Immunosuppressive activity of concanavalin A.

Two strains of mice (C-57 B] and DBA) were given skin allografts from Swiss ICR/HA mice and were treated with varying doses of concanavalin A; the dosage ranged from only two injections of 25 micrograms during the experiment to daily doses of 1000 micrograms intraperitoneally. Immullosuppression was present at all dosages, the most prolonged and consistent effect being observed at 300 micrograms per day. Grafts survived for 14 to 21 days at this dosage compared to 4 to 9 days for controls.

Clinical studies of methanol extraction residue fraction of Bacillus Calmette-Guérin as an immunostimulant in patients with advanced cancer.

Forty patients with advanced gastrointestinal cancer, all previous chemotherapy failures, were treated with a methanol extraction residue of Bacillus Calmette-Guérin (MER) alone, administered intradermally in either weekly or every-4-week schedules. The only significant side effect was local cutaneous reaction ranging from papules through pustules to draining ulcerations. On the weekly schedule these reactions frequently reached a point of clinical intolerability. In spite of the advanced nature of their disease, 29% of the patients had increased reactivity to recall antigens; 57% showed an increased reaction to dinitrochlorobenzene challenge during MER therapy; 38% had significant increases in lymphocyte blastogenesis to phytohemagglutinin mitogen, 48% to concanavalin A, and 43% to pokeweed mitogen. Increases (greater than 25%) in immunoglobulins A, M, and G were also observed in 31, 41, and 28% of patients, respectively. MER therapy was associated with increased thymus-derived (T) and bone marrow-derived (B) cells and an increased ratio of T-cells to B-cells. Increases in those determinants reflecting cellular immunity (skin tests, phytohemagglutinin and concanavalin A blastogenesis, and T-cells) showed a positive correlation with patient survival. Increases in those determinants associated with humoral immunity (pokeweed mitogen blastogenesis, immunoglobulins, and B-cells) had, if anything, a negative survival correlation. In comparing administration schedules, the weekly method produced more frequent increases in dinitrochlorobenzene response, more rapid increases with higher peaks in lymphocyte blastogenesis transformation, and more frequent increases in circulating T- and B-cells. The every-4-week method was associated with significantly greater frequencies of increases in immunoglobulins A and M. Of 36 patients with measurable disease, 3 showed greater than 50% objective responses, 2 showed a 25 to 50% response, and 1 showed a mixed response. MER is a potent simulus to cellular and humoral immunity in the patient with advanced gastrointestinal cancer. This stimulation may occasionally result in a clinically evident antineoplastic effect.

A comparative clinical and immunological assessment of methanol extraction residue of Bacillus Calmette-Guérin versus placebo in patients with advanced cancer.

Eighty-four patients with advanced cancer refractory to conventional therapeutic modalities were randomly assigned in double-blind fashion to one of three intradermal treatment regimens: "high"-dose methanol extraction residue fraction of Bacillus Calmette-Guérin (MER) (2.0 mg); "low"-dose MER (0.5 mg); or 0.9% NaCl solution placebo. Toxicity, consisting primarily of cutaneous inflammation and ulceration, was limited to patients receiving MER and was most severe with the high-dose regimen. Pretreatment clinical and immunological parameters were comparable between patient groups. Although a significant number of patients had increases in various immune parameters according to the criteria used, there was no appearent advantage to MER given in either dosage schedule compared to placebo. Patient survival was not affected by either MER regimen compared to placebo. This investigation failed to demonstrate any significant clinical or immunological benefit from MER given in two dosage regimens in patients with advanced cancer with the laboratory methodology used and emphasizes the importance of appropriate controls in evaluating immunostimulants in humans.

Comparison of portal and peripheral blood levels of carcinoembryonic antigen, CA 19-9, and CA 125 tumor-associated antigens in patients with colorectal and pancreatic cancer.

