Sclerosing Epithelioid Fibrosarcoma (SEF) versus Low Grade Fibromyxoid Sarcoma (LGFMS): Presentation and outcome in the nationwide NETSARC+ series of 330 patients over 13 years.

Sclerosing Epithelioid Fibrosarcoma (SEF) and Low Grade Fibromyxoid Sarcoma (LGFMS) are ultrarare sarcomas sharing common translocations whose natural history are not well known. We report on the nationwide exhaustive series of 330 patients with SEF or LGFMS in NETSARC+ since 2010. PATIENTS AND METHODS: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDTB). Since 2010, (i) pathological review has been mandatory for sarcoma,and (ii) tumour/patients' characteristics have been collected in the NETSARC+ nationwide database. The characteristics of patients with SEF and LGFMS and their outcome are compared. RESULTS: 35/73 (48%) and 125/257(49%) of patients with SEF and LGFMS were female. More visceral, bone and trunk primary sites were observed in SEF (p < 0.001). 30% of SEF vs 4% of LGFMS patients had metastasis at diagnosis (p < 0.0001). Median size of the primary tumor was 51 mm (range 10-90) for LGFMS vs 80 (20-320) for SEF (p < 0.001). Median age for LGFMS patients was 12 years younger than that of SEF patients (43 [range 4-98] vs 55 [range 10-91], p < 0.001). Neoadjuvant treatment was more often given to SEF (16% vs 9%, p = 0.05). More patients with LGFMS were operated first in reference centers (51% vs 26%, p < 0.001). The R0 rate on the operative specimen was 41% in LGFMS vs 16% in SEF (p < 0.001). Median event-free survival (EFS) of patients with SEF and LGFMS were 32 vs 136 months (p < 0.0001). The median overall survival (OS) was not reached. Fifty-months OS was 93% vs 81% for LGFMS vs SEF (p = 0.05). Median OS was 77 months after first relapse, similar for SEF and LGFMS. In multivariate analysis, age, tumor size, metastasis at diagnosis were independent prognostic factors for OS in LGFMS. CONCLUSIONS: Although sharing close molecular alterations, SEF and LGFMS have a different natural history, clinical presentation and outcome, with a higher risk of metastatic relapse in SEF. Survival after relapse is longer than with other sarcomas, and similar for SEF and LGFMS.

Relationship between HHV8 infection markers and insulin sensitivity in ketosis-prone diabetes.

BACKGROUND AND OBJECTIVES: Peripheral tissue resistance to insulin action is a characteristic of type 2 diabetes mellitus (T2DM). It has also been reported that some chronic viral infections can contribute to insulin resistance. Human herpesvirus (HHV)-8 infection has been detected in T2DM patients in previous studies. Our study investigated whether the presence of the virus is associated with insulin resistance in patients with ketosis-prone type 2 diabetes (KPD), as reported with other viruses. RESEARCH DESIGN AND METHODS: A total of 11 insulin-free KPD patients positive (+) and seven patients who were negative (-) for HHV-8 infection were recruited; the latter had KPD that was well controlled (HbA1c=6.2±0.7%). A two-step euglycaemic-hyperinsulinaemic clamp test coupled with deuterated [6,6-2H2]glucose was used to assess insulin sensitivity, non-esterified fatty acid (NEFA) suppression and endogenous glucose production. RESULTS: In KPD patients, whether HHV-8+ or HHV-8-, there were no differences in NEFA release, endogenous glucose production or insulin sensitivity (M value). CONCLUSION: Asymptomatic HHV-8 infection does not appear to be associated with decreased insulin sensitivity in diabetic patients. These results should now be confirmed in a larger sample population.

Ketosis-prone atypical diabetes in Cameroonian people with hyperglycaemic crisis: frequency, clinical and metabolic phenotypes.

