Standards of care for medical management of acromegaly in pituitary tumor centers of excellence (PTCOE).

PURPOSE: A series of consensus guidelines on medical treatment of acromegaly have been produced in the last two decades. However, little information is available on their application in clinical practice. Furthermore, international standards of acromegaly care have not been published. The aim of our study was to report current standards of care for medical therapy of acromegaly, using results collected through an audit performed to validate criteria for definition of Pituitary Tumor Centers of Excellence (PTCOE). METHODS: Details of medical treatment approaches to acromegaly were voluntarily provided by nine renowned international centers that participated in this audit. For the period 2018-2020, we assessed overall number of acromegaly patients under medical treatment, distribution of patients on different treatment modalities, overall biochemical control rate with medical therapy, and specific control rates for different medical treatment options. RESULTS: Median number of total patients and median number of new patients with acromegaly managed annually in the endocrinology units of the centers were 206 and 16.3, respectively. Median percentage of acromegaly patients on medical treatment was 48.9%. Among the patients on medical treatment, first-generation somatostatin receptor ligand (SRL) monotherapy was used with a median rate of 48.7%, followed by combination therapies with a median rate of 29.3%. Cabergoline monotherapy was used in 6.9% of patients. Pegvisomant monotherapy was used in 7 centers and pasireotide monotherapy in 5 centers, with median rates of 7.9% and 6.3%, respectively. CONCLUSIONS: Current standards of care in PTCOEs include use of first-generation SRLs as the first medical option in about 50% of patients, as recommended by consensus guidelines. However, some patients are kept on this treatment despite inadequate control suggesting that cost-effectiveness, availability, patient preference, side effects, and therapeutic inertia may play a possible role also in PTCOE. Moreover, at odds with consensus guidelines, other monotherapies for acromegaly appear to have a marginal role as compared to combination therapies as extrapolated from PTCOE practice data. Presence of uncontrolled patients in each treatment category suggest that further optimization of medical therapy, as well as use of other therapeutic tools such as radiosurgery may be needed.

Non-overweight depressed patients who respond to antidepressant treatment have a higher risk of later metabolic syndrome: findings from the METADAP cohort.

BACKGROUND: Major depressive disorder (MDD) is a complex disorder with a significant public health burden. Depression remission is often associated with weight gain, a major risk factor for metabolic syndrome (MetS). The primary objective of our study was to assess prospectively the impact of response to antidepressant treatment on developing MetS in a sample of MDD patients with a current major depressive episode (MDE) and who are newly initiating their treatment. METHODS: In the 6-month prospective METADAP cohort, non-overweight patients, body mass index <25 kg/m2, with MDD and a current MDE were assessed for treatment response after 3 months of treatment, and incidence of MetS after 3 and 6 months of treatment. Outcome variables were MetS, number of MetS criteria, and each MetS criterion (high waist circumference, high blood pressure, high triglyceridemia, low high-density lipoprotein-cholesterolemia, and high fasting plasma glucose). RESULTS: In total, 98/169 patients (58%) responded to treatment after 3 months. A total of 2.7% (1/38) developed MetS out of which 12.7% (10/79) (p value < 0.001) had responded to treatment after 3 months. The fixed-effect regression models showed that those who responded to treatment after 3 months of follow-up had an 8.6 times higher odds of developing MetS (odds ratio = 8.58, 95% confidence interval 3.89-18.93, p value < 0.001). CONCLUSION: Compared to non-responders, non-overweight patients who responded to treatment after 3 months of antidepressant treatment had a significantly higher risk of developing MetS during the 6 months of treatment. Psychiatrists and nurses should closely monitor the metabolic profile of their patients, especially those who respond to treatment.

Pilot study to define criteria for Pituitary Tumors Centers of Excellence (PTCOE): results of an audit of leading international centers.

