Verapamil increases the survival of patients with anthracycline-resistant metastatic breast carcinoma.

BACKGROUND: Verapamil (VER), a potent calcium channel blocker, has been found to overcome P-gp-mediated multi-drug resistance (MDR) and to increase sensitivity to cytotoxic anticancer drugs in refractory myeloma and non-Hodgkin lymphoma. The value of VER for treating solid tumors is still a matter for debate. PATIENTS AND METHODS: We performed a prospective study in 99 patients with anthracycline-resistant metastatic breast carcinoma (MBC), to assess the clinical effect of oral VER given in association with chemotherapy. Instead of retreating patients with anthracycline, we used a partially noncross-resistant regimen (VF), combining vindesine (VDS) and 5-fluorouracil given as a continuous infusion (5-FU CI). Patients were randomly assigned to two cohorts. One cohort (47 patients) was treated in 28-day cycles, each involving the administration of VDS (3 mg/m2 i.v. bolus on days 1 and 10) and 5-FU CI, (400 mg/m2/day i.v. from day 1 to day 10). The other cohort (52 patients) received the same VDS and 5-FU treatment and an additional oral VER treatment (240 mg/day divided in 2 doses), from day 1 to day 28 of each cycle. Patients were treated until progression. RESULTS: The treatment was well tolerated and no side effects that could be attributed to VER were detected. Patients treated with VER had longer overall survival (OS) (median OS: 323 vs. 209 days, P = 0.036) and a higher response rate (27% vs. 11%, P = 0.04) than those not given VER. Progression-free survival (PFS) was also longer but the difference was not statistically significant (median PFS: 4.6 and 2.7 months for the VER and non-VER groups respectively, P = 0.6). CONCLUSIONS: This clinical trial demonstrates that a chemosensitizer, such as VER, can increase the survival of MBC patients with acquired anthracycline resistance.

Primary chemotherapy and preoperative irradiation for patients with stage II larger than 3 cm or locally advanced non-inflammatory breast cancer.

BACKGROUND AND PURPOSE: To evaluate possibility of breast-conserving therapy and outcome for patients with locally advanced non-inflammatory breast cancer (LABC) and stage II >3 cm in diameter after primary chemotherapy (CT) followed by external preoperative irradiation (RT). MATERIALS AND METHODS: Between 1982 and 1990, 147 patients were treated by four courses of induction CT (doxorubicin, vincristine, cyclophosphamide, 5-fluorouracil) followed by preoperative RT (45 Gy to the breast and nodal areas) and a fifth course of CT. Three different loco-regional approaches were proposed depending on tumour characteristics and tumour response. After completion of local therapy, all patients received a sixth course of CT and a maintenance adjuvant CT regimen without anthracycline. RESULTS: Mastectomy and axillary dissection were performed in 52 patients, and conservative treatment in 95 patients (48 achieved complete remission and received additional radiation boost to initial tumour bed; 47 had a residual mass < or =3 cm in diameter and were treated by wide excision and axillary dissection followed by a boost to the excision site. Ten-year actuarial loco-regional failure rate was 20% after RT alone, 23% after wide excision and RT and 6% after mastectomy (P = 0.85). After multivariate analysis, possibility of breast-conserving therapy was related to initial tumour size. Ten-year overall survival rate was 66%; it was not influenced by local treatment (conservative vs. non-conservative local treatment, P = 0.89). However, local failure significantly decreased overall survival (P < 0.0001). After multivariate analysis, tumour response after induction CT and clinical stage had a significant impact on survival. CONCLUSIONS: The present data indicate that induction CT followed by preoperative RT may permit the selection of some patients with LABC or stage II >3 cm for conservative treatment. The impact of this treatment modality on long term survival remains to be established.

Treatment of Cushing's disease by transsphenoidal, pituitary microsurgery: prognosis factors and long-term follow-up.