AIM: It is unclear whether ketosis-prone diabetes is a specific type or a subtype of Type 2 diabetes. We aimed to describe the clinical and metabolic features of ketosis-prone diabetes in a sub-Saharan population. METHODS: We consecutively enrolled and characterized 173 people with non-autoimmune diabetes admitted for hyperglycaemic crisis at the Yaoundé Central Hospital, Cameroon. Blood samples were collected for fasting glucose, HbA1c , lipid profile and C-peptide assays with insulin resistance and secretion estimation by homeostasis model assessment. People were classified as having Type 2 diabetes (n = 124) or ketosis-prone diabetes (n = 49). Ketosis-prone diabetes was sub-classified as new-onset ketotic phase (n = 34) or non-ketotic phase (n = 15). RESULTS: Ketosis-prone diabetes was found in 28.3% of the hyperglycaemic crises. Age at diabetes diagnosis was comparable in Type 2 and ketosis-prone diabetes [48 ± 14 vs 47 ± 11 years; P = 0.13] with a similar sex distribution. Overall BMI was 27.7 ± 13.4 kg/m2 and was ≥ 25 kg/m2 in 55.8% of those taking part, however, 73.5% of those with ketosis-prone diabetes reported weight loss of > 5% at diagnosis. Blood pressure and lipid profile were comparable in both types. Ketosis-prone diabetes in the ketotic phase was characterized by lower insulin secretion and higher serum triglycerides compared with non-ketotic ketosis prone and Type 2 diabetes. Type 2 and ketosis prone diabetes in the non-ketotic phase were comparable in terms of lipid profile, blood pressure, waist-to-hip ratio, BMI and fat mass, insulin secretion and insulin resistance indices. CONCLUSIONS: Ketosis-prone diabetes is likely to be a subtype of Type 2 diabetes with the potential to develop acute insulinopenic episodes.

One-year metreleptin improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes.

Recombinant methionyl human leptin (metreleptin) therapy was shown to improve hyperglycaemia, dyslipidaemia and insulin sensitivity in patients with lipodystrophic syndromes, but its effects on insulin secretion remain controversial. We used dynamic intravenous (i.v.) clamp procedures to measure insulin secretion, adjusted to insulin sensitivity, at baseline and after 1 year of metreleptin therapy, in 16 consecutive patients with lipodystrophy, diabetes and leptin deficiency. Patients, with a mean [± standard error of the mean (s.e.m.)] age of 39.2 (±4) years, presented with familial partial lipodystrophy (n = 11, 10 women) or congenital generalized lipodystrophy (n = 5, four women). Their mean (± s.e.m.) BMI (23.9 ± 0.7 kg/m(2) ), glycated haemoglobin levels (8.5 ± 0.4%) and serum triglycerides levels (4.6 ± 0.9 mmol/l) significantly decreased within 1 month of metreleptin therapy, then remained stable. Insulin sensitivity (from hyperglycaemic or euglycaemic-hyperinsulinaemic clamps, n = 4 and n = 12, respectively), insulin secretion during graded glucose infusion (n = 12), and acute insulin response to i.v. glucose adjusted to insulin sensitivity (disposition index, n = 12), significantly increased after 1 year of metreleptin therapy. The increase in disposition index was related to a decrease in percentage of total and trunk body fat. Metreleptin therapy improves not only insulin sensitivity, but also insulin secretion in patients with diabetes attributable to genetic lipodystrophies.

Recommendations for investigation of hyperandrogenism.

1. Total testosterone assay is recommended as the first-line approach. 2. Radioimmunological assay following prior treatment of the sample (extraction or extraction + chromatography) is the recommended method pending wider experience with mass spectrometry. 3. Where testosterone is twice the upper limit of normal, it is recommended that DHEAS assay be performed. DHEAS is primarily of cortico-adrenal origin in women. Thus, a DHEAS level over 600 mg/dl indicates a diagnosis of androgen-secreting adrenal cortical adenoma.. If DHEAS is normal, the diagnosis could be either ovarian hyperthecosis, normally associated with insulin resistance, or androgen-secreting ovarian tumour. 4. More rarely, elevated testosterone is associated with a marked elevation of SHBG possibly as the result of use of medication having an estrogenic effect (tamoxifen, raloxifene, Op'DDD), or of hyperthyroidism or liver disease. 5. Normal testosterone levels in patients with clear clinical symptoms of hyperandrogenism (hirsutism, seborrhoeic acne) must be interpreted with care. SHBG is normally reduced in the event of overweight, metabolic syndrome or familial history of diabetes.

The polymorphism Arg585Gln in the gene of the sterol regulatory element binding protein-1 (SREBP-1) is not a determinant of ketosis prone type 2 diabetes (KPD) in Africans.