Synchronous serum specimens from the systemic and portal circulations of 43 patients with gastrointestinal cancer were assayed for levels of carcinoembryonic antigen, CA 19-9, and CA 125 tumor-associated antigens. The number of patients having a mean ratio of portal to systemic levels greater than 1 and the observed quantity of tumor-associated antigens were significant for carcinoembryonic antigen and CA 125 only in patients with colorectal cancer. No correlations were noted with the surgical stage of disease or with high or low (normal) levels of the three tumor-associated antigens. These findings suggest that peripheral concentrations of these antigens are in equilibrium with shedding from tumors and that hepatic clearance of a single pass does not significantly alter peripheral concentrations.

Evidence for the elevation of serum carcinoembryonic antigen and tumor-associated glycoprotein-72 levels in patients administered interferons.

Sera were collected from 111 patients diagnosed with adenocarcinoma or nonadenocarcinoma malignancies who received different schedules of interferon (IFN)-gamma or IFN-beta ser alone or in combination. Serum carcinoembryonic antigen (CEA) and tumor-associated glycoprotein-72 (TAG-72) antigen levels were measured to determine whether interferon could enhance the tumor shedding and, thereby, the serum level of either tumor antigen. Less than 10% of the sera samples from patients diagnosed with nonadenocarcinoma malignancies (e.g., hairy cell leukemia, melanoma) had positive titers of TAG-72 or CEA, and interferon neither increased nor resulted in the appearance of either tumor antigen in those sera. In contrast, 59.2% and 75.4% of the patients with adenocarcinoma had positive serum levels of TAG-72 and CEA, respectively, prior to interferon. IFN-gamma and IFN-beta ser alone or in combination significantly increased serum TAG-72 or CEA in approximately 65% of those patients. The results suggest that interferon administration to patients with adenocarcinoma can result in increased serum levels of selected tumor-associated antigens used in the diagnosis of malignancy. These preliminary findings may be important in the development of new strategies to obtain more sensitive tumor antigen serum assays for the diagnosis and monitoring for disease progression of adenocarcinoma.

Clinical trial of recombinant leukocyte A interferon as initial therapy for favorable histology non-Hodgkin's lymphomas and chronic lymphocytic leukemia. An Eastern Cooperative Oncology Group pilot study.

Twenty patients with disseminated favorable histology non-Hodgkin's lymphomas (16 patients) or chronic lymphocytic leukemia (four patients) who had not received previous chemotherapy were treated with recombinant leukocyte A interferon (IFL-rA) (Hoffmann-La Roche, Nutley, NJ). Treatment was administered in a moderate dose (12 X 10(6) U/m2) by intramuscular (IM) injection three times weekly for 8 weeks, followed by weekly maintenance therapy for an additional 16 weeks in patients responding to therapy. Five patients with stable disease at 8 weeks received four additional weeks of three-times-weekly treatment at an escalated dose (25 X 10(6) U/m2). Interferon was tolerated without severe toxicity by most patients, although treatment was discontinued prematurely due to side effects in four patients. Objective tumor responses (one complete response [CR] and six partial responses [PRs]) were seen in seven of 16 patients with lymphoma (44%). One of four patients with chronic lymphocytic leukemia also experienced a PR. Median time-to-progression from initiation of therapy among responding patients was 26 + weeks (range, 7 + to 84 + weeks). This study has demonstrated single agent antitumor activity of IFL-rA given in a tolerable outpatient dosage regimen in patients with advanced favorable histology non-Hodgkin's lymphomas, and serves as a basis for further trials of IFL-rA combined with chemotherapy as initial therapy for such patients in the future.

Leukocyte chemotaxis in diabetic patients and their nondiabetic first-degree relatives.

Leukocyte chemotaxis wasmeasured in 108 subjects: 20 normal controls, 36 insulin-taking diabetics (15 being index patients), and 52 nondiabetic first-degree relatives of index patients. The relatives had a mean chemotactic index (CI) significantly lower than that of the controls (individually, 25 per cent had CIs lower than the lowest of the controls); and the diabetics had a mean CI significantly lower than that of the relatives. The impairment of leukocyte chemotaxis measured in the first-degree relatives of diabetic index patients does not appear to be associated with an increased susceptibility to infection and suggests that the impaired leukotaxis is due to an inherent defect--perhaps genetic--in leukocyte function.

Idiopathic late-onset immunoglobulin deficiency with functional T-cell deficiency.