Transsphenoidal pituitary microsurgery is considered as the best treatment of Cushing's disease. However, some recent studies reported disappointing results, leading their authors to suggest the possibility of returning to a first line adrenalectomy treatment. The aim of this study was to evaluate long-term results of transsphenoidal surgery in Cushing's disease, with special interest in factors that could affect the surgical outcome on the one hand and particular attention to surgical endocrine effects on the other. Fifty consecutive patients (34 females, 16 males, mean age 29.64 +/- 1.52 yr) were studied. The median post-operative follow-up was 71.5 months (range 25-219). Clinical, biological, surgical and pathological data between the success and failure groups were compared. Criteria of cure were: normal urinary free cortisol excretion, circadian cortisol rhythm and low dose dexamethasone test. Recovery of corticotroph and somatotroph functions were followed using the insulin test. Particular attention is given to clinical evolution in evaluating other pituitary functions. T4 or FT4, prolactin, E2 in women, testosterone in men, were measured. TRH and LHRH tests were not systematically performed. Only two parameters differed significantly between the cured and failure groups: the size of the adenomas was smaller and the pathological confirmation of the adenoma more frequent in the cured group. One patient had permanent corticotropic failure while two other had impaired response to hypoglycemia with normal cortisol basal levels. No acquired hypothyroidism nor hypogonadism were observed except in a patient who underwent two operations and radiotherapy. Recovery of GH function was slow. Definitive short stature was observed in all the patients whose disease began before the age of 16. Two patients had permanent diabetes insipidus. In conclusion, the most favorable prognosis in transsphenoidal surgery for Cushing's disease is observed in case of microadenoma confirmed by pathological examination. With this treatment, we obtained satisfactory results in Cushing's disease with minimal complications and no necessity of life-long endocrine substitutive therapy.

Oral iodized oil for correcting iodine deficiency: optimal dosing and outcome indicator selection.

Oral iodized oil is the major alternative to iodized salt for correcting endemic iodine deficiency. This study responds to a need for better guidelines in its use. Schoolchildren, aged 6-11 yr, from a severely iodine-deficient area of Algeria received iodized poppy seed oil (Lipiodol) in a single oral dose containing 120, 240, 480, or 960 mg iodine (groups A-D) or in an im injection of 480 mg iodine (group E). Thyroid volume by ultrasonography had not changed 395 days after treatment in groups A, B, and C, had decreased in groups D and E. Urinary iodine concentration rose rapidly from an initial median of 0.21 mumol/L, but fell below 0.79 mumol/L (the currently accepted level for indicating iodine deficiency) by 150 days for groups A and B, and by 395 days for groups C and D. Median serum TSH and T4 levels were normal before and after treatment, whereas high initial serum thyroglobulin values decreased in all groups after iodized oil treatment. For correcting iodine deficiency in children, we recommend single oral doses of Lipiodol containing 240 mg iodine for 6-month coverage or 480 mg for 12 months. These doses may not completely sustain iodine sufficiency, but will prevent the worst of the iodine deficiency disorders. Additionally, we conclude that the urinary iodine concentration is the most useful epidemiological indicator for assessing current iodine status, and thyroid volume and serum thyroglobulin levels are the best markers for assessing chronic effects.

Prevention of iodine deficiency disorders by oral administration of lipiodol during pregnancy.

The prevalence of iodine deficiency disorders and the thyroid status of the population were studied in an endemic goitre area in Algeria. After oral administration of lipiodol (0.5 ml), three treated groups of mother-newborn couples were compared to an untreated group: group A, mothers treated 1-3 months before conception; group B, mothers treated during the first month of pregnancy; group C, mothers treated during the third month of pregnancy. Untreated mothers were used as a control (group D). After lipiodol treatment, all newborn babies and mothers were clinically euthyroid. All tested newborn babies were full term and no goitre was observed in the four groups. In the mothers, goitre prevalence and thyrotrophin levels decreased significantly, whereas maternal milk and urinary iodine and serum-free thyroxine levels were significantly higher after treatment. The rate of prematurity, stillbirths and abortions in the treated groups was reduced when compared to the untreated group, whereas placental and birth weights were significantly higher. In group D two cases of neonatal hypothyroidism were detected. Their re-evaluation confirmed that hypothyroidism was transient. Groups A, B and C were statistically different from group D with regard to neonatal thyrotrophin and thyroxine. Positive correlations were found between neonatal thyroxine and birth weights and placental weights on the one hand, and maternal urinary iodine and free thyroxine on the other. Consequently, these data indicate that oral administration of lipiodol before or during the first trimester of pregnancy normalizes thyroid function in newborn babies and mothers, increases placental and birth weight and reduces the frequency of iodine deficiency disorders.(ABSTRACT TRUNCATED AT 250 WORDS)

[Hypothalamic-pituitary-adrenal function in primary hypothyroidism]. / Fonction hypothalamo-hypophyso-surrénalienne au cours de l'hypothyroïdie primaire.

