Three-dimensional simulation of aesthetic outcome from breast-conserving surgery compared with viewing photographs or standard care: randomized clinical trial.

INTRODUCTION: Over half of women with surgically managed breast cancer in the UK undergo breast-conserving treatment (BCT). While photographs are shown prior to reconstructive surgery or complex oncoplastic procedures, standard practice prior to breast conservation is to simply describe the likely aesthetic changes. Patients have expressed the desire for more personalized information about likely appearance after surgery. The hypothesis was that viewing a three-dimensional (3D) simulation improves patients' confidence in knowing their likely aesthetic outcome after surgery. METHODS: A randomized, controlled trial of 117 women planning unilateral BCT was undertaken. The randomization was three-way: standard of care (verbal description alone, control group), viewing two-dimensional (2D) photographs, or viewing a 3D simulation before surgery. The primary endpoint was the comparison between groups' median answer on a visual analogue scale (VAS) for the question administered before surgery: 'How confident are you that you know how your breasts are likely to look after treatment?' RESULTS: The median VAS in the control group was 5.2 (i.q.r. 2.6-7.8); 8.0 (i.q.r. 5.7-8.7) for 2D photography, and 8.9 (i.q.r. 8.2-9.5) for 3D simulation. There was a significant difference between groups (P < 0.010) with post-hoc pairwise comparisons demonstrating a statistically significant difference between 3D simulation and both standard care and viewing 2D photographs (P < 0.010 and P = 0.012, respectively). CONCLUSION: This RCT has demonstrated that women who viewed an individualized 3D simulation of likely aesthetic outcome for BCT were more confident going into surgery than those who received standard care or who were shown 2D photographs of other women. The impact on longer-term satisfaction with outcome remains to be determined.Registration number: NCT03250260 (http://www.clinicaltrials.gov).

Most women with breast cancer are able to have an operation to remove the cancer while preserving the breast ('lumpectomy'). Whilst cancer control is the most important goal, appearance after surgery has been shown to affect long-term quality of life and is considered when planning treatment. Currently, surgeons simply describe the likely changes in appearance and, for more complex procedures, photographs of other women are shown. Patients themselves have indicated they would like more information regarding the likely changes to their breast after treatment. The authors have developed a way to simulate appearance following lumpectomy and radiotherapy using three-dimensional (3D) photographs. The study invited women undergoing lumpectomy to be assigned at random to one of three groups receiving standard care (discussion), a two-dimensional photograph, or the 3D simulation before their operation. The authors have demonstrated that showing a woman her simulation prior to surgery improves confidence going into treatment.

True hermaphroditism: from female to male endocrine status.

True hermaphroditism was revealed by monthly intrascrotal bleeding in a 21-yr-old subject of male phenotype who had undergone surgical treatment for gonadal ectopy at the age of 7 yr. The presence of an ovary was demonstrated by the endocrine profile of an ovulatory menstrual cycle. Evidence for the presence of a testis was provided by a plasma testosterone increase after hCG administration (5000 IU/day for 3 days) and its spontaneous response to an endogenous preovulatory LH peak. Further endocrine studies revealed that both gonads were stimulated by endogenous gonadotropins. At surgery, a hemiuterus and an ovary with corpus luteum were found in the left hemiscrotum, and a testis and epididymis were found in the right hemiscrotum. After removal of the ovary, the subject passed from a predominantly female to a male endocrine status, which suggests that the endocrine secretion of the testis was inhibited by the negative feedback effect of ovarian steroids on gonadotropin secretion.

The serotonin-4 receptor agonist cisapride and angiotensin-II exert additive effects on aldosterone secretion in normal man.

