Parathyroid hormone in plasma in adenomatous hyperparathyroidism, uremia, and bronchogenic carcinoma.

The concentration of parathyroid hormone (measured by radioimmunoassay) in plasma of patients with severe chronic uremia is frequently much higher than it is in the majority of cases having adenomatous hyperparathyroidism. igher-than-normal concentrations of parathyroid hormone in plasma are found in a significant percentage of unselected patients with bronchogenic carcinoma.

Magakaryocyte quantitation.

A method is described for the quantitation of megakaryocytes. In this technic bone marrow sections obtained at the time of maximal marrow uptake of previously injected plasma bound (59)Fe are counted for radioactivity as well as the number of megakaryocytes and nucleated red cells. We calculated the total megakaryocytes by relating the ratio of megakaryocyte: radioactivity with the total marrow (59)Fe activity at the time of sampling. A multiple counting correction factor which is related to cell diameter and section thickness is required for quantitation of cell numbers from section material. The normal megakaryocyte number for the rat is 11.0 x 10(6)/kg, and 6.1 x 10(6)/kg for man.

Immunoreactive forms of circulating parathyroid hormone in primary and ectopic hyperparathyroidism.

The immunoreactive forms of parathyroid hormone (iPTH) in the plasma of six patients with primary, adenomatous hyperparathyroidism and six patients with ectopic hyperparathyroidism due to non-parathyroid cancer were compared by using gel filtration on columns of Bio-Gel P-150 and radioimmunoassay of iPTH in eluted fractions after concentration. We found much less (p<0.001) small (mol wt<9,500) COOH-terminal fragments of iPTH in plasma samples from ectopic hyperparathyroid patients (0.52+/-0.13 ng eq/ml) than in samples from primary hyperparathyroid patients (3.70+/-1.15 ng eq/ml). The quantity of iPTH eluting with or before native bovine PTH [1-84] was the same in both syndromes (ectopic hyperparathyroidism, 0.82+/-0.22 ng eq/ml; primary hyperparathyroidism, 0.73+/-0.09 ng eq/ml), and these values correlated positively with plasma calcium concentration (ectopic hyperparathyroidism, r=0.908; primary hyperparathyroidism, r=0.919). In both syndromes, plasma samples had an iPTH component that eluted well before PTH [1-84] (mol wt 9,500), but this component was present in much larger quantities in three patients with ectopic hyperparathyroidism. We conclude that (a) the decreased quantity of biologically inactive COOH-terminal fragments of iPTH circulating in ectopic hyperparathyroidism accounts for the previously reported relatively lower total serum iPTH values in this syndrome as compared with primary hyperparathyroidism (Riggs et al. 1971. J. Clin. Invest. 50: 2079); (b) there appears to be sufficient iPTH with presumed biologic activity to account for the hypercalcemia in both syndromes; (c) a large PTH component, not previously recognized in plasma, is present in both ectopic and primary hyperparathyroidism and may exist as the predominant immunoreactive form of the hormone in some patients with ectopic hyperparathyroidism.

Microcytotoxicity assays of tumor immunity in patients with bronchogenic carcinoma correlated with clinical status.

Peripheral blood lymphocytes from patients with bronchogenic carcinoma were tested in microcytotoxicity assays against cultured bronchogenic cancer cells, other types of tumor cells, and skin fibroblasts. Lymphocytes from patients who were postresection with no clinical evidence of residual or recurrent tumor were more frequently toxic against bronchogenic carcinoma than were lymphocytes from normal donors or from patients with clinically evident disease. Lymphocytes from patients with minimal or no tumor were more frequently toxic against bronchogenic cancer than against skin fibroblasts. Serum samples from a few patients rendered lymphocytes toxic for bronchogenic cancer cells, but this serum activity could not be correlated with the patient's clinical status.

Cerebrospinal fluid vasopressin as a marker of central nervous system metastases from small-cell bronchogenic carcinoma.