PURPOSE: The Pituitary Society established the concept and mostly qualitative parameters for defining uniform criteria for Pituitary Tumor Centers of Excellence (PTCOEs) based on expert consensus. Aim of the study was to validate those previously proposed criteria through collection and evaluation of self-reported activity of several internationally-recognized tertiary pituitary centers, thereby transforming the qualitative 2017 definition into a validated quantitative one, which could serve as the basis for future objective PTCOE accreditation. METHODS: An ad hoc prepared database was distributed to nine Pituitary Centers chosen by the Project Scientific Committee and comprising Centers of worldwide repute, which agreed to provide activity information derived from registries related to the years 2018-2020 and completing the database within 60 days. The database, provided by each center and composed of Excel® spreadsheets with requested specific information on leading and supporting teams, was reviewed by two blinded referees and all 9 candidate centers satisfied the overall PTCOE definition, according to referees' evaluations. To obtain objective numerical criteria, median values for each activity/parameter were considered as the preferred PTCOE definition target, whereas the low limit of the range was selected as the acceptable target for each respective parameter. RESULTS: Three dedicated pituitary neurosurgeons are preferred, whereas one dedicated surgeon is acceptable. Moreover, 100 surgical procedures per center per year are preferred, while the results indicated that 50 surgeries per year are acceptable. Acute post-surgery complications, including mortality and readmission rates, should preferably be negligible or nonexistent, but acceptable criterion is a rate lower than 10% of patients with complications requiring readmission within 30 days after surgery. Four endocrinologists devoted to pituitary diseases are requested in a PTCOE and the total population of patients followed in a PTCOE should not be less than 850. It appears acceptable that at least one dedicated/expert in pituitary diseases is present in neuroradiology, pathology, and ophthalmology groups, whereas at least two expert radiation oncologists are needed. CONCLUSION: This is, to our knowledge, the first study to survey and evaluate the activity of a relevant number of high-volume centers in the pituitary field. This effort, internally validated by ad hoc reviewers, allowed for transformation of previously formulated theoretical criteria for the definition of a PTCOE to precise numerical definitions based on real-life evidence. The application of a derived synopsis of criteria could be used by independent bodies for accreditation of pituitary centers as PTCOEs.

Nitric Oxide Synthase activity in major depressive episodes before and after antidepressant treatment: Results of a large case-control treatment study.

BACKGROUND: Nitric oxide synthase (NOS) activity, an enzyme potentially involved in the major depressive episodes (MDE), could be indirectly measured by the L-Citrulline/L-Arginine ratio (L-Cit/L-Arg). The aim of this study was: (1) to compare the NOS activity of patients with a MDE to that of healthy controls (HC); (2) to assess its change after antidepressant treatment. METHODS: A total of 460 patients with a current MDE in a context of major depressive disorder (MDD) were compared to 895 HC for NOS activity (L-Cit/L-Arg plasma ratio). L-Arg and L-Cit plasma levels were measured using a MS-based liquid chromatography method. Depressed patients were assessed at baseline, and after 3 and 6 months of antidepressant treatment for depression severity and clinical response. RESULTS: Depressed patients had a lower NOS activity than HC at baseline [0.31 ± 0.09 v. 0.38 ± 0.12; 95% confidence interval (CI) -0.084 to -0.062, p < 0.0001]. Lower NOS activity at baseline predicted a higher response rate [odds ratio (OR) = 29.20; 95% CI 1.58-536.37; p = 0.023]. NOS activity in depressed patients increased significantly up to 0.34 ± 0.08 after antidepressant treatment (Est = 0.0034; 95% CI 0.0002-0.0067; p = 0.03). CONCLUSIONS: Depressed patients have a decreased NOS activity that improves after antidepressant treatment and predicts drug response. NOS activity may be a promising biomarker for MDE in a context of MDD.

Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper.

Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare (∼10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription of immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy.

A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up.

Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.

A consensus on the diagnosis and treatment of acromegaly complications.

In March 2011, the Acromegaly Consensus Group met to revise and update the guidelines on the diagnosis and treatment of acromegaly complications. The meeting was sponsored by the Pituitary Society and the European Neuroendocrinology Association and included experts skilled in the management of acromegaly. Complications considered included cardiovascular, endocrine and metabolic, sleep apnea, bone diseases, and mortality. Outcomes in selected, related clinical conditions were also considered, and included pregnancy, familial acromegaly and invasive macroadenomas. The need for a new disease staging model was considered, and design of such a tool was proposed.

Growth hormone effects on cortical bone dimensions in young adults with childhood-onset growth hormone deficiency.