AIM: Ketosis prone type 2 diabetes (KPD) is an atypical form of diabetes described mainly in people of sub-Saharan African origin. Its pathogenesis is unknown, although we have previously described a high prevalence of glucose-6-phosphate-dehydrogenase (G6PD) deficiency in patients with KPD. However, 50% of these deficient patients lacked the G6PD gene mutation. The isoforms of the transcription factor sterol regulatory element binding protein 1 (SREBP-1) are known to stimulate G6PD gene expression, and some polymorphisms in the SREBP-1 gene (SREBF-1) have been described only in Africans. We investigated one of these, the Arg585Gln polymorphism, in a candidate gene approach for KPD. METHODS: We examined the presence of the Arg585Gln polymorphism in SREBF-1 in 217 consecutive unrelated Africans [73 patients with KPD, 80 with classical type 2 diabetes (T2D) and 64 nondiabetic subjects]. Patients underwent clinical and biochemical evaluations, and were assessed for G6PD activity and insulin secretion (glucagon test). RESULTS: There were no differences in frequency of the Arg585Gln polymorphism and the 585Gln allele among the three groups (allele frequency: KPD: 0.089, T2D: 0.031, nondiabetic group: 0.070; P=0.1). When the 585Gln allele frequency was compared separately between patients with KPD and those with T2D, it was significantly higher in the former (P=0.032). There was no difference between carriers and noncarriers of the 585Gln allele regarding G6PD activity and insulin secretion. CONCLUSION: The results of this exploratory study show that the polymorphism Arg585Gln in SREBF-1 is not associated with the KPD phenotype. Further studies in larger populations are needed to confirm our findings.

Evidence of a marked 25-hydroxyvitamin D deficiency in patients with congenital ichthyosis.

BACKGROUND: Vitamin D is essential for bone mineralization, and its deficiency may be the cause of skeletal fractures and osteomalacia. Geographical or ethnic factors may modulate the cutaneous synthesis of vitamin D. We hypothesized that major changes in keratinization may similarly alter the cutaneous synthesis of vitamin D. OBJECTIVES: To explore calciotrophic hormones, parameters of bone remodelling and bone mineral density (BMD) in nine patients with non-bullous congenital ichthyosis. PATIENTS AND METHODS: Six patients were European, three were North African. Four had received acitretin over a long period of time. A complete biological investigation, including serum and urinary calcium and phosphorus, calciotrophic hormones [intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25-(OH)D) and 1,25-dihydroxyvitamin D (1,25-(OH)2D)], bone formation and resorption markers, was performed on all patients during the winter season and repeated among four patients after summer. BMD was measured in all patients. RESULTS: All patients had a marked 25-(OH)D deficiency, clearly below the deficiency threshold of 25 nmol/L. Patients from North Africa had a greater deficiency than European patients, perhaps because of the difference in skin pigmentation. iPTH remained normal in European patients but was elevated among the North Africans. After sun exposure, an improvement in vitamin status was visible in only one patient. Bone formation and resorption markers remained normal. Femoral neck osteodensitometry indicated values near the osteopaenic threshold in two young North African females. No deleterious effect of retinoids on vitamin D metabolism was observed. CONCLUSION: Patients, and in particular pigmented patients, with congenital ichthyosis present a severe deficiency in vitamin D. Care provided to protect the skeletal future of these patients involves measuring BMD and prescribing supplementation.

A very high incidence of low 25 hydroxy-vitamin D serum concentration in a French population of patients with primary hyperparathyroidism.

Since the demonstration that vitamin D status might influence the clinical and biological expression of primary hyperparathyroidism (PHPT), a serum 25-hydroxy vitamin D (25-OHD) concentration of 50 nmol/l has been considered by an expert panel as the minimum level to be maintained in asymptomatic PHPT patients. Two yr after this recommendation, we aimed to evaluate the frequency of serum 25-OHD concentrations below this threshold in PHPT patients. In the present study, serum 25-OHD, second- and third-generation PTH, calcium, phosphate, magnesium, albumin and creatinine were measured in 72 out 145 consecutive PHPT patients operated on in our Endocrine Surgery Department, in whom blood samples were available before as well as two days after surgical intervention. Before surgery, the frequency of serum 25-OHD levels <50 nmol/l ranged from 91.5 to 100% whatever the classification used to identify patients: whole group, symptomatic vs asymptomatic, patients with calcium levels >3 vs <3 mmol/l. 25-OHD concentrations correlated negatively with the weight of adenoma, PTH levels, and total calcium concentrations measured before surgery. Pre-operative PTH levels, whatever the assay used, and total calcium concentrations were positively and significantly correlated. Two days post-surgery, 13 patients were moderately hypocalcemic. Neither pre-surgery 25-OHD nor PTH, calcium or phosphorus level or adenoma weight were predictive of post-operative hypocalcemia. The dramatic frequency of low 25-OHD concentrations in our PHPT patients demonstrates that the above-mentioned recommendation is far from being applied in France despite evidence of worsening expression of PHPT with decreasing 25-OHD serum levels.

An unusual somatotropin and thyreotropin secreting pituitary adenoma efficiently controlled by Octreotide and Pegvisomant.