Vasopressin (ADH) was measured in CSF and plasma in 75 evaluable patients with known or suspected CNS metastases from small-cell bronchogenic carcinoma (SCBC), and in 66 control patients having neither malignant disease nor organic CNS disease. The presence of CNS metastases was confirmed or excluded on the basis of computed tomographic scans, neurologic examination, and autopsy. Twenty-four of the 75 patients had no CNS metastases. Ten of the 51 patients with CNS metastases had leptomeningeal carcinomatosis (MC). CSF-ADH was significantly increased in patients with MC (P less than .05), but not in patients having exclusively parenchymatous CNS metastases. Taking 2 pg/mL (95th percentile of control patients) as the upper limit of normal, 15 SCBC patients had elevated CSF-ADH, including 12 patients with CNS metastases and six patients with MC. The CSF-ADH to plasma ADH ratio was significantly increased in patients with CNS metastases (P less than .05). Patients without CNS metastases had a ratio less than or equal to 0.8 whereas the ratio was greater than 0.8, in 21 of the 51 patients with CNS metastases. The positive and negative predictive values with 95% confidence limits were 84% to 100% and 31% to 59%, respectively. Patients with inappropriate secretion of ADH (SIADH) constituted a significantly greater proportion of patients with elevated CSF-ADH than of patients with normal CSF-ADH levels (P less than .05). In addition, patients with SIADH constituted a significantly greater proportion of patients with MC than of patients with parenchymatous metastases (P less than .05). The diagnostic application of these findings is limited because of the large number of false-negative results, but it may prove to be of value in conjunction with the measurement of other tumor markers.

Long-term survivors in metastatic non-small-cell lung cancer: an Eastern Cooperative Oncology Group Study.

Between December 1979 and June 1983 the Eastern Cooperative Oncology Group (ECOG) treated 893 good-performance status patients with metastatic non-small-cell lung cancer (NSCLC) on one of seven phase III combination chemotherapies. The overall median survival was 23.5 weeks with no significant differences between treatments. One hundred sixty-eight patients (19%) survived greater than 1 year and 36 (4%) for greater than 2 years. The etoposide-platinum combination had the highest proportion of 1-year survivors (25%). Mitomycin-vinblastine-platinum (MVP), which had demonstrated the highest response rate, had significantly fewer 1-year survivors (12%) than any other regimen (P = .003). Analysis of pretreatment characteristics that distinguished patients who survived greater than 1 year from those who did not demonstrated that an initial performance status of 0, no bone metastases, female sex, no subcutaneous metastases, non-large-cell histology, less than 5% prior weight loss, no symptoms of shoulder or arm pain, and no liver metastases were predictors of longer survival. Of particular interest was the finding that response duration was significantly longer (P = .002) for those patients who experienced a longer time to best response. In addition, patients who survived greater than 1 year experienced greater degrees of nonlethal toxicity, in particular, gastrointestinal and hematologic, than patients who did not survive 1 year, (P = .006). A detailed chart review of 32 2-year survivors and 32 matched controls demonstrated that maintenance or improvement of performance status and maintenance of serum albumin levels at 3 months from the initiation of treatment were both important predictors of longer survival.

Serum calcitonin after pentagastrin stimulation in patients with bronchogenic and breast cancer compared to that in patients with medullary thyroid carcinoma.

Serum immunoreactive calcitonin (iCT) was measured in the peripheral blood of 29 normocalcemic patients with bronchogenic carcinoma of various pathological types and nine patients with breast cancer before and after pentagastrin stimulation. These results were compared to those found in 22 normal subjects and 30 patients with histologically proven medullary carcinoma of the thyroid. Our results revealed that 1) serum iCT levels may be abnormally high in all pathological types of bronchogenic carcinoma and in patients with breat cancer; 2) the basal level of serum iCT may be normal, but it is abnormally high after pentagastrin stimulation; 3) the increment rise of iCT after pentagastrin stimulation in the bronchogenic and breast cancer patients was significantly less than that seen in patients with medullary carcinoma of the thyroid (P less than 0.001).

Specific radioimmunoassay of human beta-endorphin in unextracted plasma.

With an antiserum against human beta-endorphin (beta-EP) crossreacting less than 2% with human beta-lipotropin (beta-LPH) by weight we have developed a radioimmunoassay that can detect 1 pg beta-EP in diluted raw plasma. In a.m. fasting plasma of 14 normal subjects beta-EP ranged from less than 5 to 45 pg/ml. beta-EP was elevated in untreated, but normal in successfully treated Cushing's disease; undetectable in a patient with adrenal adenoma; extremely high in Nelson's syndrome; and elevated in a patient with bronchogenic carcinoma before, but undetectable after tumor resection. In subjects with intact hypothalamic-pituitary-adrenal axis, beta-EP was undetectable after dexamethasone and increased after metyrapone administration and insulin-induced hypoglycemia. beta-EP concentration was considerably lower in serum than in simultaneously collected plasma, but increased in serum left unfrozen for several hours after clot removal. Thus, beta-EP behaves like a hormone responding to the same stimuli as ACTH and beta-LPH and blood appears to contain enzymes both generating and destroying immunoreactive beta-EP.