OBJECTIVES: Hypothyroidism is known to lead to a certain degree of functional insufficiency of the adrenal gland by affecting both the hypophyseal axis and peripheral metabolism of cortisol. This study was conducted to evaluate hypothalamic, pituitary, and adrenal function in a homogeneous group of patients with long-standing major hypothyroidism. METHODS: Forty-five patients (32 females, 13 males; mean age 42.9 +/- 9.6 years; range 20-59) with major primary hypothyroidism known to be long-standing (> 1 year in 1 and for an undetermined duration of several years in all the others) were included. Twenty-nine age-matched subjects served as controls. Insulin-induced hypoglycaemia and oral metyrapone tests were performed before and after treatment had induced euthyroidism. Plasma ACTH and cortisol were measured every 20 min for 2 hours during the hypoglycaemia test and ACTH before and after the last dose of metyrapone. Plasma cortisol levels were determined before and 30 min after injection of tetracosactide. RESULTS: Baseline ACTH and cortisol were not different in patients and controls and were unchanged by treatment. ACTH and cortisol response to hypoglycaemia were weaker in patients with ongoing hypothyroidism (p < 0.05 vs controls) and improved significantly (p < 0.05 vs baseline) after treatment. Adreno-cortical response to exogenous ACTH stimulation was weaker in patients with hypothyroidism (p < 0.05 vs controls) and returned to normal after treatment. CONCLUSIONS: Modifications of the hypothalamic-pituitary-adrenal system resulting from hypothyroidism were minimal and evidenced only by dynamic exploration. Levels returned to normal after adequate treatment and the deficit restricted to the hypothalamus and pituitary might also involve the adrenal gland.

The sella turcica in Sheehan's syndrome: computerized tomographic study in 54 patients.

A CT scan study of the sella turcica and its contents was conducted in patients with Sheehan's syndrome with a search for correlation between the radiological data and the degree of endocrine insufficiency on one hand, and the time course of the disease on the other. Fifty-four patients with Sheehan's syndrome were included: 32 with complete anterior hypopituitarism, 22 with at least one spared pituitary function. Subgroups of equal size were obtained with a cut-off of 9 years evolution. The CT scan appearance of the pituitary was never normal in Sheehan's syndrome. The sella turcica was totally empty in 39 patients. A pituitary remnant was visible in 15 patients, more frequently in those with incomplete hypopituitarism (p less than 0.005) and those with short evolution (p less than 0.025). The size of this pituitary residue never exceeded one third of the normal pituitary gland. The pituitary stalk was always visualized. On the other hand, the size of the fossa was significantly (p less than 0.001) smaller in the patients, as compared to a 12-female control group, matched for age and number of pregnancies. Among the patients there was no difference when considering the disease duration nor the degree of hypopituitarism. An empty or partially empty sella of normal or reduced size is a constant feature of Sheehan's syndrome. The presence of a pituitary remnant is inversely correlated to the duration and extension of the disease. Arachnoid herniation alone does not induce a dilatation of the fossa.

Conjugated catecholamines in human plasma: where are they coming from?

