Carcinoembryonic antigen: a useful prognostic marker in small-cell lung cancer.

Plasma carcinoembryonic antigen (CEA) was determined in 180 patients with small-cell lung cancer (SCLC) before treatment. An abnormal level (greater than or equal to 6 ng/mL) was found in 34% of patients tested. Patients with extensive disease (39/83) had a significantly higher frequency of abnormal CEA (P = .001) than those with limited disease (22/97). There was a strong correlation between obtaining an objective response--particularly a complete response (P = .00003)--and the absence of an elevated CEA. Patients with an abnormal CEA also had a shorter survival time (P = .0007) and the difference remained statistically significant after logrank adjustment for extent of disease and ECOG (Eastern Cooperative Oncology Group) performance status. There was also a negative correlation between survival time and the quantitative level of CEA. In this series, only the group of patients with normal initial CEA levels included all survivors beyond 2.5 years. We conclude that CEA is a useful prognostic factor in SCLC.

Activation of thyroid adenyl cyclase by antisera to thyroid plasma membrane preparations.

Adenyl cyclase was assayed in a series of plasma membrane fractions prepared from bovine thyroids using sucrose density gradient ultracentrifugation. The activity of adenyl cyclase in the plasma membranes was found to be stimulated several-fold by antisera raised in rabbits against the plasma membranes and by purified IgG prepared from these antisera. The data indicate that the antibodies to thyroid plasma membrane manifest properties similar to those of the immunoglobulins long-acting thyroid stimulator (LATS) and human specific thyroid-stimulating immunoglobulin (HTSI) found in patients with Graves' disease. It is suggested that, in these patients, the antigen which leads to the production of LATS and HTSI is most likely situated in the thyroid plasma membrane.

Functional analysis of a proline to serine mutation in codon 453 of the thyroid hormone receptor beta 1 gene.

Mutations in the gene encoding human thyroid hormone receptor beta (hTR beta) have been associated with generalized resistance to thyroid hormone (GRTH). This disorder is associated with significant behavioral abnormalities. We examined the hTR beta gene in a family with members who manifest inappropriately normal TSH, elevated free T4, and free and total T3. Sequence analysis showed a cytosine to thymine transition at nucleotide 1642 in one allele of the index patient's genomic DNA. This altered proline to serine at codon 453. The resulting mutant receptor when expressed in vitro bound DNA with high affinity, but the T3 affinity of the receptor was impaired. The mutant TR demonstrated a dominant negative effect when cotransfected with two isoforms of wild-type receptor and also in the presence of TR variant alpha 2 in COS-1 cells. Mutations of codon 453 occur more frequently than at other sites, and four different amino acid substitutions have been reported. Significant differences in phenotype occur among affected individuals, varying from normality to moderately severe GRTH. There is no clear correlation between Ka or in vitro function of the mutant receptor, and phenotype. This study extends the association between GRTH and illness, and indicates that early diagnosis and counseling are needed in families with TR beta 1 abnormalities.

Activation of thyroid adenyl cyclase by antisera to thyroid plasma membrane preparations: effects of IgG and non-IgG antiserum components.

We have previously shown that IgG isolated from rabbit antibovine thyroid plasma membrane (anti-BTPM) antibodies exhibits properties similar to long acting thyroid stimulator (LATS) and HTS-lg in that it activates thyroid adenyl cyclase. In order to test whether another immunoglobulin class, eg, IgM, of anti-BTPM antiserum can also stimulate the bovine thyroid adenyl cyclase system, protein molecules of the antiserum were separated into different molecular sizes by gel filtration chromatography on Sephadex G-200. It was observed that the low molecular weight fraction, consisting predominantly of albumin, was inactive in stimulating adenyl cyclase of the thyroid gland. In contrast, both IgM-enriched and IgG-enriched fractions of the immune serum were fully active. Furthermore, the thyroid-stimulating activity of the IgM-enriched fraction can only be inhibited by anti-IgM and that of the IgG-enriched fraction by anti-IgG. Our data suggest that IgM, in addition to IgG, may also have LATS or LATS-like activities in terms of activating adenyl cyclase of the thyroid gland.