Plasma pregnenolone and 17-OH-pregnenolone in patients with adrenal tumors, ACTH excess, or idiopathic hirsutism.

Plasma levels of the delta5-pregnenes, pregenolone and 17-OH-pregnenolone, were measured in patients with disordered steroidogenesis. While 17-OH-pregnenolone was within the normal range in patients with hypercortisolemia due to Cushing's disease, ectopic ACTH or adrenal adenrenal adenoma, 4 of 6 patients with an adrenal carcinoma had elevated levels of this precursor. Thus, elevated plasma 17-OH-pregnenolone levels in patients with Cushing's syndrome indicate adrenal carcinoma, although a normal value does not exclude this diagnosis. Abnormal resistance of delta5-pregnenes to suppression with dexamethasone proved useful in detecting the presence of residual tumor in the post-operative evaluation of adrenal carcinoma. Basal plasma pregnenolone was within the normal range in 19 of 20 patients with Cushing's disease and was invariably normal in patients with other varieties of hypercortisolism. Since acute administration of ACTH causes marked elevation of delta5-pregnene levels while patients with chronic ACTH excess (Cushing's disease and ectopic ACTH production) have normal levels, it is suggested that ACTH has a chronic influence on the intraadrenal utilization of delta5-pregnenes in addition to stimulating their formation. In pre-menopausal women with idiopathic hirsutism, basal levels of both delta5-pregnenes were elevated (P less than 0.001). Following dexamethasone administration the absolute decrease in delta5-pregnenes levels was greater than that seen in normal subjects. This observation indicates that the metabolism of delta5-pregnenes is abnormal in patients with idiopathic hirsutism.

Factor VII inhibitor.

Factor VII inhibitor activity was identified in a 66 year old man with probable bronchogenic carcinoma. Initial studies indicated a normal partial thromboplastin time (PTT) and a prothrombin time (PT) prolongation which increased with incubation. PT correction failed to occur with 50 per cent normal plasma in vitro and 2 U of fresh frozen plasma in vivo, indicating inhibitor activity. Specific factor assay levels fell within normal limits except for a factor VII level of 30 per cent. Subsequent evaluation with antiglobulin studies suggested an inhibitor of immunoglobulin G [IgG] origin.

Plasma arginine vasopressin in the syndrome of antidiuretic hormone excess associated with bronchogenic carcinoma.

A study of plasma arginine vasopressin in 17 patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) associated with bronchogenic carcinoma, revealed that the arginine vasopressin levels were distinctly elevated in most. In 14 patients with bronchogenic carcinoma, but without overt SIADH, plasma levels of arginine vasopressin were significantly higher than in normal subjects (p less than 0.001). This, together with the finding of a lower than normal plasma osmolality in this group, suggests that inappropriate ADH excess might be much more common in patients with bronchogenic carcinoma than previously thought. The normal positive correlation between plasma osmolality and plasma arginine vasopressin was found to be reversed in SIADH. Seven of nine patients with overt SIADH, studied after fluid deprivation, showed an increase in plasma arginine vasopressin coincident with an increase in plasma osmolality (r = +0.8, p less than 0.01); in one patient, plasma arginine vasopressin returned to the original level following rehydration. The possibility that this might imply a degree of physiologic control to what is generally considered an autonomous secretion is discussed. It is, however, considered more likely that other factors, including changes in plasma volume and glomerular filtration, might explain the increase in plasma levels of arginine vasopressin.

Radiation myelitis and survival in the radiotherapy of lung cancer.

A previous survey of patients who survived more than 6 months after radiotherapy for carcinoma of the bronchus using a 6 fraction regimen revealed a considerable incidence of radiation myelitis. In a further survey, in which the data bank has been increased from a total of 303 to 754 cases, analyses have confirmed that radiation myelitis occurs once a threshold dose of 33.5 Gy to the spinal cord has been reached. The incidence was positively related to the hemoglobin concentration, but not to the blood pressure at the time of radiotherapy. In the same group of patients survival was positively related to radiation dose, the hemoglobin concentration, and the systolic blood pressure. In other patients who were treated with 6 fractions, but who received a lower minimum tumor dose, either because this was planned or as a result of cord shielding, no relationship was shown between survival and radiation dose, hemoglobin concentration and systolic or pulse pressure. Radiosensitivity is dependent upon the oxygen concentration which, in normal tissues, is related to the hemoglobin concentration and in tumor to both the hemoglobin and the systolic blood pressure. The achievement of a threshold radiation dose appears essential before these prognostic factors become relevant.

