 also decreased the severity of thyroiditis in high responder mice when injected 2-4 weeks after immunization. In low responder mice, however, the same treatment increased the thyroiditis level. The effects of late injection of T-5 were dose-dependent. In all experiments, the antibody titres were not affected by T-5 treatment. The results demonstrate the ability of T-5 to modulate development and intensity of EAT. The contrasting effects of T-5 in high and low responder mice illustrate the relationship between the effects of T-5 and host immune status prior to study, suggesting that the level of immunoregulatory cell activity may differ in these two strains.

Effects of smoking and age on serum levels of immune reactive proteins.

In patients with head and neck squamous carcinoma, prior studies demonstrating correlations among levels of certain immunosuppressive acute phase proteins, tumor extent, and immune reactivity suggest that these protein levels may be useful parameters for assessing tumor status and clinical course after treatment. Because of the consistent association of chronic smoking with the development of cancers of the head and neck, the effects of smoking and age on levels of acute phase proteins (alpha 1-antitrypsin, haptoglobin, alpha 1-acid glycoprotein) and other immune reactive proteins (alpha 2HS-glycoprotein, prealbumin) were determined in smoking and nonsmoking normal subjects. In smokers, levels of alpha 1-antitrypsin were uniquely and significantly elevated and were not related to smoking extent or age. Levels of haptoglobin increased with smoking extent and age. In comparisons of age- and sex-matched smokers and nonsmokers, levels of alpha 1-acid glycoprotein increased with age among both groups. The demonstration of correlations of levels of immunosuppressive acute phase proteins with smoking extent and age among normal subjects suggests that changes in the levels of these proteins may be related etiologically to the association of smoking and age with the development of head and neck cancers.

Combination chemotherapy for advanced squamous cell carcinoma of the head and neck.

Fifty-one patients (32 previously untreated, 19 previously treated) with advanced squamous cell carcinoma of the head and neck received a single course of combination chemotherapy consisting of high dose cis-platinum (DDP), bleomycin (Bleo), +/- high dose methotrexate (MTX). Thirty-three (65%) patients responded to therapy; 5 (10%) of these patients had a complete response. Previously untreated patients and those who received the three drugs (DDP, Bleo and MTX) had the highest response rates. The duration of response was 8 to 12 weeks. Seven (15%) patients showed a two-year survival rate. All nonresponders were dead of disease within two years. Three (56%) of the five complete-response patients and 4 (21%) of the partial-response patients survived for two years. The role of preoperative chemotherapy in head and neck cancer is yet to be conclusively defined.

A surgical technique for hip disarticulation.

Hip disarticulation is usually elected for malignant bony and soft tissue tumors below the lesser trochanter of the femur. The operation is performed with the patient in a posterolateral position; in the first phase of the procedure the surgeon stands anterior to the patient. After incision of the skin and division of the femoral vessels and nerve, muscles of the anterior thigh are transected off the pelvic bone from lateral to medial starting with the sartorius and finishing with the adductor magnus. Muscles are divided at their origin except for the iliopsoas and obturator externus which are divided at their insertion on the lesser trochanter of the femur. The quadratus femoris muscle is identified and preserved, then the flexor muscles are transected at their site of origin from the ischial tuberosity. During the next phase the surgeon is posterior to the patient, and the pelvis is rotated from the posterolateral to the anterolateral position. After completion of the skin incision, the gluteal fascia, tensor fascia lata, and the gluteus maximus muscles are divided and dissected free of their posterior attachments to expose the muscles inserting by way of a common tendon onto the greater trochanter. These muscles are then transected at their insertion on the bone. The posterior aspect of the joint capsule is then exposed and transected. Finally, the sciatic nerve is divided and allowed to retract beneath the piriformis muscle. To close the wound the preserved muscles are approximated over the joint capsule and the gluteal fascia secured to the inguinal ligament over suction drains. The skin is closed with interrupted sutures.

Effects of smoking and age on serum levels of immune-reactive proteins altered in cancer patients.

In patients with solid malignancies, such as those associated with chronic smoking, levels of immunosuppressive acute-phase proteins (haptoglobin, alpha 1-acid glycoprotein, alpha 1-antitrypsin) are increased and correlate directly with extent of tumor and inversely with immune reactivity. Other serum proteins with immunorestorative properties (alpha 2HS-glycoprotein, prealbumin) are decreased and correlate directly with immune reactivity. Serum levels of these glycoproteins and albumin were measured in normal volunteers (132 cigarette smoking and 140 nonsmoking) to determine the effects of smoking history, age, and sex on protein levels. The alpha 1-acid glycoprotein increased, whereas albumin decreased with age in both groups, and haptoglobin increased with age in smokers. The alpha 1-acid glycoprotein, haptoglobin, and albumin levels also correlated with the extent of smoking (pack-years). In a comparison of age- and sex-matched smokers and nonsmokers, alpha 1-antitrypsin uniquely and significantly increased (P less than 0.001) in smokers but was not related to age or extent of smoking. The diagnostic and immunological implications of smoking and age-related changes in serum protein levels are discussed.

