G. F. F. M. Pieters

Disease-free interval and estrogen receptor activity in tumor tissue of patients with primary breast cancer: analysis after long-term follow-up

SummarySpecific estrogen receptor activity (ER) was found in 115 of 175 (66%) tumors of patients treated for primary breast cancer in the period 1974–1981; 60 patients had ER-negative tumors. All patients were under observation for at least 48 months (median 76 months). The 24 patients who received adjuvant chemotherapy as part of their initial treatment, were excluded from the analysis of the disease-free interval (DFI). Groups of patients with ER-positive or ER-negative tumors did not differ significantly in clinical characteristics. Patients with ER-positive tumors had a significantly longer DFI than those with ER-negative tumors only in the first year after initial treatment. After prolonged observation a significant difference in recurrence rates was no longer found. In premenopausal women, the DFI was not different for those with ER-positive compared to those with ER-negative tumors, not even in the first year of observation. However, in postmenopausal women, those with ER-positive tumors had a significantly longer DFI up to 3 years after initial treatment but not thereafter. There was no difference in DFI between the ER-positive and ER-negative groups when the tumor stage was taken into account. It is concluded that the ER status of the primary tumor affects prognosis only on the short term.

Transition from Pituitary-Dependent to Adrenal-Dependent Cushing's Syndrome

PITUITARY-DEPENDENT bilateral adrenocortical hyperplasia (Cushings disease) is present in 70 to 80 percent of all patients with Cushings syndrome. In 20 to 40 percent of patients with Cushings d...

HUMAN PANCREATIC GROWTH HORMONE RELEASING HORMONE FAILS TO STIMULATE HUMAN GROWTH HORMONE BOTH IN CUSHING'S DISEASE AND IN CUSHING'S SYNDROME DUE TO ADRENOCORTICAL ADENOMA

An absent or severely blunted hGH response to an i.v. bolus injection (100 μg) of human pancreatic growth hormone releasing hormone (hpGRF1–44) was found in seven female patients with Cushings syndrome (five with pituitary dependent Cushings disease and two due to an adrenal adenoma) and four men with pituitary dependent Cushings disease. Three of the female and three of the male patients had an adequate hypoglycaemia after insulin administration. All these patients showed an absent or blunted hGH response after insulin induced hypoglycaemia. The GHRH data in these patients are in agreement with those in older literature on hGH responsiveness to stimuli such as L‐dopa, arginine and insulin induced hypoglycaemia. It is concluded that hypercortisolism inhibits hGH release to various stimuli at the pituitary level.

Hypotensive effects of ovine and human corticotrophin-releasing factors in man

SummaryThe haemodynamic effects of i.v. bolus injections of 100 and 200 µg ovine CRF and human CRF in man have been compared. Neither ovine CRF 100 µg nor human CRF 100 µg caused a significant change in blood pressure, although the pulse rate was increased in all the subjects tested. The mean maximum increase in pulse rate after human CRF was almost twice that after ovine CRF (21 vs 12 beats·min−1;p<0.05). After 200 µg ovine CRF in all subjects the diastolic blood pressure declined gradually from 77 mm Hg to a nadir of 67 mm Hg at 22 min (p<0.002). After 200 µg human CRF diastolic blood pressure fell from 78 mm Hg to a nadir of 61 mm Hg at 6 min (p<0.002); the fall after human CRF was significantly greater than after ovine CRF (p<0.05). After 200 µg ovine CRF there was a slight increase in pulse rate lasting for 6 min, and after 200 µg human CRF there was a marked (reflex) tachycardia for 30 min. Only after the highest dose of human CRF did a slight increase in systolic blood pressure occur. The haemodynamic effects of both doses of human CRF were accompanied by significant increases in plasma noradrenaline concentrations, which were significantly greater after the higher dose.

Progression of a Nelson’s adenoma to pituitary carcinoma; a case report and review of the literature

A 25-year-old woman developed Nelson’s syndrome, 3 years after successful bilateral adrenalectomy for Cushing’s disease. Despite pituitary surgery and radiotherapy the tumour showed invasive growth, Ieading to visual disturbance, paresis of the oculomotor nerve and, 34 years after adrenalectomy, to death by widespread purulent leptomeningitis. Autopsy revealed a large adenohypophyseal carcinoma with a metastasis attached to the dura, both tumours showing immunocytochemical staining for ACTH and TSH. We review the literature on metastatic adenohypophyseal carcinoma in Cushing’s disease and Nelson’s syndrome and discuss the role of proliferation markers as indicators of malignant progression.

Progesterone receptor activity and relapse-free survival in patients with primary breast cancer: the role of adjuvant chemotherapy

The prognostic significance of progesterone receptor activity (PgR) with regard to the estimated relapse-free survival (RFS) was studied in 350 one-center patients with primary breast cancer. All receptor assays were performed in one laboratory; PgR levels >10 fmol/mg protein were considered positive. Univariate as well as multivariate statistical analyses were used to examine the prognostic significance of several variables. Eighty-nine of the 350 patients received adjuvant CMF chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil). The median observation period was 69 months (range 12–125 months).In the group of 261 patients who did not receive adjuvant CMF, the PgR-status lacked prognostic significance; only the lymph node status significantly affected the RFS (p<0.00001). In contrast, in the CMF-treated group of patients, the PgR-status was the most powerful predictor of recurrence (p<0.0001). The menopausal and the lymph-node status increased the predictive value of PgR (p<0.001). Premenopausal CMF-treated patients with PgR+ tumors had a significantly longer RFS than those with PgR− tumors (p<0.02). The present data urge the need for a reappraisal of the prognostic significance of PgR and of the mechanism of action of adjuvant chemotherapy in primary breast cancer.