UNLABELLED: Growth hormone (GH) treatment in young adults with childhood-onset GH deficiency has beneficial effects on bone mass. The present study shows that cortical bone dimensions also benefit from GH treatment, with endosteal expansion and increased cortical thickness leading to improved bone strength. INTRODUCTION: In young adults with childhood-onset growth hormone deficiency (CO GHD), GH treatment after final height is reached has been shown to have beneficial effects on spine and hip bone mineral density. The objective of the study was to evaluate the influence of GH on cortical bone dimensions. METHODS: Patients (n = 160; mean age, 21.2 years; 63% males) with CO GHD were randomised 2:1 to GH or no treatment for 24 months. Cortical bone dimensions were evaluated by digital x-ray radiogrammetry of the metacarpal bones every 6 months. RESULTS: After 24 months, cortical thickness was increased compared with the controls (6.43%, CI 3.34 to 9.61%; p = 0.0001) and metacarpal index (MCI) (6.14%, CI 3.95 to 8.38%; p < 0.0001), while the endosteal diameter decreased (-4.64%, CI -7.15 to -2.05; p < 0.001). Total bone width did not change significantly (0.68%, CI -1.17 to 2.57%; not significant (NS)). A gender effect was seen on bone width (p < 0.0001), endosteal diameter (p < 0.01) and cortical thickness (p < 0.01), but not with MCI (NS). CONCLUSIONS: Cortical bone reacts promptly to reinstitution of GH beyond the attainment of final height by increasing the cortical thickness through endosteal bone growth. This leads to a higher peak bone mass and may reduce the risk of cortical bone fragility later in life.

Current management practices for acromegaly: an international survey.

To determine whether peer-reviewed consensus statements have changed clinical practice, we surveyed acromegaly care in specialist centers across the globe, and determined the degree of adherence to published consensus guidelines on acromegaly management. Sixty-five acromegaly experts who participated in the 7th Acromegaly Consensus Workshop in March 2009 responded. Results indicated that the most common referring sources for acromegaly patients were other endocrinologists (in 26% of centers), neurosurgeons (25%) and primary care physicians (21%). In sixty-nine percent of patients, biochemical diagnoses were made by evaluating results of a combination of growth hormone (GH) nadir/basal GH and elevated insulin like growth factor-I (IGF-I) levels. In both Europe and the USA, neurosurgery was the treatment of choice for GH-secreting microadenomas and for macroadenomas with compromised visual function. The most widely used criteria for neurosurgical outcome assessment were combined measurements of IGF-I and GH levels after oral glucose tolerance test (OGTT) 3 months after surgery. Ninety-eight percent of respondents stated that primary treatment with somatostatin receptor ligands (SRLs) was indicated at least sometime during the management of acromegaly patients. In nearly all centers (96%), the use of pegvisomant monotherapy was restricted to patients who had failed to achieve biochemical control with SRL therapy. The observation that most centers followed consensus statement recommendations encourages the future utility of these workshops aimed to create uniform management standards for acromegaly.

ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy.

Pregnancies are rare in women with pituitary adenomas, which may relate to hormone excess from secretory subtypes such as prolactinomas or corticotroph adenomas. Decreased fertility may also result from pituitary hormone deficiencies due to compression of the gland by large tumours and/or surgical or radiation treatment of the lesion. Counselling premenopausal women with pituitary adenomas about their chance of conceiving spontaneously or with assisted reproductive technology, and the optimal pre-conception treatment, should start at the time of initial diagnosis. The normal physiological changes during pregnancy need to be considered when interpreting endocrine tests in women with pituitary adenomas. Dose adjustments in hormone substitution therapies may be needed across the trimesters. When medical therapy is used for pituitary hormone excess, consideration should be given to the known efficacy and safety data specific to pregnant women for each therapeutic option. In healthy women, pituitary gland size increases during pregnancy. Since some pituitary adenomas also enlarge during pregnancy, there is a risk of visual impairment, especially in women with macroadenomas or tumours near the optic chiasm. Pituitary apoplexy represents a rare acute complication of adenomas requiring surveillance, with surgical intervention needed in some cases. This guideline describes the choice and timing of diagnostic tests and treatments from the pre-conception stage until after delivery, taking into account adenoma size, location and endocrine activity. In most cases, pregnant women with pituitary adenomas should be managed by a multidisciplinary team in a centre specialised in the treatment of such tumours.

Persistent cortisol response to desmopressin predicts recurrence of Cushing's disease in patients with post-operative corticotropic insufficiency.