We describe the first case of a 36 year-old male patient with a somatotropin and thyreotropin secreting pituitary adenoma, co-treated by a long-acting releasing somatostatin analog (Octreotide) and a GH receptor antagonist (Pegvisomant). The patient normalized his biological disease activity reflected by hormone levels but his tumor size remained unchanged as measured by MRI. The co-treatment was well tolerated and induced a synergic effect on IGF1 levels that allowed us to use low doses of both therapies.

Hyperglycaemia acutely decreases circulating dehydroepiandrosterone levels in healthy men.

OBJECTIVE: This study was conducted in order to evaluate the effect of glucose-insulin homeostasis on adrenal steroids and was designed to separate the effects of hyperglycaemia from those of insulin. DESIGN: Eight healthy men aged 22.6 +/- 3.4 (SD) underwent an 80 mU/m2/min hyperinsulinaemic euglycaemic 100-min clamp, a 200-min graded glucose infusion at 2-16 mg/kg/min and a measurement of fat mass. MEASUREMENTS: Circulating glucose, insulin and adrenal steroid levels including dehydroepiandrosterone (DHEA) were determined before and during both infusion tests. Steroid variations in relation to insulinaemia and glycaemia were analysed using univariate, multivariate tests and nonlinear mixed models. RESULTS: Hyperinsulinaemia induced no significant modification of adrenal steroid levels. By contrast, hyperglycaemia decreased all adrenal steroids except DHEA-sulphate by 47-66%. The drop occurred early, averaging 51% for 17OH pregnenolone and 57% for DHEA at the 80th minute of glucose infusion, whereas blood glucose was 7.1 +/- 1.2 mmol/1. This effect was independent of insulinaemia, fat mass and waist circumference. Thus, we estimated models that could best predict steroid variations according to blood glucose. At thresholds defining impaired fasting glycaemia and diabetes, the estimated decrease in DHEA was 40% and 45%, respectively, culminating at 60% at 9.3 mmol/1 glycaemia, with no detectable further decrease. CONCLUSIONS: Our data suggest that hyperglycaemia dramatically decreases adrenal androgen levels in men, possibly by acting at early steps of synthesis, independently of insulinaemia and fat mass.

Absence of exercise-induced variations in adiponectin levels despite decreased abdominal adiposity and improved insulin sensitivity in type 2 diabetic men.

OBJECTIVE: We investigated the effect of an intensive training program on fasting leptin and adiponectin levels. METHODS: Sixteen middle-aged men with type 2 diabetes were randomly assigned to either a training or control group. The training program consisted of 8 weeks of supervised endurance exercise (75% VO(2peak), 45 min) twice a week, with intermittent exercise (five 2 min exercises at 85% VO(2peak) separated by 3 min exercises at 50% VO(2peak)) once a week, on an ergocycle. RESULTS: Training decreased abdominal fat by 44%, increased mid-thigh muscle cross-sectional area by 24%, and improved insulin sensitivity by 58% without significant change in body weight. Compared with controls, no significant variation in leptin or adiponectin levels was observed. However, in the trained group, change in adiponectin correlated with change in body weight (Spearman rank correlation, r(s):-0.76, P=0.03) but not with insulin sensitivity or abdominal adiposity variations. CONCLUSIONS: An 8 week intensive training program inducing a marked reduction in abdominal fat and increase in insulin sensitivity does not affect adiponectin and leptin levels in men with type 2 diabetes.

Characterization of human NOV in biological fluids: an enzyme immunoassay for the quantification of human NOV in sera from patients with diseases of the adrenal gland and of the nervous system.

Immunochromatography has shown that human NOV (NOVH), a member of the CCN (CTGF/CYR61/NOV) family, forms a physiological complex with fibulin-1 in blood. We developed an enzyme immunoassay specific for NOVH and showed for the first time that the concentration of NOVH differs in each of these biological fluids. The normal concentration of NOVH circulating in the blood is 350-400 ng/ml, but this concentration varies with age. By using sera from patients with adrenal gland diseases we found that in vivo ACTH or glucocorticoids are not responsible for the high concentration of NOVH in this endocrine gland. However, the NOVH concentration was significantly modified in malignant adrenocortical tumors, but not in benign adrenocortical tumors. The concentration of NOVH was significantly decreased in patients suffering from astrocytomas or multiple sclerosis, two diseases of the nervous system. Thus, NOVH is a potentially useful marker for the diagnosis of these diseases.

Effects of minoxidil 2% vs. cyproterone acetate treatment on female androgenetic alopecia: a controlled, 12-month randomized trial.