In animals and man, serotonin (5-HT) exerts a direct stimulatory action on adrenocortical cells through activation of 5-HT4 receptors. In rats, 5-HT also potentiates the stimulatory effect of angiotensin-II (Ang II) on aldosterone secretion. The aim of the present study was to investigate the effect of concomitant administration of the 5-HT4 receptor agonist, cisapride, and Ang II on aldosterone secretion in normal human subjects. Eight healthy male volunteers pretreated with dexamethasone received, at 1-week intervals in random order and simple blind fashion, the following treatments: 1) a single oral dose of 10 mg cisapride, 2) a single oral dose of placebo, 3) a perfusion of graded doses of Ang II (from 1-4 ng/kg.min), 4) a perfusion of placebo, and 5) a single oral dose of 10 mg cisapride associated with a perfusion of Ang II. The oral doses of cisapride and placebo were also administered after a 3-day period of a low sodium diet (10 mmol/day). Plasma aldosterone levels increased significantly within 90 min after the administration of cisapride without any change in renin levels. The comparison between the net increase in aldosterone production induced by cisapride, Ang II, and cisapride plus Ang II showed that the stimulatory effects of cisapride and Ang II on aldosterone secretion were only additive. Similarly, the increase in plasma aldosterone levels induced by a sodium-restricted diet was just additive with the cisapride-evoked stimulation of aldosterone secretion. These results provide further evidence that the action of 5-HT on glomerulosa cells is mediated through activation of 5-HT4 receptors. The data also indicate that in humans, 5-HT does not potentiate the stimulatory effect of Ang II on aldosterone secretion.

Effect of the serotonin-4 receptor agonist zacopride on aldosterone secretion from the human adrenal cortex: in vivo and in vitro studies.

We have recently shown that serotonin (5-HT) stimulates cortisol secretion from human adrenocortical tissue in vitro through activation of 5-HT4 receptors. The aim of the present study was to investigate the effect of the 5-HT4 agonist racemic zacopride on aldosterone secretion from the human adrenal gland in vivo and in vitro. In vivo studies were conducted on 28 healthy volunteers pretreated with dexamethasone. The subjects received a single oral dose of placebo, 10 micrograms zacopride, or 400 micrograms zacopride. Plasma aldosterone levels increased significantly within 90 min after the administration of 400 micrograms zacopride, remained elevated for 60 min, and gradually returned to the baseline within 180 min. In contrast, the administration of 10 micrograms zacopride or placebo did not modify the aldosterone concentration. No significant changes were observed in renin, ACTH, or cortisol levels. In vitro studies were conducted on perifused human adrenocortical slices. Administration of 20-min pulses of zacopride (from 10(-11) - 10(-6) mol/L) induced a dose-dependent increase in aldosterone secretion. The minimal effective dose was 10(-10) mol/L, and half-maximal stimulation was obtained with a dose of 7 x 10(-8) mol/L. Zacopride was 100 times more potent in stimulating aldosterone than cortisol release. Taken together, the present data suggest that 5-HT-evoked aldosterone secretion involves the activation of 5-HT4 receptors.

Serotonin-induced stimulation of cortisol secretion from human adrenocortical tissue is mediated through activation of a serotonin4 receptor subtype.

The occurrence of serotonin in the human adrenal gland was demonstrated both by immuno-histochemical and biochemical approaches. Using specific polyclonal antibodies to serotonin, the presence of numerous immunoreactive cells was revealed by means of the peroxidase-antiperoxidase technique. These cells exhibited the morphological characteristics of mast cells. Combination of high performance liquid chromatography and electrochemical detection showed the presence of substantial amounts of both serotonin and its metabolite 5-hydroxyindolacetic acid in adrenocortical extracts. The role of serotonin in the regulation of steroidogenesis from human adrenocortical slices was studied in vitro using a perifusion system technique coupled to a specific radioimmunoassay for cortisol. Graded doses of serotonin (from 10(-8) M to 3 x 10(-7) M) increased cortisol production in a dose-dependent manner. Prolonged exposure of adrenal fragments to serotonin (10(-7) M) induced a biphasic response, i.e. a rapid and transient increase in cortisol secretion followed by a plateau phase, suggesting the existence of a desensitization phenomenon. The stimulatory effect of serotonin (10(-7) M) was not altered during infusion of the serotonin1 and/or serotonin2 receptor antagonists methysergide (10(-6) M) and ketanserin (10(-6) M), respectively. In contrast, ICS 205 930 (10(-6) M), a non-selective serotonin3/serotonin4 antagonist, totally abolished the response of adrenal slices to serotonin (10(-7) M). The benzamide derivative zacopride, considered as a serotonin4 agonist, induced a robust stimulation of cortisol secretion. In addition, the corticotropic effects of serotonin (10(-7) M) and zacopride (10(-6) M) were not additive. Incubation of adrenocortical fragments with zacopride (10(-6) M) or serotonin (10(-6) M) caused a significant increase in cAMP formation. Taken together, these data suggest that serotonin, locally released by intra-adrenal mast-like cells, may act as a paracrine factor to stimulate cortisol secretion in man. Our results also indicate that serotonin-induced corticosteroid production is mediated through activation of a serotonin4 receptor subtype positively coupled to adenylate cyclase.