The origins of conjugated catecholamines remain poorly known. The aim of the present study was to see whether a major contribution comes from the sympathetic nervous system. We have assumed some kind of parallelism between the activity of the sympathetic nervous system, the amount of catecholamines released and taken up, and the amount of conjugated catecholamines circulating in plasma. Accordingly, an increase in sympathetic activity should be followed by an increase in the plasma level of conjugated catecholamines. The plasma levels of sulfoconjugated and glucuroconjugated catecholamines were measured in 10 patients with mental disease resistant to drug treatment, before and after electroconvulsive therapy. As expected, blood pressure, norepinephrine concentration, and epinephrine concentration in plasma were transiently increased. Neither sulfoconjugated nor glucuroconjugated catecholamines were significantly changed. Conjugated catecholamines were measured in 10 volunteers before and at the nadir of insulin-induced hypoglycemia. As expected, plasma levels of norepinephrine and epinephrine were drastically increased. Plasma levels of sulfoconjugates were decreased and glucuroconjugates increased; these were narrow but statistically significant variations. Data reported in the present article do not support a major role for the activity of the sympathetic system in fixing the level of conjugated catecholamines in human plasma. This is a negative, but nonetheless important, observation. In human subjects, currently available information suggests an important role for the intestinal wall and renal function in determining the level of circulating sulfoconjugates.

Comparative study of neurological and myxoedematous cretinism associated with severe iodine deficiency.

The clinical and biochemical features of myxoedematous and neurological cretinism were studied in an endemic goitre area in Algeria (goitre prevalence 51.3%; endemic cretinism 1.1%; mean urinary iodine level 127.6 nmol/l). When comparing the data collected in six different villages of the area, significant negative correlations were found between the decrease in urinary iodide and iodide/thiocyanate ratio (I/SCN) and the increase in prevalences of visible goitres, endemic cretinism and transient neonatal hypothyroidism. The cretins were divided on clinical signs into two groups: myxoedematous (MC) and neurological (NC) cretinism. Differences were noted in the neurological signs and the type of deafness encountered in both types. Although some overlap did exist, proximal spasticity and rigidity were characteristic of NC. The hormonal profiles of the two groups, including TRH tests, were clearly different. The two groups were similar with regard to the percentage of palpable thyroids, the absence of antimicrosomal and anti-thyroglobulin antibodies, seropositive viral antibodies and thiocyanate concentrations in serum and urine. Thus it is unlikely that these factors have any significant aetiological role in NC. The data collected in the general population in this area and those obtained in the mothers of the myxoedematous and neurological cretins support the hypothesis that the neurological signs are the result of hypothyroxinaemia in the mothers and the fetus at different periods of pregnancy. They could be aggravated by neonatal hypothyroidism, which may be transient in NC and permanent in MC.

In vitro evidence that hypothyroidism modifies glucocorticoid receptors.

We have previously reported that hypothyroidism is accompanied by modifications of the cytosolic rat liver glucocorticoid receptors. In the present study we have used molybdate, which stabilizes the glucocorticoid receptor from hypothyroid rats, allowing its characterization. We confirm a decrease in the number of glucocorticoid binding sites in the liver of hypothyroid rats as compared to that in normal rats (8000 per cell versus 23,000 per cell for normal rats). At 22 degrees C and in the absence of molybdate, thermal activation shows the same kinetics in both complexes from normal and hypothyroid rats, though activated hormone-receptor complexes from hypothyroid rats are progressively degraded (t 1/2 = 230 min). At the same temperature the dissociation rate of native complexes from hypothyroid rats is slower (k-1 = 8 X 10(-3) min-1) than normal (k-1 = 16 X 10(-3) min-1). Competitive dissociation studies using [3H]dexamethasone indicate that native complexes from hypothyroid rats show altered affinities for agonist and antagonist. Hypothyroidism decreases the number of rat liver glucocorticoid receptors and alters their properties, as evidenced by their greater instability and differences in steroid binding. These effects may be due to regulating factors and/or slight, probably post-transcriptional, modifications of the binding protein.

Plasma catecholamines after insulin hypoglycemia in Sheehan's syndrome.

The plasma catecholamine response to hypoglycemia was studied in a group of hypopituitary patients with Sheehan's syndrome before (group A) and after (group B) combined cortisol and thyroid hormone treatment as well as in a group of normal women (group C). The mean basal plasma norepinephrine (NE) level was significantly increased in group A compared to levels in groups B and C, in which values were similar. The mean basal plasma epinephrine (E) level was not significantly altered by hypopituitarism. The plasma NE response to hypoglycemia was similar in the three groups, while the plasma E response was blunted in groups A and B. However, the plasma E response was significantly decreased only in half of the patients. The basal E/NE ratio was similar in the three groups, but it was significantly decreased in groups A and B compared to that in group C at the peak. From these data we conclude that 1) hypopituitarism is characterized in the basal state by increased adrenergic tone, probably related to secondary hypothyroidism; and 2) during hypoglycemia adrenal stimulation is impaired only in some patients. The role of ACTH in the regulation of E secretion is minor. Impaired neurogenic regulation in some patients with Sheehan's syndrome could contribute to their illness.