Alteration of lymphocyte reactivities by thyroid hormones.

The effects of thyroid hormones (L-T4, L-T3 and rT3) on the proliferative response of rabbit peripheral blood lymphocytes to T-cell mitogens, PHA and Con A, and B cell specific goat anti-rabbit light chain antibodies (Anti-L) were investigated. It was observed that L-T4 potentiated the lymphocyte response to mitogens and Anti-L in a dose-dependent manner: 10(-9) M and 10(-8) M had no effect while 10(-7)-10(-5) M significantly enhanced the lymphocyte response. L-T3 (10(-11)-10(-8) M) had no effect on the lymphocyte response to PHA and Con A. At 10(-7) M, L-T3 inhibited the response to PHA but not Con A. L-T3 (10(-11)-10(-7) M) suppressed the lymphocyte response to Anti-L. The suppression was directly proportional to the L-T3 concentration. rT3 (10(-11)-10(-7) M) inhibited the proliferative response to PHA and Anti-L in a dose-related manner. Its effect on the lymphocyte response to Con A was stimulatory at 10(-11) M but inhibitory at higher concentrations (10(-8) and 10(-7) M). rT3 suppressed the enhancement by L-T4 of the lymphocyte response to the mitogens and Anti-L. The degree of suppression was proportional to its concentration. This data indicated that thyroid hormones can alter the reactivities of lymphocytes. The direction and magnitude of the alteration appear to depend on the concentration of a specific thyroid hormone encountered by the responding cells.

Activation of adrenal adenyl cyclase by anti-thyroid plasma membrane antibodies.

We have previously shown that IgG isolated from rabbit anti-bovine thyroid plasma membrane (anti-BTPM) antiserum exhibits properties similar to thyroid stimulating antibodies (TSAb) in that it activates thyroid adenyl cyclase. In this study, the organ non-specificity of this reaction was investigated. It was observed that anti-BTPM IgG stimulated not only adenyl cyclase of bovine thyroid but also that of the adrenal. The stimulatory activities on the thyroid and adrenal adenyl cyclase were abolished by absorption of the IgG with bovine adrenal plasma membrane (BAPM). These results indicate that anti-BTPM antibodies, similar to TSAb, exert both thyroidal and extra-thyroidal effects. Thus anti-BTPM antibodies may be directed against antigenic determinants that are common to both thyroid and adrenal plasma membranes. Like the anti-BTPM IgG, anti-BAPM IgG also activated both thyroid and adrenal adenyl cyclase. However, when IgG of the anti-BAPM antiserum was absorbed with thyroid plasma membranes, only the thyroid, but not the adrenal stimulating activity was abolished. It was concluded that the anti-BAPM antiserum contained antibodies directed against membrane antigens specific for the adrenal as well as common antigens shared by the thyroid.

Clinical correlations of carcinoembryonic antigen in post-operative patients with epithelial ovarian cancer.

Plasma CEA as a tumor marker was studied in 681 postoperative patients with invasive epithelial cancer of the ovary. The sensitivity of a single CEA value was low in correlating with tumor burden, relapse status or in predicting subsequent relapse. The false negative rate was high. Serial samples were helpful in predicting relapse in a small number of patients where the value was persistently high. CEA showed greater sensitivity and prognostic value in patients with the mucinous tumor subtype, than other histologies. A clinically useful role for CEA is likely to be restricted to small subsets of patients, such as those with mucinous tumors where CEA may have a complementary role with other markers. A change in assay method during the course of the study resulted in a weakening of the value of CEA as a tumor marker.

Imaging studies and the prognostic value of serum calcitonin in staging small-cell lung cancer.

