Survival of patients managed in France for duodenal neuroendocrine tumors (D-NET): a 20-year multicenter cohort study from the GTE group: a cohort study.

INTRODUCTION: Duodenal neuroendocrine tumours (D-NETs) have a low incidence; however, their diagnosis has been increasing. Features such as tumour location, size, type, histological grade, and stage were used to adapt the treatment to either endoscopic (ER) or surgical (SR) resections. There is no consensus regarding the definitive treatment. The authors' study aimed to describe the management of non-metastatic, well-differentiated D-NETs in France and its impact on patient survival. METHODS: A registry-based multicenter study using prospectively collected data between 2000 and 2019, including all patients managed for non-metastatic G1 and G2 D-NETs, was conducted in the GTE group. RESULTS: A total of 153 patients were included. Fifty-eight benefited from an ER, and 95 had an SR. No difference in recurrence-free survival (RFS) was observed regardless of treatment type. There was no significant difference between the two groups (ER vs. SR) in terms of location, size, grade, or lymphadenopathy, regardless of the type of incomplete resection performed or regarding the pre-therapeutic assessment of lymph node invasion in imaging. The surgery allowed for significantly more complete resection (patients with R1 resection in the SR group: 9 vs. 14 in the ER group, P<0.001). Among the 51 patients with positive lymph node dissection after SR, tumour size was less than or equal to 1 cm in 25 cases. Surgical complications were more numerous (P=0.001). In the sub-group analysis of G1-G2 D-NETs between 11 and 19 mm, there was no significant difference in grade (P=0.977) and location (P=0.617) between the two groups (ER vs. SR). No significant difference was found in both morphological and functional imaging, focusing on the pre-therapeutic assessment of lymph node invasion (P=0.387). CONCLUSION: Regardless of the resection type (ER or SR) of G1-G2 non-metastatic D-NETs, as well as the type of management of incomplete resection, which was greater in the ER group, long-term survival results were similar between ER and SR. Organ preservation seems to be the best choice owing to the slow evolution of these tumours.

Subclinical haemorrhage in non-functional adenomas.

AIM: The prevalence and risk factors of subclinical haemorrhage on non-functional adenomas (NFA) remain controversial. The primary aim of our study was to assess the incidence of subclinical haemorrhage (SH) and the secondary objectives were to evaluate the risk factors of SH and the impact of SH on pituitary function at diagnosis. PATIENTS AND METHODS: This retrospective transversal analysis included 95 patients between January 2012 and December 2014. The patients included in this series were all adults (>18 years of age), who presented a non-functional adenoma confirmed by an endocrinological evaluation and on dedicated MRI pituitary imaging. Sixty-four patients were eligible for this study. Subclinical haemorrhage was defined by the presence of haemorrhage within pituitary adenoma confirmed by pituitary MRI with no clinical symptoms. A senior neuroradiologist blinded to the diagnosis reviewed all MRI. The population was prospectively divided into two groups based on MRI results (SH group vs. group control) to determine risk factors. RESULTS: SH was diagnosed in 22 patients (34.38%). No risk factors (age, sex, tumor size, chronic hypertension, diabetes mellitus, malignant disease, the use of anticoagulation or antithrombotic medication or Cabergoline treatment) were involved as regards the SH. At the diagnosis, pituitary deficiency was statistically significantly more frequent in the SH group (45.45%) than in the control group (19.04%) (P=0.04). CONCLUSION: The SH within NFA was observed in 34.38% of cases without an association of risk factors.

An unusual pituitary stalk lesion: What is the place of surgery?

BACKGROUND: Sellar and suprasellar primary melanocytic tumors are exceptional occurrences. Besides the difficulty of differential diagnosis between a primary and secondary lesion, treatment of these pathologies is still unclear and controversial. CASE REPORT: We describe the case of a 36-year-old woman with no relevant previous medical history who presented with 1 month history of diabetes insipidus, blurred vision and generalized weakness; a brain MRI disclosed an atypical pituitary stalk lesion; initially the tumor was biopsied through an endonasal endoscopic approach that revealed a melanocytic tumor; the patient was afterwards managed by a second stage extended endonasal endoscopic approach achieving a subtotal tumor removal. The overall survival was of 14 months due to the multidisciplinary management including surgery, radio and chemotherapy. CONCLUSION: If a biopsy is essential to deal with these invasive lesions, treatment including surgical resection should be part of a multidisciplinary approach.

Clinical presentation of hyperthyroidism in a large representative sample of outpatients in France: relationships with age, aetiology and hormonal parameters.