Aldosterone in panhypopituitarism: dynamic studies and therapeutic effects in Sheehan's syndrome.

To appreciate the aldosterone secretion status in panhypopituitarism, the steroid response to stimulation was studied in a homogeneous group of 20 female patients presenting with global hypopituitarism. Specific effects of glucocorticoid and thyroid hormone deficiencies were also assessed by studying the same patients before and after cortisol (F) and cortisol plus thyroid hormone (F + T) substitution. The patients were submitted to two stimulation tests before and after each treatment: the orthostasis test (O-T) and the furosemide test (Furo-T). The results obtained in the 3 situations were compared, each patient serving as her own control. Comparison was also established with the results obtained in healthy women serving as control group. Basal plasma aldosterone levels in the untreated patients were not significantly different from those of the control group (5.43 +/- 0.51 vs 7.16 +/- 0.80 ng/100 ml, mean +/- SEM). They were significantly lower after F (3.91 +/- 0.42) and F + T substitution (3.31 +/- 0.23) than those of untreated patients and controls. Response to both stimulations was blunted in the untreated patients (O-T: 14.10 +/- 2.81; Furo-T: 9.78 +/- 1.35) as compared to the control group (O-T: 26.46 +/- 4.67; Furo-T: 23.96 +/- 3.30). F treatment did not improve the response to either tests, (O-T: 11.42 +/- 2.55; Furo-T: 10.32 +/- 1.23). F + T treatment normalized the orthostasis response (20.83 +/- 3.59) and increased the response to furosemide which remained, however, lower (15.28 +/- 1.83) than in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Association of peroxidase enzyme defect and low thyroglobulin content in a case of endemic cretinism.

Neurological endemic cretinism is highly prevalent in severe endemic goiter areas. Often associated to euthyroid goiter, it is probably related to iodine deficiency. However the exact pathogenetic mechanism is yet unclear. We report the biochemical study of thyroid tissue obtained from a 26 year-old female cretin with a grade III multinodular goiter, neurological signs and euthyroidism. After surgery, thyroid tissue was analysed: iodoproteins where characterized by gel filtration, electrophoresis, sedimentation coefficient and antigenicity. Iodoalbumin was predominant while thyroglobulin was quantitatively reduced and poorly iodinated. In vitro, iodination with hog thyroid peroxidase was normal. There was no difference in peroxidase affinity for iodide in the oxidation reaction but a significantly reduced ability to iodinate in vitro thyroglobulin and free tyrosine. Oxidation of acetyltyrosilamide into bityrosine was also markedly reduced. These abnormal findings are known to occur in sporadic cases with or without hypothyroidism. The neurological defects could be linked to transient hypothyroidism during the critical period of nervous system maturation, however a role of iodine deficiency per se cannot be ruled out.

Evidence of a preferential inactivation of the paternally derived X chromosome in a 46,XX true hermaphrodite.

The pattern of inheritance of several X polymorphic markers is studied in the pedigree of a 46,XX true hermaphrodite. The results of the Xga, 12E7, and G6PD segregation analysis favour the hypothesis of a preferential inactivation of the paternally derived X chromosome.

Antidiuretic function in Sheehan's syndrome.

Twenty patients with postpartum hypopituitarism underwent a dehydration test followed by the administration of synthetic arginine-vasopressin (DDAVP; desmopressin). Panhypopituitarism was confirmed by hormonal assays in the basal state and after stimulation with combined luteinising hormone releasing hormone-thyrotrophin releasing hormone-insulin. All the patients were given replacement therapy with hydrocortisone and thyroid hormones. Results were compared with those in 12 normal women. Urinary concentrating ability was diminished in the patients as compared with the controls (maximum urine osmolality 688 (SEM 23) mmol (mosmol)/kg in the patients v 967 (SEM 29) mmol/kg in the controls). Also the change in urine osmolality after administration of desmopressin was greater in the patients (+9.55 (SEM 1.98)% in the patients v 2.49 (SEM 0.96)% in the controls). Partial diabetes insipidus is apparently common in Sheehan's syndrome. This association should be borne in mind when managing these patients, especially those in acute failure.