Acro-oto-ocular syndrome: further evidence for a new autosomal recessive disorder.

We report on a patient born to consanguineous parents and presenting with pseudopapilledema, mixed hearing loss, and minor facial and limb anomalies. To our knowledge, there is just one similar description of this syndrome in three members of a Brazilian kindred whose parents were also consanguineous, suggesting autosomal recessive inheritance. We compare the findings of our patient with these previous reported cases and discuss the differential diagnoses of this new syndrome, which we suggest be named the acro-oto-ocular syndrome.

Identification of a novel mutation in the autoimmune regulator (AIRE-1) gene in a French family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is clinically characterized by the presence of two of the three major clinical symptoms: Addison's disease and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. Because of its autosomal recessive inheritance, this rare disorder constitutes an interesting model for understanding the molecular background of autoimmunity. Recently, mutations in the autoimmune regulator (AIRE-1) gene have been identified in APECED patients. Here we report, in a large French APECED family, the identification of a novel AIRE-1 missense mutation (Pro326Leu) in association with the Arg257Stop mutation which is detected in more than 80% of mutant Finnish AIRE-1 alleles. This Pro326Leu substitution occurs in the first plant homeodomain (PHD)-type zinc-finger domain of the protein which has been identified in a number of nuclear proteins involved in chromatin-mediated transcriptional regulation, such as ATRX, TIF1, KRIP-1 and Mi-2 autoantigen. This mutation highlights the key role of this amino acid in the structure of the PHD domain and confirms that exon 8 constitutes a mutational hotspot.

Renal tubular damage: an extraintestinal manifestation of chronic inflammatory bowel disease.

OBJECTIVE: To investigate whether treatment of inflammatory bowel disease (IBD) with 5-aminosalicylate or sulphasalazine in IBD may induce renal tubular damage. DESIGN AND METHODS: The urinary enzymes beta-N-acetyl-D-glucosaminidase ( beta-NAG), dipeptidylpeptidase 4 (DPP4) and alanine aminopeptidase (AAP) were measured as markers of renal tubular damage in 104 consecutive patients with Crohn's disease and in 43 consecutive patients with ulcerative colitis (all with normal serum creatinine values). Control values were gained from 65 healthy persons. RESULTS: The normal values (mean +/- SD) for the urinary enzymes investigated (U/g creatinine in the urine) were: DPP4 4.5 +/- 2.2, beta-NAG 1.6 +/- 1.4, AAP 11.4 +/- 6.5. In 28% of the patients with ulcerative colitis elevated beta-NAG levels of more than the mean + 2 x SD were measured. This pathological enzymuria was nearly exclusively found in patients with active disease (CAI > 6): DPP4 15.6 +/- 25.3, beta-NAG 8.3 +/- 10.1, AAP 24.7 +/- 50.1 (all three enzymes were significantly elevated). The highest values were measured in patients with active ulcerative colitis before start of therapy. Nineteen per cent of the patients with Crohn's disease had elevated beta-NAG levels of more than the mean + 2 x SD. There was no significant difference in enzymuria between patients with active (CDAI > 150) and patients with inactive Crohn's disease (CDAI < or = 150). DPP4 and AAP were normal in both groups. A correlation between the enzymuria and the cumulative doses of 5-aminosalicylic acid, sulphasalazine or prednisolone could not be found. The courses of enzymuria in three patients who presented with the first severe manifestation of IBD are described. They were treated with either corticosteroids and 5-aminosalicylic acid or corticosteroids and sulphasalazine. Before onset of therapy, very high urine enzyme values were measured. They almost normalized in the course of successful medical therapy despite increasing cumulative doses of 5-aminosalicylic acid or sulphasalazine. CONCLUSIONS: Renal tubular damage can frequently be observed in IBD. Our results suggest that this is an extraintestinal manifestation of the disease and not a toxic side-effect of anti-inflammatory therapy using 5-aminosalicylic acid or sulphasalazine.