OBJECTIVE: Signs and symptoms of thyrotoxicosis are not specific, and thyroid function tests are frequently prescribed to recognize such thyroid dysfunction. Ultrasensitive assays of thyroid-stimulating hormone (TSH) allow early diagnosis and identification of mild hyperthyroidism (generally designed as 'subclinical'). The aim of this study was to re-evaluate the clinical picture of thyrotoxicosis in the context of the current large utilization of ultrasensitive TSH assays. DESIGN: Prospective descriptive cohort. METHODS: Clinical presentation of 1572 patients with a recent (<3 months) diagnosis of thyrotoxicosis recruited by a large representative sample of 263 French endocrinologists was studied using two questionnaires (one at inclusion and the second after 3 months) concerning symptoms, hormonal evaluation and treatment. RESULTS: A total of 1240 (78·9%) patients were women, mean age 48 ± 17 years. Subclinical hyperthyroidism (SCHT) was present in 86 patients (10·4%). Symptoms of thyrotoxicosis were in decreasing frequency order: palpitations, weakness, heat-related signs and disturbed sleep. A total of 64·9% of patients had lost weight. Signs and symptoms were more frequent in Graves' disease, in young patients, and were partially related to biochemical severity. Symptoms were less frequent in elderly patients except for cardiac manifestations (atrial fibrillation). Most patients with SCHT had one or several signs or symptoms of thyrotoxicosis. CONCLUSION: This study confirms that elderly patients have less symptoms of thyrotoxicosis than younger subjects but are at increased risk of cardiac complications. Our results show that most patients with 'subclinical' HT have in fact signs or symptoms of thyrotoxicosis.

Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study.

BACKGROUND: MEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1. METHODS: The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software. RESULTS: Intrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs. CONCLUSION: The present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

Patient information ahead of thyroid surgery. Guidelines of the French Society of Oto-Rhino-Laryngology and Head and Neck Surgery (SFORL).

OBJECTIVE: The authors present the guidelines of the French Society of Oto-Rhino-Laryngology and Head and Neck Surgery (SFORL) on patient information ahead of thyroid surgery. METHODS: A multidisciplinary medical team was tasked with a scientific literature review on this topic. The texts retrieved were analyzed by an independent committee. A joint meeting drew up the final guidelines. The strength of the recommendations (grade A, B or C) was based on levels of evidence. RESULTS: It is recommended that the results of preoperative exploration and the indications for surgery should be explained to the patient. Patients should be informed as to the type of surgery, surgical objectives, risks and consequences. It is mandatory to obtain the patient's written consent before surgery. CONCLUSION: Appropriate medical information is a critical step in patient management.

[Secondary adrenal insufficiency due to exogenous glucocorticoid therapy]. / Insuffisance surrénalienne cortico-induite.

Prolonged glucocorticoid therapy is considered to be the most common cause of secondary adrenal insufficiency. Despite this, its true incidence remains unknown and the risk of acute adrenal insufficiency seems to be overestimated. The cosyntropin stimulation test is a very valuable test to assess the adrenal reserve but not to predict the risk of acute adrenal insufficiency. Otherwise, this test is well correlated with the adrenal response to a stress but not with clinical events. The corticosteroid withdrawal modalities are very heterogeneous, non-consensual, and have never been strictly evaluated. Several studies have demonstrated that the need for glucocorticoids coverage during a stress has been overestimated and that hydrocortisone doses should not necessarily be markedly increased. A prospective study of patients after withdrawal would be the only mean to assess the true incidence of this complication and to propose a rational strategy to prevent it. Meanwhile, the education of patients and physicians should be a mandatory step in the management of the patients with a potential risk of adrenal insufficiency.

Short-term very low-calorie diet in obese females improves the haemostatic balance through the reduction of leptin levels, PAI-1 concentrations and a diminished release of platelet and leukocyte-derived microparticles.

BACKGROUND: In obesity, metabolic stress and inflammation in injured tissues could favour enhanced shedding of procoagulant microparticles (MPs). At sites of endothelium injury, the swift recruitment of procoagulant leukocyte-derived MPs enables the initiation of blood coagulation and thrombus growth. OBJECTIVES: In obese females, we sought to evaluate the impact of a very low-calorie diet (VLCD) on procoagulant MP levels, fibrinolytic status, inflammation and endothelium damage. METHODS: Circulating biomarkers of vascular damage, fibrinolytic status, platelet activation and inflammation were measured before, 30 and 90 days after starting a short-term VLCD. MPs were measured by flow cytometry and capture assays. Their procoagulant potential was quantified using functional prothrombinase assays and their cellular origin were determined using flow cytometry (endothelium, platelet, leukocyte, lymphocyte and erythrocyte-derived MP) or capture assays. RESULTS: A total of 24 obese females (39 ± 10 years) with a mean body mass index of 35 ± 4 kg m(-2) were prospectively enroled. Procoagulant leukocyte-derived MPs were associated with the waist circumference at baseline (r=0.534; P=0.010) and at 90 days follow-up (r=0.487; P=0.021). At 90 days, weight reduction (-9.8%) was associated with a lowering of blood pressure, improvement of metabolic parameters and a significant reduction of plasminogen activator inhibitor-1 (PAI-1) (-38%), procoagulant platelet-derived MPs (-43%), leukocyte-derived MPs (-28%) and leptin (-32%) levels. CONCLUSION: In obese females, a short-term VLCD results in an overall improvement of the haemostatic balance characterized by the reduction of PAI-levels, diminished release of platelet and leukocyte-derived MPs and a reduction in leptin levels, an adipocyte-derived cytokine.