Concordance and discordance of estrogen and progesterone receptor content in sequential biopsies of patients with advanced breast cancer: Relation to survival

In 75 patients with advanced breast cancer, sequential biopsies were analyzed for estrogen receptor (ER). In 50 of these patients progesterone receptor (PgR) was also measured. All pairs of biopsies met the following criteria: (i) interval between the two biopsies: at least 6 weeks; (ii) biopsies performed at least 6 weeks after stopping endocrine therapy; and (iii) concordant histology. Discordance in ER was found in 14 of 75 patients (18.7%); PgR was discordant in 14 of 50 patients (28.0%). No significant differences were found between concordant and discordant groups of patients in age at first diagnosis, menopausal state, diameter of the primary tumor, time interval between the two biopsies and intervening therapy. The initial ER level in patients whose ER changed from positive to negative was significantly lower than in patients whose ER remained positive. PgR levels exhibited a rise only when ER rose at the same time. Sequential assays have increased the prognostic significance of ER and as a consequence the estimated survival time for patients whose tumors were ER-negative in both biopsies was significantly shorter than for patients whose tumors were ER-negative in only one of the two biopsies. We found no prognostic significance for PgR in either single measurements or repeated biopsies.

Plasma IGF-I is a useful marker of growth hormone deficiency in adults.

Diagnosing growth hormone deficiency in adults is difficult. Provocation tests are most commonly used for the diagnosis with the insulininduced hypoglycemia test nowadays considered as the “gold standard”. The role of IGF-I concentrations in diagnosing growth hormone deficiency in adults is under discussion. In 58 adult patients with proven growth hormone deficiency, the sensitivity and specificity of IGF-I concentrations in relation to growth hormone deficiency were evaluated. Reference values of plasma IGF-I were obtained from 53 healthy volunteers. Using a calculated cut-off concentration of 15 nmol/l we were able to demonstrate that IGF-I concentration is a reliable screening method for growth hormone deficiency. Using this cut-off point in a patient population younger than 40 years of age, sensitivity was 90% and specificity 89%. For patients exceeding the age of 40 years, sensitivity, specificity and positive predictive value were rather low, but the negative predictive value was as high as 90%, indicating that for patients over 40 years IGF-I concentrations above 15 nmol/l exclude growth hormone deficiency. In summary, under the age of 40 years measuring plasma IGF-I provides an useful tool to diagnose growth hormone deficiency, whereas above 40 plasma IGF-I values exceeding 15 nmol/l virtually exclude growth hormone deficiency.

Differential effects of ovine and human corticotrophin-releasing factor in human subjects.

Ten healthy subjects received 200 μg of human CRF (hCRF) and 200 μg of ovine CRF (oCRF) as an intravenous bolus injection on two different occasions. After hCRF plasma ACTH levels rose significantly (P< 0.0005, by Friedmans nonparametric analysis of variance) from a basal value of 35 ± 3 pg/ml (mean ± SEM) to a peak value of 80 ± 7 pg/ml 30 min after hCRF administration. This ACTH response was followed by a rise in plasma cortisol levels (P< 0.0005, by Friedmans test) from a baseline value of 0.32 ± 0.03 /μmol/l to a peak value of 0.56 ± 0.02 /μmol/l 60 min after hCRF. Ovine CRF elicited similar rises in the plasma ACTH and cortisol levels. However, as derived from the faster rate of decline of ACTH and cortisol after hCRF than after oCRF, human CRF had a significantly shorter duration of action than ovine CRF in humans. Human CRF not only stimulated ACTH release by the human pituitary gland but also prolactin release. After hCRF administration prolactin levels rose significantly (P< 0.005, by Friedmans test) from a basal value of 179 ± 18 mU/l to a peak value of 288 ± 34 mU/l at 10 min.

Pancreatic Exocrine and Gallbladder Function during Long-Term Treatment with Octreotide (SMS 201–995)

Since octreotide (SMS 201-995, Sandostatin; Sandoz Pharmaceuticals) is a potent inhibitor of pancreatic exocrine secretion and gallbladder contraction, long-term treatment with this drug may theoretically result in impaired pancreatic function and gallstones. However, we observed excellent pancreatic exocrine function--as assessed by the PABA/PAS test--in acromegalics who received octreotide treatment for more than 6 months. Plasma cholecystokinin showed a significant, although blunted, postprandial response, which exceeded the threshold for gallbladder contraction in healthy controls. Remarkably, postprandial gallbladder contraction was completely abolished for at least 2 h during octreotide treatment. In contrast to other studies, none of 16 acromegalic patients on long-term octreotide treatment developed gallstones. Although the incidence of gallstones in patients on long-term octreotide treatment may be increased, the risk seems to be variable.