[Hypoglycemia induced by cibenzoline in the elderly]. / Hypoglycémie induite par la cibenzoline chez le sujet âgé.

Hypoglycaemia induced by class IA antiarrhythmic agents has been described. A case of cibenzoline-induced hypoglycaemia with favourable outcome is reported. The patient's age (84 years), increased renal impairment and malnutrition acted as facilitating factors. Blood insulin levels were normal in both absolute and relative values. Therapeutic overdosage in relation to age and renal function has been found in 20 out of 24 cases published or recorded by the French pharmacovigilance system. The mechanism of this hypoglycaemia is uncertain; absolute or relative hyperinsulinism has been detected in only 5 out of 14 controlled cases.

[Plasma growth hormone in obese patients. Comparison of response to arginine and L-dopa (author's transl)]. / Secrétion d'hormone de croissance chez l'obèse. Etude comparative de la stimulation par arginine et L-dopa.

The present study aimed at testing the hypothesis that l-dopa could obtain a better growth hormone (G.H.) stimulation than metabolic stimuli in obese patients. Arginine (30 g i-v) and l-dopa (1 g per os) were used in 12 obese, non diabetic, female in patients. No significant difference of plasma G.H. peak level (arginine : 11,3 ng/ml +/- 8.6. L-dopa : 9.2 +/- 5.6) appeared between these two types of stimulation

[Cyproterone acetate. 15 cases of hirsutism treated for 1 year]. / Acétate de cyprotérone. 15 cas d'hirsutisme traités un an.

Fifteen women with idiopathic hirsutism (N = 11) or hirsutism with androgen excess (N = 4) were treated by Cyproterone acetate orally (50 mg from the 5 th to the 25 th day of the menstrual cycle) and Ethinyl Estradiol (day 15-25). Hirsutism was improved in 86% of cases with progressive improvement at 3, 6, 12 months. At 12 months, the clinical score for hirsutism was 56% of the original score. Disturbance of menstrual cycles was more frequent than reported with Hammerstein's pattern of treatment. Clinical and biological tolerance was good. delta 4 androstenedione decreased significantly at 6 months (respectively 2,26 ng/ml - 1,25 ng/ml). There was no significant decrease of plasma testosterone. Result of B 1-24 corticotropin test remained normal after 12 months of treatment.

[Proceedings: Prolactin adenoma revealed by gemellary? pregnancy after clomiphen therapy. Hypophysectomy during 5 th month of pregnancy (author's transl)]. / Adénome à prolactine révélé par une grossesse gemellaire après traitement par clomiphène. Hypophysectomie au 5 mois de la grossesse

A 25 year old woman had galactorrhea and secondary amenorrhea since her first pregnancy at 20 years. After several treatments with Clomiphene, menses reappeared for 2 months and she became pregnant. At admission, she was in her 4th pregnancy month and had headaches and bitemporal hemianopsia. Hypophysectomy was performed during 5th pregnancy month. Prolactin adenoma with hemorragic lesions was found. Parturition of normal twins occurred 8th month. Partial hypophyseal recovery took place for the following 2 years, but hyperprolactinemia reappeared too.

[A hormone assay as a therapeutic choice in male sterility]. / Apport de l'enquête hormonale au choix thérapeutique d'une stérilité masculine.