BACKGROUND: Hormone studies have demonstrated the androgen-dependent character of female androgenetic alopecia, but there have been few controlled studies of therapies for alopecia in women. OBJECTIVES: To compare topical minoxidil 2% and cyproterone acetate in the treatment of female alopecia. METHODS: Sixty-six women with female-pattern alopecia were randomly assigned for 12 cycles into two groups, 33 received two local applications (2 mL day-1) of topical minoxidil 2% plus combined oral contraceptive and 33 received cyproterone acetate 52 mg day-1 plus ethinyl oestradiol 35 microg for 20 of every 28 days. RESULTS: A mean reduction of 2.4 +/- 6.2 per 0.36 cm2 in hairs of diameter > 40 microm was observed in the cyproterone acetate group (P = 0.05) and a mean increase of 6.5 +/- 9 per 0.36 cm2 in the minoxidil group (P < 0.001). Comparison of the total number of hairs at 12 months and the body mass index (BMI) revealed a borderline positive correlation in the cyproterone acetate group (r = 0.39, P = 0.06) and a negative correlation in the minoxidil group (r = -0.42, P < 0.05). No significant difference was observed in the total number of hairs among cyproterone acetate patients according to the presence or absence of other symptoms of hyperandrogenism, whereas in the minoxidil group, the total number of new hairs was higher in patients with isolated alopecia (Delta = 8.1; P < 0.05). Variations in scalp seborrhoea were significant in both groups, but the result was better (for acne and hirsutism as well) in the cyproterone acetate group than in the minoxidil group (P < 0.001). CONCLUSIONS: Minoxidil treatment was more effective in the absence of other signs of hyperandrogenism, hyperseborrhoea, and menstrual cycle modifications when the BMI was low, and when nothing argued in favour of biochemical hyperandrogenism. Cyproterone acetate treatment was more effective when other signs were present and when the BMI was elevated, factors that favoured a diagnosis of biochemical hyperandrogenism.

Comparison of progesterone concentration determination by 12 non-isotopic immunoassays and gas chromatography/mass spectrometry in 99 human serum samples.

A single serum progesterone determination may be highly predictive for early pregnancy and in vitro fertilisation and embryo-transfer outcomes. We therefore compared 12 direct non-isotopic progesterone immunoassays with gas-chromatography/mass spectrometry (GC/MS). For each assay, data from the analysis of 99 individual sera were compared with data obtained by GC/MS, using regression and bias plot analyses and the ratio method. We observed a larger difference in concentration between high and low values and a broader distribution of results for immunoassays than for GC/MS. All immunoassays displayed bias in the calibration process and a lack of specificity and/or sensitivity, to various degrees. We tried to identify the parameters of the assay procedure that might contribute to these discrepancies. None of the criteria investigated (antibodies, control and preparation of calibrators, blocking agents and choice of tracer) had a significant effect when studied alone.

Exercise training-induced triglyceride lowering negatively correlates with DHEA levels in men with type 2 diabetes.

OBJECTIVE: To investigate the effect of an exercise training program on lipid profile in correlation with DHEA level and body weight and body composition in type 2 diabetic men. DESIGN: Longitudinal, controlled clinical intervention study with exercise training consisting of an 8 week supervised program of aerobic exercise (75% VO(2) peak, 45 min), twice a week and intermittent exercise, once a week, on a bicycle ergometer. SUBJECTS: Sixteen men (age 45.4+/-7.2 y (mean+/-s.d.), HbA1c 8.15+/-1.7%, body mass index (BMI) 29.6+/-4.6 kg/m(2)) were randomly divided into two groups: trained group (n=8) and control group (n=8). MEASUREMENTS: Lipid, apo- and lipoprotein and DHEA concentrations. Cross-sectional areas of subcutaneous and visceral adipose tissue and mid-thigh muscle by magnetic resonance imaging. RESULTS: Training decreased visceral (153.25+/-38.55 vs 84.20+/-21.30 cm(2), P<0.001), subcutaneous (241.55+/-49.55 vs 198.00+/-39.99 cm(2), P<0.001) adipose tissue area and triglyceride levels (2.59+/-1.90 vs 1.79+/-1.08 nmol/l, P<0.05) and increased mid-thigh muscle cross-sectional area (148.30+/-36.10 vs 184.35+/-35.85 cm(2), P<0.001), and DHEA levels (11.00+/-3.10 vs 14.25+/-4.10 nmol/l, P<0.05) with no modification in body weight. Changes in triglycerides were negatively correlated with changes in DHEA (r=-0.81, P=0.03). This correlation was independent of changes in abdominal fat distribution. CONCLUSION: Training decreases abdominal fat depots, improves muscular mass and affects favourably triglyceride and DHEA levels. Changes in triglycerides and DHEA were inversely related.