The common features in our two patients were late onset of infections that are known to complicate both T-cell and B-cell deficiencies, decreased numbers of circulating B-cells with low serum immunoglobulin levels, and normal numbers of circulating T-cells, which were, however, defective in the response to delayed hypersensitivity skin test antigens and to mitogens in vitro. The composite of clinical and immunologic aberrations is consistent with the presence of an immune deficiency involving the B-cell system quantitatively and the T-cell system qualitatively.

Lymphocyte blastogenesis in patients receiving hemodialysis.

Lymphocyte blastogenic transformation in response to plant lectins and allogenic cells was studied in patients with nonuremic, far-advanced, chronic renal failure and in healthy controls. Cell cultures were studied in the presence of normal sera, patient's sera, and with media of different buffering capacities. Minimal blastogenic depression was observed when patient's lymphocytes were cultured in indifferent plasma with effective bicarbonate buffering compared with the use of pooled patient's plasma or HEPES buffer. Fresh plasma in culture depressed concanavalin A (Con A) blastogenesis. The data suggest that, under optimal conditions, lymphocytes from patients with chronic severe renal insufficiency are more responsive to stimuli than previously reported and as a group are near normal control values. Further, the defect observed may be a result of intracellular acidosis.

A prospective controlled evaluation of combined pelvic radiotherapy and methanol extraction residue of BCG (MER) for locally unresectable or recurrent rectal carcinoma.

Forty-four patients with unresectable primary, residual, or recurrent colorectal carcinoma confined to the pelvis were randomized to treatment with split course megavoltage radiotherapy alone (5,000 rad given over 7 weeks) or in combination with the intradermal administration of the methanol extraction residue of BCG (MER) over an eight-month period. No improvement was observed in frequency of symptomatic palliation, interval to progression, or survival among patients receiving MER. Furthermore, there was no evidence of enhanced immunological status in patients receiving MER as compared to those receiving radiation alone. Although temporary pain relief was seen in 94% of patients with pretreatment pelvic or perineal pain, 37 patients (84%) have experienced subsequent progressive malignant disease. Regional recurrences within the radiotherapy port were observed in 28 of 31 patients who were evaluable for analysis of pattern of sites of initial progression. Eleven of the 28 patients with local failure also had distant metastasis at the time of tumor progression. There was no discernible clinical value associated with MER treatment in combination with radiotherapy as employed in this study. The high frequency of pelvic recurrence following radiotherapy at the dose and schedule we employed highlights the need for more effective treatment strategies for this group of patients.

Soluble proteins of human bronchogenic carcinomas.

Solid-phase affinity chromatography has been used to search for tumor-associated proteins of bronchogenic carcinomas. All of the apparently normal proteins were removed from extracts of squamous cell carcinoma, large cell carcinoma, and adenocarcinoma of the lung. The remaining soluble proteins were partially characterized as to heat stability, approximate molecular size, electrophoretic mobility, and biologic function. These tumor-associated proteins were not tumor-specific by current definition. Neither lung cancer patients' lymphocytes nor serum proteins were specifically reactive with these tumor-associated proteins.

Abnormal chemotaxis in patients with cutaneous anergy.

Chemotaxis of polymorphonuclear leukocytes and mononuclear leukocytes was studied in six patients who had persistent cutaneous anergy. Four had previous infections (three fungal and one caused by Mycobacterium kansasii), one had sarcoidosis, and one had late-onset immunoglobulin deficiency. Our data indicate that some patients with persistent cutaneous anergy have a combined defect of leukocyte function. Lymphocytes incubated in vitro with mitogen failed to elaborate active lymphocyte-derived chemotactic factor when compared with controls. Polymorphonuclear leukocytes and mononuclear leukocytes responded poorly to normal chematactic factors compared with controls. The abnormal mononuclear leukocyte chemotaxis may play a role in the persistent cutaneous anergy of these patients.

An assessment of cell-mediated immunity in acute allograft rejection in man. A prospective study.