In order to study the function of the hypothalamic-pituitary-testicular axis in men referring for severe oligospermia, the hormonal pattern of 57 oligospermic men was compared to those of 19 healthy volunteers. Fourteen patients had plasma gonadotrophin levels in the normal range contrasting with low plasma testosterone (T) levels. An hyperprolactinemia was found in 2 of these men who were treated with bromocriptine. A dramatic increase in sperm count was obtained on month 9 to 12 of the therapy and 5 pregnancies were obtained. Two men with hypogonadotrophic hypogonadism and azoospermia were treated with gonadotrophins. Such a treatment induced a desquamation of immature germinal cells in the sperm on month 6 and the maturation et spermatozoa on month 18. By contrast to the latter patients, 8 men had a decrease in plasma T levels without clinical signs of hypoandrogenism. The spermocytogram showed numerous immature germinal cells. On month 7 of a treatment using gonadotrophins, the sperm count rose and 4 pregnancies were obtained after 3 to 12 months of therapy. In 2 patients an isolated FSH deficiency was suspected on the basis of undetectable FSH levels unresponsive to the infusion of GnRH. These patients were treated with hMG. This treatment induced a sharp increase in sperm count on month 6. Forty-three patients had an increase in either LH and/or FSH: 24 men had plasma testosterone and LH levels in the normal ranges, contrasting with an increase in plasma FSH level. In such men, the mean of testosterone level was significantly (p less than 0.001) lower than in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

[Thyroid pathology and lymphoproliferative diseases]. / Pathologie thyroïdienne et maladies lymphoprolifératives.

Four cases are reported, of an association between a thyroidal illness (1 hypothyroidism, 3 hyperthyroidism) on one hand, and a lymphocytic proliferation and/or monoclonal gammapathy on the other. The following findings: HLA B8 or DrW3 in 3, antithyroid antibodies at a very high level in 2, and thyroid stimulating immunoglobulin in 2 support the conclusion of thyroidal diseases of auto-immune nature. Simultaneous appearance of both thyroidal and hematologic illness favors the hypothesis of a non coincidental association. A direct thyroidal activity of the monoclonal paraprotein has been found only once among the 4 published and our 2 cases in which it has been studied. A more likely link would be a common physiopathology: a functional deficiency of T suppressor lymphocytes allowing the proliferation of a cellular clone producing an abnormal immunoglobulin, would also allow the development of a thyroidal illness when favored by a genetic predisposition.

[Study of corticotropic function: respective values of short tests using metropirone and exogenous ACTH regardless of the hour administered]. / Exploration de la fonction corticotrope: valeurs respectives des tests courts à la métopirone et à l'ACTH exogène quelle que soit l'heure de sa réalisation.

Basal plasma cortisol levels and adrenal responses to stimulation by endogenous and exogenous ACTH were compared between a group of controls and a group of patients with corticotrophic insufficiency. In addition, the adrenal response to the administration of exogenous ACTH was compared in each of these groups in relation to the timing of the test. There was a clear parallel between respective adrenal responses to exogenous ACTH and endogenous ACTH. Adrenal stimulation by exogenous ACTH may be used to investigate the residual secretion of endogenous ACTH and in the diagnosis or corticotrophic insufficiency, when a lesion interrupting functional hypothalamo-pituitary connections has been excluded. In the opposing case, use of a short test with metopirone is essential in order to confirm corticotrophic insufficiency. This test is better tolerated than the classical test and is not subject to sources of error due to urine collections.

[Latent and postpartum thyroiditis. Prospective study]. / Thyroïdite latente et post-partum. Etude prospective.

Thyroid evaluation was performed in 85 women at childbirth, then between 2 and 7 months, and 14 months later. Transient subclinical hypothyroidism was found in one woman; antithyroid antibodies were found in 10 and were persistent in 6, suggesting a late thyroiditis. For these 6 cases, 5 HLA typing showed 3 Locus DR4. The proportion of antithyroid antibody was the same in a reference population. This finding would be in agreement with the hypothesis of a latent thyroiditis, revealed by pregnancy. Relative iodine deficiency in France could explain the low frequency of post partum thyroiditis in the present study.