The controversial prognostic significance of serum calcitonin in small-cell lung cancer (SCC) prompted this retrospective study relating serum levels to (1) stage of disease [limited disease (LD) vs. extensive disease (ED)], (2) imaging studies of metastases to bone, liver, and brain, and (3) survival. Of the 127 previously untreated patients with SCC presenting from 1979 to 1984, calcitonin levels could be compared to the stage of the disease in 69 patients (25 LD and 44 ED) and to various staging procedures including 99mTc methylene diphosphonate bone scans (63 patients), 99mTc sulfur colloid liver-spleen scans (64 patients), computed tomography of the head (63 patients) and serum calcium (61 patients). 71% (49/69) of patients had elevated calcitonin of whom 65% (32/49) had ED. 29% (20/69) had normal levels of whom 60% (12/20) had ED. 40% (18/45) of patients with raised calcitonin had liver metastases. 100% (19/19) with normal calcitonin had no liver involvement. Two patients with hypercalcemia and increased calcitonin had extensive bony metastases. The survival experiences of patients with normal and elevated serum calcitonin levels were analyzed. No significant differences were found within each stage or in the group overall. The positive correlation of serum calcitonin to liver metastases was statistically significant. No such relationship could be demonstrated with stage of disease, bone metastases, brain metastases, or survival.

3,5,3'-Triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) synthesis in rats hosting the R3230AC mammary tumour.

Generation of T3 and rT3 from T4 was studied in R3230AC mammary tumours grown in Fischer 344 rats as well as in the liver and kidney of these tumour-bearing hosts. The primary objective of this study was to determine if reversion of T3 to rT3 synthesis occurs in this experimental tumour model and in organs remote from the tumour site. Tumours, hepatic and renal homogenates were analyzed 14-16 days following tumour implantation for 5- and 5'-iodothyronine deiodinase activity using thyroxine as substrate. It was observed that similar to the liver and kidney, the mammary tumour was capable of generating both T3 and rT3 from T4; renal synthesis of T3 was significantly greater than that of rT3 in tumour hosts and controls. In contrast, there was no significant difference between T3 and rT3 synthesis in the tumour itself and the livers of normal and tumour-bearing animals. Hepatic and renal T3 synthesis were greater in the tumour-bearing than in the normal rats; no difference in the hepatic and renal rT3 synthesis was observed between the tumour-bearing and the normal animals. Despite the fact that serum T3 was significantly lower in the tumour-bearing than in the normal rats, no difference in the serum rT3 level was observed between the two groups of animals. Our data demonstrate that in this particular animal model there is no evidence of dedifferentiation of iodothyronine deiodinase activity either within the tumour or in remote tissues.

Carcinoembryonic antigen in breast cancer.

Carcinoembryonic antigen (CEA) levels were determined in 742 postoperative patients with breast cancer. Within this group the percentage of elevated (greater than or equal to 4.0 ng/ml) assays increased with UICC clinical stage and was 14.8% (12/81), 23.7% (27/114), 73.1% (190/260) and 20.0% (49/245) for stages I, II, III, IV and X (unstagable due to insufficient data) patients. We have now followed the above 482 stages I, II, III and X patients in whom CEA was performed less than or equal to 3 months after initial surgery at a time when there was no evidence of residual disease, for an average interval of 255 days from date of diagnosis. At present 16.2% (17/105) of patients with elevated CEA values compared to only 4.8% (18/377) of patients with normal values have developed recurrent disease (p less than .0005). There is an association of elevation of CEA postoperatively with different clinical stages of breast cancer. Elevated CEA levels postoperatively are associated with an increased risk of development of recurrent disease in breast cancer patients.

Changes in thyroid hormones, thyroid stimulating hormone and cortisol in acute spinal cord injury.

To determine the hormonal response to acute spinal cord injury, serial serum samples were collected from 18 patients with acute spinal cord injury and from 14 control patients with spinal fractures without cord injury. The first sample was taken within 24 hours of injury, the second at 24-48 hours; and the third at 7 days for determination of thyroxine (T4), free T4 (FT4), triiodothyronine (T3), reverse T3 (rT3), T3 uptake (T3U), thyroid stimulating hormone (TSH), thyroxine binding globulin (TBG), growth hormone (GH), cortisol, and insulin. Significant increases were observed in rT3 levels and transient changes were observed in the T4 and T3 levels in the spinal cord injured group but not in the group with spinal fractures alone. The changes in the spinal cord injured patients are consistent with the 'low T3 syndrome'. However, the persisting rise of rT3 at 7 days was an unexpected finding. In addition to the cord injury, these changes may also be related to dexamthasone administration and nutritional factors.