A detailed multifactorial computer analysis of several in vitro tests of cell-mediated immunity has been carried out before and after surgery in 15 renal transplant recipients. Factors studied include lymphocyte blastogenesis, T- and B-cell levels, and lymphocyte protein synthesis. Large doses of immunosuppressive agents chnage lymphocyte subpopulations. This is seen especially in transplant patients who have rejection and who have decreased numbers of circulating lymphocytes. The T cells are selectively depressed more than the B cells. This is also reflected in the greater responsiveness of pokeweed mitogen-stimulated lymphocytes compared with lymphocyte responsiveness to phytohemagglutinin and concanavalin A. In this environment, rejection takes place. These observations suggest that rejection may be initiated by cortisone-resistant lymphocytes of the thymic medullary type. Measurements of changes in lymphocyte responsiveness to mitogens or changes in lymphocyte subpopulations do not reliably predict rejection. However, measurement of lymphocyte protein synthesis fills the criterion of providing a reliable test that can be carried out quickly, and in the future may be valuable in predicting rejection.

Diagnostic role of serum CA 19-9 for cholangiocarcinoma in patients with primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) predisposes to the development of cholangiocarcinoma, a usually fatal complication that is difficult to diagnose. Serum concentrations of CA 19-9, a tumor-associated antigen, are frequently increased in patients with only cholangiocarcinoma. The aim of this study was to assess the value of an increased serum CA 19-9 level for the diagnosis of cholangiocarcinoma in patients with preexisting PSC. We analyzed serum samples from 9 patients with PSC and superimposed cholangiocarcinoma and from 28 patients with only PSC. Serum concentrations of CA 19-9 were measured in a blinded manner with use of an immunoradiometric assay. The serum CA 19-9 concentrations were increased in 8 of 9 patients (89%) with PSC and cholangiocarcinoma (mean +/- SE, 391 +/- 86 U/ml; range, 4 to 677), whereas they were increased in only 4 of 28 patients (14%) with only PSC (mean +/- SE, 61 +/- 16 U/ml; range, 2 to 370). The sensitivity of a CA 19-9 value greater than 100 U/ml for cholangiocarcinoma in PSC was 89%, and the specificity was 86%. The measurement of serum concentrations of CA 19-9 is a promising test for detecting cholangiocarcinoma in patients with PSC.

Phagocytosis and cutaneous delayed hypersensitivity in patients with chronic obstructive pulmonary disease.

The objective of this study was to determine if the phagocytic and intracellular killing capacity of peripheral granulocytes or an expression of cellular-mediated immunity, delayed cutaneous reactivity, as measurements of native and acquired immunity, might be risk factors associated with chronic obstructive pulmonary disease (COPD). Over 100 patients with a value for their forced expiratory volume in one second (FEV1) less than or equal to 70 percent of normal were carefully matched with healthy participants having an FEV1 greater than or equal to 86 percent of normal, and together they served as the study group. Phagocytosis and intracellular killing were normal in patients with COPD; however, these patients demonstrated a significant impairment in the ability of their peripheral leukocytes to reduce nitroblue tetrazolium. The delayed-hypertensitivity response rate and the degree of reactivity were similar in the two groups, except for the patients with COPD having a significantly greater degree of reactivity to Monilia albicans extract ("canadin.") This finding is thought to be a consequence of reduced mucociliary clearance rather than a risk factor. The significance of decreased resting and stimulated cells' reduction of nitroblue tetrazolium in patients with COPD is not clear.

Studies of mitogen-induced lymphocyte transformation by a semi-microtechnic.

The authors have demonstrated that mitogen-induced lymphocyte transformation can be effectively studied in a semi-microsystem allowing multiple studies from a reasonably small volume of blood, which makes the technic more feasible for clinical studies of cellular immune mechanisms. The variability among individuals, and from day to day in the same individual, makes repeated, careful kinetic studies necessary for valid data. Moreover, the very wide range of normal responses in man makes the interpretation of cellular hyporesponsiveness difficult in pathologic states and necessitates the use of several mitogen concentrations and sequential kinetic studies to establish the validity of results.

Transfer factor versus combination chemotherapy: a preliminary report of a randomized postsurgical adjuvant treatment study in osteogenic sarcoma.