[Pituitary adenoma treated with a somatostatin analog]. / Adénome thyréotrope traité par un analogue de la somatostatine.

We studied for over 7 months the use of SMS 201-995, in 1 woman with pituitary adenoma. Eight years after surgical and irradiation therapy, adenoma relapsed with hyperthyroidism (T4 L = 71pmol/l, TSH = 5.3 mU/l, subunit: 309 micrograms/l) and was complicated by meningitis. It was invasive and removed only partly. SMS therapy, 100 micrograms SC q 8 h, allowed partial reduction of clinical hyperthyroidism and decreased TSH and alpha subunit of 47%. Increased dosage and changing route of administration did not increase efficacy. A modest decrease of adenoma was probably caused by several reasons. In summary in an adenoma unusual by the extremely high value of alpha subunit in contrast with modest value of TSH, SMS therapy allowed partial control only.

[Hematologic repercussions of disorders of thyroid secretion]. / Répercussions hématologiques des troubles de la sécrétion thyroïdienne.

The effects on blood of abnormal thyroid hormone secretion were investigated in a prospective study involving 80 patients. Anaemia, when present, could usually be ascribed to association with another pathology. In non-anaemic patients an excess or a deficiency of thyroid hormones had opposite effects on erythrocytes. Leucocytes as a whole were not influenced by hypothyroidism, but untreated hyperthyroidism seemed to be responsible for a relative decrease in the number of neutrophils and a relative increase in the number of eosinophils and mononucleate cells. Platelet counts were unaffected by variations in thyroid hormone levels. Excluding the effects on blood of synthetic antithyroid drugs, the changes observed were generally reversible after correction of the abnormal hormone secretion.

[Dynamics of gonadotropin secretion in oligospermia with isolated elevation of follicle stimulating hormone (FSH)]. / Dynamique de la sécrétion gonadotrope dans les oligospermies à FSH isolément élevée.

The mechanism of oligospermia with high level of follicle stimulating hormone (FSH) and normal levels of luteinizing hormone (LH) and testosterone is subject to controversy: pituitary origin with slowing down of LH pulses, or primary gonadal deficiency? We studied 23 men presenting with this hormonal profile. Compared with a control population, these men had decreased mean testosteronaemia, increased mean LH level, both at baseline and under LHRH, and increased area under the LH pulsatility curve. A positive correlation was found between LH and FSH plasma levels. These data are in favour of a primary gonadal deficiency, and we therefore expected to find an increased frequency and amplitude of LH pulses. In fact, the frequency was normal and the amplitude increased in one half of these men, while the frequency was reduced and the amplitude also increased in the other half. There was no difference in plasma FSH levels between these two groups. Pulsed administration of LHRH restored physiological stimulation, but it did not result in normalisation of the FSH/LH ratio and cannot be regarded as a suitable treatment. It would therefore seem that the mechanism of oligospermia with isolated high FSH level is an abnormal feedback of gonadal peptides and steroids.

[Male hypertestosteronemia]. / Hypertestostéronémie masculine.

Male hypogonadism is characterized by a lowering of plasma testosterone level below the lower limit of physiological variations. Conversely, some adult males, apparently eugonadic, have a plasma testosterone level much higher than normally. In most cases, male hypertestosteronaemia - defined by a plasma testosterone level above 13 ng/ml and due to various physiopathological mechanisms - is part of a wider pathological context. It betrays hyperandrogenism (elevated free testosterone) during treatment with androgens or chorionic gonadotropic hormone. In other cases, it seems to underlie a relative hypoandrogenism with rise of testosterone bound to transport proteins and/or excess of oestrogens. Hypertestosteronaemia therefore appears as a biochemical sign not to be ignored, but it also suggests that men with abnormally high testosterone levels present with new pathology and that aetiological investigations are necessary.