[Non thyroidal illnesses (NTIS)]. / Les dyshormonémies des affections non thyroïdiennes.

Abnormalities in the circulating levels of thyroid hormones, without evidence of coexisting thyroid or pituitary gland disease can be observed in all general diseases. These nonthyroidal illnesses (NTIS) are the result of complex mechanisms that combine the effect of some drugs, cytokines, nutritional and endocrine factors at all levels of the thyrotropic axis, from the hypothalamus to the cellular transporters and nuclear receptors of thyroid hormones. The patterns of NTIS depend on the underlying disease and its severity. Thirtyfive years after the initial description, the pathophysiological significance of these anomalies remains controversial. One of the dilemma of NTIS is whether the hormone responses represent an adaptive and normal, physiologic response to conserve energy and protect against hypercatabolism in case of aggression, or whether it is a maladaptive response contributing to a worsening of the disease. This debate is not just a theoretical question, because in the first case the process must be respected, in the other case a vigorous treatment to restore circulating thyroid hormone levels is justified. There have been very few clinical studies designed to address whether the substitution with thyroid hormone is advantageous, and there is at current time no permissive evidence for the use of thyroid hormone replacement in patients with NTIS. But the clinical context, the choice of the molecule or of the dose and the way of administration were not necessarily the most relevant. Theoretically, stimulation of thyreotrope axis used a continuous infusion of TRH seems to provide clinical benefit. With the expectation that randomized clinical trials will provide demonstration of NTIS treatment efficiency, the question might remain unanswered for several more years.

Value of (18)F-FDG-PET/CT in patients with fever of unknown origin and unexplained prolonged inflammatory syndrome: a single centre analysis experience.

OBJECTIVE: The aim of our study was to evaluate the diagnostic contribution of (18)F-fluoro-deoxyglucose ((18)F-FDG)-positron emission tomography (PET)/computed tomography (CT) in patients with fever of unknown origin (FUO) or unexplained prolonged inflammatory syndrome (UPIS) in real life. PATIENTS AND METHODS: We performed a retrospective study including 14 patients with FUO or UPIS hospitalised in our institution (Strasbourg University Hospital, France) between January 2005 and July 2006. (18)F-FDG-PET/CT was considered helpful when abnormal results allowed an accurate diagnosis. RESULTS: (18)F-FDG-PET/CT was helpful in half the patients (7/14) for final diagnosis. A diagnosis was reached in 87.5% of the patients (7/8) with an abnormal (18)F-FDG-PET/CT but only in 50% of the patients (3/6) with a normal (18)F-FDG-PET/CT. Conventional chest and abdominal CT was performed in 13 patients before ordering (18)F-FDG-PET/CT. We considered that (18)F-FDG-PET/CT was essential to establish the final diagnosis in only 23% of the patients (3/13) since neither chest nor abdominal CT identified abnormalities consistent with the final diagnosis. However, among the three patients, two were diagnosed with large vessel vasculitis and one patient with local prosthetic infection. CONCLUSIONS: Our study supports the potential interest of (18)F-FDG-PET/CT in the diagnostic workup of FUO and UPIS as it helped establish a fine diagnosis in half of the cases. However, (18)F-FDG-PET/CT appeared to be essential to the final diagnosis in only 23% of the cases. In our opinion, this protocol should be performed as a second level test, especially when conventional CT is normal or is unable to discriminate between active and silent lesions.

[Cardiac manifestations of pheochromocytoma]. / Manifestations cardiaques des phéochromocytomes.

Pheochromocytoma is a rare cause of secondary hypertension which may have protean clinical presentations. Noteworthy, it may be revealed or complicated by cardiovascular symptoms such as arrythmia, cardiomyopathy, acute coronary syndrome and cardiogenic shock. These cardiac manifestations of pheochromocytoma may delay diagnosis and must be known in order to provide the best chance at early detection. In some cases pheochromocytoma may be associated to a large apical dyskinesia of the left ventricule apex, tako-tsubo-like which is a reversible acute myocardiopathy. These acute cardiologic manifestations appear to be induced by a toxic effect of elevated catecholamine levels.

