James S. Marshall

Progesterone Receptors as a Prognostic Factor in Stage II Breast Cancer

Abstract The presence of estrogen receptors in breast cancers is now accepted as a predictor of extended disease-free survival, but the relative value of progesterone receptors for this purpose has not been established. We have examined both receptors along with other risk factors in 189 patients receiving adjuvant therapy for Stage II breast cancer. The presence of either estrogen receptors or progesterone receptors was positively correlated with disease-free survival when analyzed separately, whether or not the adjuvant regimen included an endocrine component. However, when estrogen receptors and progesterone receptors were analyzed together in multivariate models, the presence of progesterone receptors was more significant than that of estrogen receptors for predicting time to recurrence, regardless of what other variables were included in the model. These data suggest that determination of the progesterone-receptor concentration is of equal or greater value than determination of the estrogen-receptor ...

Measurement of Circulating Desialylated Glycoproteins and Correlation with Hepatocellular Damage

Addition of increasing amounts of (125)I-labeled desialylated thyroxine-binding globulin (DTBG) to hepatic cell membranes resulted in a progressive increase in binding. Saturability of membrane sites was indicated by a concentration beyond which further increases in [(125)I]DTBG resulted in no further binding. The binding curve for [(125)I]DTBG was similar to binding curves of desialylated orosomucoid, fetuin, and ceruloplasmin. An inhibition assay system using hepatic cell membranes showed that desialylated orosomucoid had a greater affinity for membrane binding sites than did DTBG but desialylated fetuin and ceruloplasmin bound less avidly than DTBG. Serum from normal persons and patients with a variety of illnesses was tested for its ability to inhibit [(125)I]DTBG binding. The inhibitory activity of 1 ml of normal serum was equivalent to that of 0.2-2 mug DTBG. Patients with Laënnecs cirrhosis, biliary cirrhosis, and hepatic metastases had greatly increased inhibitory activity in their serum. Patients with jaundice due to extrahepatic obstruction had inhibitory activity not significantly different from that found in normal serum. Column chromatography of normal serum on Sephadex G-200 resulted in inhibitory activity throughout the range of protein molecular weight. Desialylation of normal serum with neuraminidase enhanced the inhibitory activity but did not change the distribution of the activity. Gel chromatography of cirrhotic serum showed markedly increased inhibitory activity associated with the macroglobulins and the 4.5S peak and a new peak of inhibitory activity in the low molecular weight area was also seen. Inhibition of desialylated glycoprotein binding to liver cell membranes by serum from patients with hepatocellular disease raises the possibility that desialylated serum glycoproteins accumulate in the circulation and that patients with compromised hepatocellular function may no longer be able to clear them from the circulation. Alternatively, accumulation of desialylated glycoproteins in the circulation could result from defective protein synthesis by the diseased liver.

Studies on thyroxine-binding globulin (TBG): II. Separation from human serum by affinity chromatagraphy☆

Abstract Thyroxine-binding globulin (TBG) has been separated from human serum by affinity chromatography using Sepharose to which l -thyroxine had been covalently attached. Further purification of the TBG in the material eluted from the T4-Sepharose was carried out by DEAE-Sephadex column chromatography. The final product produced a single stained band on analytic disc-gel electrophoresis. Radio-autography of this material to which tracer amounts of radioactive thyroxine had been added prior to electrophoresis on cellulose acetate showed a single band of thyroxine radioactivity with the electrophoretic mobility of TBG in normal human serum. The calculated yield of TBG by this procedure was 18–37%.

Antihormone treatment of stage IV breast cancer

The antiestrogen Tamoxifen (T), given orally to 113 patients with stage IV breast cancer, induced objective remission in 50%. Duration of remission in the first 39 patients, with minimum 27 months follow up, is 18+ months; these results are equal to those of surgical hypophysectomy. T prolonged survival in responders. Older age, previous response to endocrine therapy and positive estrogen receptors predicted response to T. T was effective in hypophysectomized patients in whom serum growth hormone and prolactin were undetectable, but serum estrogens were present in low amount, suggesting a direct stimulatory effect of estrogens at the tumor level. Hypophysectomy induced further palliation after treatment with T, indicating that pituitary hormones may also play a role in the growth of some human breast cancers. Side effects from T were minimal. T is the initial treatment of choice for postmenopausal women with hormone responsive stage IV breast cancer. Cancer 43:444–450, 1979.

Estrogen receptor status as a prognostic indicator for stage I breast cancer patients

SummaryThe prognostic value of estrogen receptor determination was studied for 510 stage I (axillary node negative) breast cancer patients treated by mastectomy alone.Results at 60 months after mastectomy indicate that stage I patients whose tumors lack estrogen receptors fall into a significantly poorer prognostic group for both recurrence and survival than those whose tumors contain estrogen receptors.Within the postmenopausal group, estrogen receptor negative (ER −) patients are recurring more rapidly than estrogen receptor positive (ER +) patients. Within the premenopausal group, ER + patients have a recurrence rate identical to ER− patients, which is apparent only after prolonged follow-up.In contrast to postmenopausal ER + patients, premenopausal ER + patients appear to have no prognostic advantage over the ER − patients, and thus constitute a high risk group for which adjuvant endocrine therapy might prove beneficial.