The influence of plasma glucose levels on fluorine-18-fluorodeoxyglucose uptake in bronchial carcinomas.

PET studies with 2-18F-fluorodeoxyglucose (FDG) were carried out in 15 patients with bronchial carcinomas, first under fasting conditions and then 2 days later during intravenous infusion of a 20% glucose solution which raised the plasma glucose level from 84.6 +/- 14.7 to 168.3 +/- 23.6 mg/100 ml (n = 15, p < 0.001). Tumor metabolism was quantified by the dose absorption ratio (DAR) of FDG uptake [DAR = tissue concentration/(injected dose/body weight)] and also by the rate of glucose consumption (MR) as measured by the Patlak graphical approach in 12 patients. The DAR decreased from 5.07 +/- 1.89 under fasting conditions to 2.84 +/- 0.97 (-41.8% +/- 15%, n = 15, p < 0.001) during glucose infusion, while the MR remained constant (4.71 +/- 2.38 mg/100 ml/min versus 4.96 +/- 2.46 mg/100 ml/min, n = 12, ns). Correction of the DAR data by plasma glucose level eliminated the significant difference between the fasting and glucose load [4.24 +/- 1.59 versus 4.70 +/- 1.45 (n = 15, ns)], but considerable changes in individual patients remained. These data indicate that the DAR of FDG uptake in bronchial carcinomas is influenced significantly by plasma glucose levels. Dynamic quantification of glucose metabolism using the Patlak approach is less dependent on the plasma glucose level and appears advantageous when high reproducibility is needed.

Factor VIII inhibitor and bronchogenic carcinoma.

An inhibitor to procoagulant factor VIII (FVIIIC) developed in a patient three years after palliative resection of a bronchogenic carcinoma. The inhibitor was not active against ristocetin cofactor but possibly had some activity against factor XI. It responded to immunosuppressive therapy. This is apparently the first reported association of carcinoma and factor VIII inhibitor.

Changes in T cell population in patients with bronchogenic carcinoma.

Absolute numbers of T cells were measured in a series of 84 patients with bronchogenic carcinoma and were compared with T cell percent with regard to clinical stage, course, and histologic type. Although T cell percent declined in accordance with the advancement of stage, the differences between the stages were not statistically significant. On the other hand, the absolute number of T cells decreased prominently in Stages III and IV as compared to Stages I and II (p less than 0.05 between Stages I and III, P less than 0.001 between Stages I and IV, and p less than 0.05 between Stages II and IV). Likewise in patients who were followed serially after resection, the absolute number of T cels correlated well with the postoperative course. These results lead us to the conclusion that it is more useful estimate the absolute T cell count rather than T cell percentage in lung cancer.

Soluble interleukin 2 receptor in lung cancer. An indirect marker of tumor activity?

Circulating levels of the soluble interleukin 2 receptor (sIL-2R) could provide an in vivo measure of the immunologic response to human tumors. We performed a total of 326 sIL-2R serum assays in 126 patients with lung cancer (67 at diagnosis, 59 during and after treatment), 112 patients with pulmonary benign diseases, and 63 voluntary healthy subjects. Patients with lung cancer had a median value of sIL-2R of 791 U/ml, which was superior to that of both controls (398 U/ml, p less than 0.001) and patients with noninflammatory benign diseases (583 U/ml, p less than 0.02). However, infectious pulmonary disorders, such as tuberculosis and pneumonia, were associated with the highest values of the substance (median, 1150 U/ml; p less than 0.001). At the diagnosis of lung cancer, sIL-2R correlated neither with the stage of disease nor with the cell type. On the contrary, posttreatment levels of the receptor were significantly related to disease status (RO = .41, p less than 0.002), particularly in the subgroup of nonsurgical patients (RO = .48, p less than 0.001). Patients with abnormal sIL-2R levels had a nearly significant reduction in survival as compared with patients with normal values (p less than 0.1). Measurements of sIL-2R could be useful in monitoring patients under treatment for bronchogenic carcinoma, as well as in prognostication. In this setting, sIL-2R might open a new class of biologic markers, providing information that is complementary to those of the more classic tumor-derived markers.