Twenty-six patients with classic osteosarcoma were randomized to receive either transfer factor or combination chemotherapy. Eight of 14 patients who received transfer factor converted their skin test markers, evidence of activity of the transfer factor. Of these eight patients, all are alive; four are free of disease. Of the 18 patients who received combination chemotherapy, 14 are alive, 12 of whom are free of disease. The immunologic test procedures performed sequentially reveal that transfer factor appears to enhance cell-mediated immunity, but it is evident that in this study, a control (saline) arm in the protocol could not be included. It is of interest that the chemotherapy regimen used does not appear to suppress such activity permanently. The individual test results, however, are not very helpful for predicting response to treatment. The small numbers of patients and the short duration of this study, combined with the exclusion of parosteal osteogenic sarcomas and jaw tumors, do not permit a meaningful comparison with other published studies.

Comparison of preoperative serum CA19-9 levels with results of diagnostic imaging modalities in patients undergoing laparotomy for suspected pancreatic or gallbladder disease.

A prospective, blinded study of CA19-9 in 2,467 patients having abdominal surgery yielded 356 patients with pancreatic, gallbladder, and biliary disease who submitted coded preoperative serum specimens. In this group, there were 84 patients with pancreatic cancer and 24 patients with gallbladder-biliary cancer; the remainder had benign lesions. The recorded imaging data and marker results were merged with the patients' demographic, clinical, and surgical data and tissue diagnoses for analysis. Receiver operator character calculation suggested that a reference value of 100 U/ml for CA19-9 was appropriate rather than the 37-40 U/ml value most frequently employed and yielded a specificity of 97% in the 467 operated patients with a sensitivity of 8.3% for all nonpancreatic-biliary cancers and 62% overall for these lesions. In the more diagnostically challenging nonicteric patients, CA19-9 sensitivity was 55%, specificity was > 99%, positive predictive value (PPV) was 97%, and negative predictive value (NPV) was 88%. When CA19-9 results were combined with those from endoscopic retrograde cholangiopancreatography, ultrasound (US), or computed tomography (CT), the PPV, and especially the NPV were increased. The addition of carcinoembryonic antigen results did not affect overall results. The addition of CA19-9 results to ambiguous or indeterminant imaging interpretation clearly improved the combined specificity, sensitivity, and PPV, but the change was less impressive, albeit positive, for NPV. The combination of CA19-9 and CT (or US) is a reasonable, cost-effective, noninvasive approach to establishing the diagnosis of pancreatic, cholangitic, or biliary cancer in nonicteric patients. Although no single procedure or combination of procedures was found to detect early, small lesions, CA19-9 is clearly a clinically useful adjunct to imaging in nonjaundiced patients suspected of having these malignancies.

A controlled study of combined methotrexate, BCG, and INH therapy for squamous cell carcinoma of the head and neck.

In a randomized prospective study of patients with advanced squamous cell carcinoma of the head and neck, treatment with MTX plus BCG and with MTX plus BCG plus INH produced no better response rate or survival time than treatment with MTX alone.

T-lymphocyte subsets in patients with idiopathic dilated cardiomyopathy.

T-cell subsets were measured in the peripheral blood of 33 patients with heart failure from idiopathic dilated cardiomyopathy, 22 patients with heart failure from other causes, and 33 normal controls. Mean T-suppressor cell percentage was 30% in normals, 21% in patients with idiopathic dilated cardiomyopathy whose duration of symptoms was less than 1 year (P = 0.0005), and 26% in those with symptoms for greater than 1 year (P = 0.05). Similarly, percentage of T-suppressor cells in the group with heart failure from causes other than idiopathic dilated cardiomyopathy was significantly lower (23%; P = 0.005) in those with short duration of symptoms. When both heart failure groups were combined those with symptoms for less than 1 year had significantly lower T-suppressor frequencies (22%) than those with symptoms for more than 1 year (P = 0.015). Multivariate analysis identified duration of symptoms and age as the only independent predictors of T-suppressor cell frequencies. Decreased percentage of T-suppressor cells in patients with idiopathic dilated cardiomyopathy may be an epiphenomenon related to duration of heart failure. This should be taken into account in assigning an etiologic mechanism for T-suppressor cells in idiopathic dilated cardiomyopathy.