Adjuvant therapy of stage II breast cancer

SummaryA prospective, randomized clinical trial of adjuvant treatment of 318 stage II breast cancer patients, using chemotherapy, the antiestrogen tamoxifen, and immunotherapy is reported at 48 months follow-up.Women whose primary tumors have no estrogen receptors fall into a significantly poorer prognostic group than those whose tumors contain estrogen receptors. None of the adjuvant regimens appeared to offer any clear-cut advantage for the estrogen receptor negative patients.Those women whose primary tumor contains estrogen receptors appear to be in a prognostically favorable group, when their treatment regimen included the antiestrogen, tamoxifen. The adjuvant use of BCG immunotherapy does not appear to offer additional benefit, but the follow-up period of these treated patients is too brief to be conclusive.A longer period of observation is needed to determine whether this systemic treatment in estrogen receptor positive patients is preventing recurrence or merely delaying it.

Studies on human thyroxine-binding globulin: VIII. Isoelectric focusing evidence for microheterogeneity of thyroxine-binding globulin

Abstract Highly purified thyroxine-binding globulin from pooled human serum homogeneous by conventional criteria, subjected to isoelectric focusing in polyacrylamide gels in a pH gradient from 3–6, produced a pattern of at least nine stainable protein bands. All of these bands appeared to bind thyroxine. Completely desialylated thyroxine-binding globulin subjected to isoelectric focusing produced the same number and pattern of bands located at a different area in the pH gradient. Thyroxine-binding globulin purified from the serum of a single donor was subjected to isoelectric focusing. This thyroxine-binding globulin had the same pattern of protein bands with the exception that one of the major bands seen in the thyroxine-binding globulin from pooled serum was absent. Several possible explanations for these phenomena are discussed.

Coexistent Idiopathic Thrombocytopenic Purpura and Hyperthyroidism

Excerpt Since 1931, sporadic reports have appeared noting an apparent association between hyperthyroidism and idiopathic thrombocytopenic purpura (ITP) (1-4). During a recent survey of our patients...

Metabolism of thyroxine-binding globulin in man. Abnormal rate of synthesis in inherited thyroxine-binding globulin deficiency and excess.

It has been previously suggested that inherited thyroxine-binding globulin (TBG) abnormalities in man may be due to mutations at a single X-chromosome-linked locus controlling TBG synthesis. However, abnormalities in TBG degradation have not been excluded. The availability of purified human TBG and its successful labeling with radioiodide allowed us to examine such possibility. Human TBG was purified by affinity chromatography, labeled under sterile conditions with 131I or 125I,, and mixed with [125I]thyroxine (T4) or [131I]T4, respectively, before their intravenous injection. Blood and urine samples were collected over a 10-day period, and the turnover parameters were calculated. In eight normal volunteers mean values +/-SD for TBG and T4 respectively, were as follows: Half time (t1/2) 5.3 +/- 0.4 and 7.0 +/- 0.6 days; distribution space (DS) 7.2 +/- 1.0 and 10.8 +/- 1.2 liters; and total daily degradation (D) 0.211 +/- 0.053 and 0.088 +/- 0.011 mumol/day. In all subjects, t1/2 of TBG was shorter than that of T4; and the DS was smaller. 2.4 mol of TBG was degraded for each mole of T4. In five of six subjects from four families, comprising hemizygous and heterozygous carriers of TBG absence, decrease, and excess, the t1/2 and DS for TBG were within the normal range. The D of TBG was proportional to the serum concentration of the protein. Changes in the T4 kinetics in these patients were compatible with euthyroidism and with the known alterations in the extrathyroidal T4 pool associated with the changes in serum TBG concentration. A striking decrease in the t1/2 of TBG was found only in a patient with acquired diminution in TBG concentration and in patients with thyrotoxicosis or other conditions apparently unrelated to thyroid dysfunction. TBG t1/2 was 2.5 days in a patient with multiple myeloma and 3.6 days in two patients with thyrotoxicosis. Decreased TBG t1/2 was also observed in three of six patients with nonthyroidal pathology and was associated with an increase in TBG D disproportionate to their level of serum TBG. These studies indicate that changes in TBG concentration in patients with X-chromosome-linked TBG abnormalities are due to alterations in its rate of synthesis. In other conditions, abnormalities of TBG degradation and/or rate of synthesis may be found.

Studies on thyroxine-binding globulin (TBG): III. Some physical characteristics of TBG and its interaction with thyroxine

Thyroxine-binding globulin (TBG) purified from human serum by affinity chromatography had a mol wt of 63,000–65,000, a sedimentation constant of 3.4S, and E 1 cm 1% at 280 mμ of 6.9. The purified TBG bound thyroxine (T 4 ) in a molar ratio of approximately 1:1. Binding of T 4 to TBG was maximal over a pH range of 6.4–10.4. Below pH 6.4 the T 4 -TBG interaction began to decline and at pH 4.2 binding nearly disappeared. Purified TBG treated with 8 m urea migrated as a single band with a slower electrophoretic mobility than the native protein and did not bind T 4 . After removal of urea by dialysis, five to six protein bands were detectable by polyacrylamide disc gel electrophoresis. The most anodal band had the same mobility as the native protein and regained the ability to bind T 4 , but none of the slower moving bands bound T 4 .