Increased reverse triiodothyronine is associated with shorter survival in independently-living elderly: the Alsanut study.

OBJECTIVE: Increased reverse tritiodothyronine (T(3)) used to be described as a part of euthyroid sick syndrome (ESS). It was demonstrated to be associated with increased mortality in acutely ill patients. It can also be found with low or normal T(3) in non-severely ill subjects but its significance remains unclear. PATIENTS AND DESIGN: The Alsanut study included a representative sample of 440 independently-living subjects aged 65 or over constituted between January 1988 and September 1989. Past and current medical history and nutritional data were collected at inclusion. Baseline thyroid hormone (TSH, FT(4), FT(3) and rT(3)) serum levels were measured. Life status was determined on 1 December 2005. RESULTS: Of the 374 elderly subjects included in the final analysis, 52 had abnormal TSH (43 with hyperthyroidism, nine with hypothyroidism) and 80.7% had died by 1 December 2005. There was no statistical difference in survival between subjects according to thyroid function (P=0.54). Of the 322 elderly subjects with normal TSH, mortality rate was 81.1%. ESS was found in 3.4%, whereas 8.1% of the participants displayed elevated rT(3) with normal FT(3). Time to death was strongly related to rT(3) (P<0.0001) and FT(3) (P<0.0001) in a univariate analysis. After adjusting for other confounding variables, rT(3) was the only thyroid hormone associated with shorter survival (P=0.014). CONCLUSIONS: RT(3) was the only thyroid hormone associated with shorter survival in a representative population of independently-living elderly. In these subjects, isolated elevated rT(3) might be an equivalent of ESS, reflecting declining health.

[Bayesian statistic: an approach fitted to clinic]. / La statistique bayésienne : une approche des statistiques adaptée à la clinique.

Bayesian statistic has known a growing success though quite limited. This is surprising since Bayes' theorem on which this paradigm relies is frequently used by the clinicians. There is a direct link between the routine diagnostic test and the Bayesian statistic. This link is the Bayes' theorem which allows one to compute positive and negative predictive values of a test. The principle of this theorem is extended to simple statistical situations as an introduction to Bayesian statistic. The conceptual simplicity of Bayesian statistic should make for a greater acceptance in the biomedical world.

[Value of left atrial dilation in the diagnosis of silent myocardial ischemia in diabetes mellitus patients]. / Facteurs prédictifs de l'existence d'une ischémie myocardique silencieuse chez le patient diabétique. Intérêt de l'évaluation de la surface de l'oreillette gauche.

BACKGROUND: Accelerated atherothrombosis is a common feature in diabetes mellitus patients (DM), which can be related to abnormalities in vascular cell apoptosis and activation leading to the release of procoagulant microparticles (MPs). In DM patients, we hypothesized that circulating levels of biomarkers involved in atherothrombosis processes as well as cardiac and carotid echocardiography variables could be useful in the detection of silent myocardial diagnosed by myocardial perfusion imaging. METHODS AND RESULTS: We investigated, in 55 patients with diabetes (mean age 62+/-10 years) and 15 nondiabetics (46+/-14 years) patients the prevalence of silent myocardial ischemia (SMI) detected by a treadmill exercise or dipyridamole (99m)Tc-sestamibi stress test. Echocardiographic and -carotid variables were obtained using standardized methods. Biomarkers assessing endothelial apoptosis or activation (CD31+-MPs, CD62+-MPs, VCAM-1), inflammatory status (CD11a +/- MPs, MCP-1, CRP), platelet activation (GPIb+/-MPs, CD40-L, P-selectin, GPV) ventricular stretch (BNP) were measured in the plasma. SMI was diagnosed in 23/55 (42%) diabetics patients and in 3/15 (20%) nondiabetics patients. Enhanced inflammatory status and leukocyte damage (CD11a+-MPs) were evidenced in diabetic patients. Within the diabetic population, biomarkers levels of atherothrombosis were not significantly associated to the detection of SMI. In multivariable analyses adjusted for LV hypertophy, left atrial surface (LA) remained independent predictor of silent myocardial ischemia (OR 4.14; IC [1.7-16.13]; P=0.039). CONCLUSIONS: In diabetes mellitus patients, LA surface independently predicted silent myocardial ischemia after adjustment for established echocardiographic, and inflammatory risk factors. This simple measure of LA dilation could be helpful in the identification of diabetes mellitus patients at heightened cardiovascular risk.