Absence of H-Y antigen in a case of sporadic pure gonadal dysgenesis.

H-Y activity, endocrine function and gonadal histology were studied in a phenotypic female presenting with features of sporadic 46,XY pure gonadal dysgenesis. H-Y activity was absent, hormonal data revealed a primary ovarian failure with a blunted response of FSH to LHRH; there was no testicular tissue nor microscopic evidence of gonadal tumor in the gonads. The current view on the role of H-Y antigen in the differentiation of the gonads and in the occurrence of gonocytoma is discussed.

Arginine-vasopressin in postpartum panhypopituitarism: urinary excretion and kidney response to osmolar load.

The response to an osmolar load (750 ml 2.5% NaCl solution iv preceded by 500 ml water by mouth) was studied in 20 patients with Sheehan's syndrome and 12 normal women. Sodium and osmolality were determined in plasma and urine and arginine-vasopressin (AVP) was measured by RIA in urine. The test was performed in each patient when untreated (group P), after hydrocortisone replacement alone (group F), and combined hydrocortisone and thyroid hormone replacement (group F+T). After the osmolar loading, maximum urinary osmolality in the patients was lower than in the normal women and remained unaffected by both hydrocortisone alone and hydrocortisone and thyroid hormone. Comparison of the mean hourly urinary volume before and after NaCl infusion demonstrated an increase in group P, a decrease in group C, and no change in groups F and F+T. Although free water clearance became negative in all groups, values in groups P, F, and F+T were constantly above that of group C. None of the patients in groups P and F had a significant rise in urine AVP excretion during or after NaCl infusion. Those in group F+T had a slight AVP response which was less than in normal women. Impaired response of AVP to an osmolar load appears to be a constant feature of Sheehan's syndrome even without overt diabetes insipidus.

The renin-angiotensin system in panhypopituitarism: dynamic studies and therapeutic effects in Sheehan's syndrome.

To gain insight in the influence of the pituitary gland on the renin-angiotensin system plasma renin substrate (PRS) and the response of PRA to stimulation were studied in a homogeneous group of 20 female patients with the same etiology and degree of pituitary failure, before treatment (group P), after hydrocortisone substitution (group F), and after hydrocortisone and thyroid hormone treatment (group F + T). All patients were studied before and after each treatment by response to two stimulatory tests, acting through two different pathways; orthostasis test (O-T) and the furosemide test (Furo-T). Results were compared between groups, each patient serving as her own control, and with those obtained in a 12 healthy women control group (group C). The diet contained about 85 meq Na/day. Compared to group C (O-T response, 5.97 +/- 0.54 ng ml-1 h-1; Furo-T response, 6.71 +/- 0.82 ng ml-1 h-1; mean +/- SEM), PRA response to both tests was blunted in group P (O-T: 2.48 +/- 0.46, P less than 0.001; Furo-T: 3.02 +/- 0.53, P less than 0.001) and remained so in F (O-T: 2.18 +/- 0.40, P less than 0.001; Furo-T: 2.52 +/- 0.28, P less than 0.001), In group F + T, the response to both tests was greater than in P and F (O-T, 6.61 +/- 1.19; Furo-T, 4.36 +/- 0.44; 0.001 less than P less than 0.05). However, whereas the response to orthostasis is entirely normalized, the response to a diuretic remained significantly smaller than in group C (P less than 0.01). These improvements were observed without significant change in PRS concentration which remained low. We conclude that panhypopituitarism is accompanied by an altered renin angiotensin system. Basal levels of PRS and PRA are low and unresponsive to adequate stimulation. Whereas glucocorticoid therapy alone is without effect on this hyporeninism, addition of thyroid hormones completely normalized the response to orthostasis and significantly improved furosemide response.