Improvement of impaired leukocyte migration inhibition by thymosin in patients with head and neck squamous carcinoma.

In a preliminary study of the effects of SK-SD and thymosin on leukocyte migration inhibition in patients with squamous carcinoma of the head and neck, the cancer patients had significantly lower leukocyte migration inhibition of SK-SD than normal subjects. Thymosin increased the inhibition to SK-SD in the cancer patients to levels similar to those in normal subjects, and decreased the inhibition in normal subjects. These results confirm and extend the results of previous studies of the effects of thymosin in vitro, which show restoration of immune reactivity in patients with impaired cellular immunity and either no effect or a decrease in immune reactivity in subjects with normal cellular immunity. These combined observations provide a rationale for determining the clinical effects of thymosin in immunoincompetent patients with head and neck cancer and suggest that immunorestorative agents such as thymosin be used with caution in patients with normal cellular immunity.

Serum glycoproteins in cancer patients: first report of correlations with in vitro and in vivo parameters of cellular immunity.

Serum levels of proteins previously shown to be elevated [acute-phase proteins (APP)-haptoglobin, alpha 1-acid glycoprotein, alpha 1-antitrypsin] or depressed (alpha 2 HS-glycoprotein, prealbumin, albumin) in cancer patients were correlated with tumor extent, in vitro lymphocyte reactivity (LR) to phytohemagglutinin (PHA), and quantitative delayed hypersensivity (DH) to dinitrochlorobenzene (DNCB) in 147 preoperative patients with operable solid malignancies either confined to the primary site or with regional spread only. Compared to 58 normal controls, levels of the APP were significantly elevated, alpha 2 HS-glycoprotein and prealbumin depressed, and albumin levels unchanged in patients with either local or regional tumors. In patients with normal DH to DNCB, the APP were higher and prealbumin was lower than in controls; in patients with impaired DH to DNCB, haptoglobin and alpha 1-acid glycoprotein were higher and alpha 2 HS-glycoprotein and prealbumin lower than in patients with normal DH to DNCB. Albumin levels did not differ from normals in any of the groups. Serum protein levels appeared to be more related to the immune status of the patient than to tumor extent. The levels of the three APP correlated directly with each other but inversely with alpha 2 HS-glycoprotein and prealbumin; levels of alpha 2 HS-glycoprotein and prealbumin correlated directly with each other. Levels of haptoglobin and alpha 1-acid glycoprotein correlated inversely with LR to PHA; however, levels of alpha 2 HS-glycoprotein correlated directly with LR to PHA, and uniquely the levels of alpha 2 HS-glycoprotein and LR to PHA both showed similar changes for each of the four quantitative levels of DH to DNCB measured in the cancer patients. The data show that the proteins studied, except for albumin, correlate inversely (APP) or directly (alpha 2 HS-glycoprotein and prealbumin) with in vitro and in vivo parameters of cellular immunity. The results provide a rationale for attempts to improve depressed cellular immunity by lowering circulating levels of APP, as is being attempted in ongoing trials using plasmapheresis, and assessing the effect of exogenous alpha 2 HS-glycoprotein or prealbumin in patients with low levels of these glycoproteins and depressed cellular immunity. The correlations between serum glycoprotein levels and in vitro and in vivo parameters of cellular immunity lend rationale to investigations of the interactions of serum glycoproteins and blood cells having immunologic function that determine the level of cellular immunity expressed in vivo.

Paraplegia due to posttraumatic pelvic arteriovenous fistula treated by surgery and embolization. Case report.

A case is presented in which a posttraumatic pelvic arteriovenous fistula caused progressive paraplegia because of voluminous shunting into the epidural venous system. Surgical ligation and transcatheter embolization of major and minor arterial feeders decreased shunt flow sufficiently to permit direct embolization of the fistula by an injectable plastic. This combined approach may allow obliteration of unresectable acquired or congenital arteriovenous malformations.

Thymosin fraction V and intensive combination chemotherapy. Prolonging the survival of patients with small-cell lung cancer.

Patients with small-cell bronchogenic carcinoma who received intensive remission-induction chemotherapy randomly received either thymosin fraction V, 60 mg/sq m or 20 mg/sq m twice weekly, or no thymosin treatment during the initial six weeks of chemotherapy. Chemotherapy was then continued for two years. Thymosin administration did not increase the complete response rate. Patients receiving thymosin, 60 mg/sq m, had significantly prolonged survival times relative to the other treatment groups. This benefit was due to prolonged relapse-free survival in complete responders to treatment. The mechanism by which thymosin increased survival duration is unclear but may relate to restoration of immune deficits due to disease or treatment.