BAL neopterin : a novel marker for cell-mediated immunity in patients with pulmonary tuberculosis and lung cancer.

BACKGROUND: Neopterin is derived from guanosine triphosphate and is produced by stimulated macrophages under the influence of gamma-interferon of lymphocyte origin. It has been suggested that it is an excellent marker for the activation of the monocyte/macrophage axis in some clinical situations. However, to our knowledge, the relationship of BAL neopterin levels to disease states has not been studied. AIM: To assess the usefulness of BAL neopterin levels as an index of disease activity in patients with pulmonary tuberculosis and lung cancer. METHODS: BAL and serum neopterin levels were evaluated in 20 patients with pulmonary tuberculosis, 20 patients with bronchogenic carcinoma, and 10 healthy individuals. The concentration of neopterin was evaluated by radioimmunoassay technique. The BAL level of neopterin was standardized using the BAL urea level. RESULTS: The neopterin levels (mean +/- SD) in the BAL and serum of tuberculous patients (88.6 +/- 27.4 nmol/L epithelial lining fluid [ELF], 61.3 +/- 29.4 nmol/L, respectively) were significantly higher when compared with those in lung cancer patients (40.7 +/- 16.6 nmol/L ELF, 26.8 +/- 6.58 nmol/L, respectively, p < 0.001) and when compared with those in control subjects (26.3 +/- 11.3 nmol/L ELF, 6.8 +/- 2.7 nmol/L, respectively, p < 0.001). In the tuberculous group, BAL and serum neopterin levels in patients with far-advanced disease were significantly higher when compared with those in patients with moderately and minimally advanced diseases (p < 0.001). BAL and serum neopterin levels were significantly higher in patients with small cell carcinoma than in those with adenocarcinoma (p < 0.05). BAL neopterin levels were significantly (p < 0.001) higher than serum levels in all patients and control groups. In addition, there were significant positive correlations between BAL and serum neopterin levels in tuberculous (r = 0.92, p < 0.001), lung cancer (r = 0.62, p < 0.001), and control groups (r = 0.93, p < 0.001). CONCLUSIONS: The levels of neopterin in BAL fluid may reflect the degree of disease activity in pulmonary tuberculous patients. In addition, BAL neopterin levels are elevated in patients with lung cancer, especially the small-cell carcinoma type.

Increased serum calcitonin levels in bronchogenic cancer.

A study of 26 men with bronchogenic cancer demonstrated high serum calcitonin levels in 62 percent (16). Levels were particularly high in patients with small-cell cancer and adenocarcinoma. Two varieties of hypercalcitonemia have been encountered: (1) ectopic hypercalcitonemia, in which the hormone is secreted by the tumor, and (2) thyroidal hypercalcitonemia, in which the high values emanate from the thyroid gland. In several patients, serum calcitonin levels decreased following therapy for the cancer. Further studies are needed to evaluate the diagnostic value and clnical utility of serum calcitonin levels as a marker substance in bronchogenic cancer.

Plasma glutamate levels, lymphocyte reactivity and death rate in patients with bronchial carcinoma.

Elevated glutamate concentrations are commonly observed in patients with advanced carcinoma, and glutamate was recently found to inhibit the membrane transport of cystine and to impair the function of macrophages and lymphocytes in vitro. We therefore investigated the possibility that elevated plasma glutamate levels may be quantitatively correlated with reduced lymphocyte reactivity and an impaired host response to the tumor. Here we report the results of a study on patients with bronchial carcinoma, which show that patients with plasma glutamate levels above 120 microM have a lower lymphocyte response to mitogens and a substantially higher death rate than those with glutamate levels below 120 microM. This correlation does not prove a causal role of glutamate, but it confirms predictions from the in vitro laboratory data.

High colony stimulating activity in a patient with disseminated carcinoma and neutrophil leucocytosis.

The case of a man with widespread bronchogenic carcinoma associated with pronounced neutrophil leucocytosis is presented. There was no evidence of infection or metastatic bone marrow infiltration. Increased levels of colony stimulating activity were shown in the patient's serum using three methods. Findings in this patient suggest that the leukaemoid blood picture was related to inappropriate tumour associated production of colony stimulating factors.