OBJECTIVE: Cushing's disease (CD) may recur despite corticotropic insufficiency (COI) following pituitary surgery. The predictive value of the desmopressin test (DT) for recurrence in this setting remains controversial. We have evaluated whether the disappearance of the response to DT predicts a low probability recurrence in a large cohort of patients with post-operative COI. DESIGN: Multicentre retrospective study. METHODS: Ninety-five patients with CD (women 82%, age 41 ± 14 years), responding preoperatively to DT and with early post-operative COI (08 00 am cortisol: <138 nmol/L), underwent a DT within 3 months post-surgery. Association between DT findings and the prediction of recurrence was tested using regression and ROC analyses. RESULTS: Recurrence occurred in 17/95 patients within 29 to 91 months. The cortisol peak (327, 95% CI (237-417) vs 121 (79-164) nmol/L, P = 0.0001) and absolute increment during DT (208 (136-280) vs 56 (22-90) nmol/L, P = 0.005) were greater in the recurrence vs remission group. Cortisol peak (AUC: 0.786 (0.670-0.902)) and increment (0.793 (0.672-0.914)) yielded a higher prognostic performance for recurrence than did the early post-operative 08 00 am cortisol (0.655 (0.505-0.804)). In the context of COI, cortisol peak >100 nmol/L and increment >30 nmol/L had a high negative predictive value (94, 95% CI (88-100) and 94, (88-100), respectively). Patients with a cortisol peak ≤100 nmol/L (vs >100) or an increment ≤30 nmol/L (vs >30) were less likely to have CD recurrence (odds ratios: 0.12, 95% CI (0.03-0.41) and 0.11 (0.02-0.36), respectively). CONCLUSION: The disappearance of the response to the post-operative DT was independently associated with a lower odds of CD recurrence and offers an incremental prognostic value, which may help to stratify patients with COI and refine their follow-up according to the risk of recurrence.

Discordant biological parameters of remission in acromegaly do not increase the risk of hypertension or diabetes: a study with the Liege Acromegaly Survey database.

PURPOSE: Acromegaly is a rare disease due to growth hormone (GH)-secreting pituitary adenoma. GH and IGF-1 levels are usually congruent, indicating either remission or active disease; however, a discrepancy between GH and IGF-1 may occur. We aimed to evaluate the outcome of diabetes mellitus (DM) and hypertension (HT) in acromegalic patients with congruent GH and/or IGF-1 levels vs. discordant biochemical parameters. METHODS: Retrospective analysis of the data of 3173 patients from the Liege Acromegaly Survey (LAS) allowed us to include 190 patients from 8 tertiary referral centers across Europe, treated by surgery, with available data concerning DM and HT both at diagnosis and at the last follow-up (LFU). We recorded the number of anti-HT and anti-DM drugs used at the first evaluation and at LFU for every patient. RESULTS: Ninety-nine patients belonged to the REM group (concordant parameters), 65 patients were considered as GHdis (high random GH/controlled IGF-1), and 26 patients were considered as IGF-1dis (high IGF-1/controlled random GH). At diagnosis, 72 patients (37.8%) had HT and 54 patients had DM (28.4%). There was no statistically significant difference in terms of the number of anti-HT and anti-DM drugs at diagnosis versus LFU (mean duration: 7.3 ± 4.5 years) between all three groups. CONCLUSION: The long-term outcome of DM and HT in acromegaly does not tend to be more severe in patients with biochemical discordance in comparison with patients considered as in remission on the basis of concordant biological parameters, suggesting that patients with biochemical discordance do not require a closer follow-up.

Growth hormone excess and sternohyoid muscle mechanics in rats.

In vitro isotonic and isometric mechanical properties of the sternohyoid (SH) muscle, an upper airway dilator muscle, were studied in rats with a growth hormone (GH)-secreting tumour (GH tumour group; n = 10). The effects of muscle fatigue were also studied. Stress and shortening were measured in muscles contracting from zero load up to isometric load under tetanic conditions. Isometric stress and maximum unloaded shortening velocity were determined and compared with values obtained from control rats (n = 10). Crossbridge kinetics and energetics and mechanical efficiency were calculated from Huxley's equations. Compared with controls, isometric stress, mechanical efficiency, crossbridge number and crossbridge single force were lower in the GH tumour group. The probability of crossbridge being in the power stroke configuration was lower in the GH tumour group than in controls. Muscle fatigue significantly impaired maximal muscle efficiency and crossbridge single force in the GH tumour group but not in controls. In conclusion, mechanical and energetic properties of the SH muscle and crossbridge properties were worse in the GH tumour group than in controls. This may partly account for impairment of the upper airway dilator muscle function and the increased occurrence of obstructive sleep apnoea in acromegaly.

Benefits of Ophdiat, a telemedical network to screen for diabetic retinopathy: a retrospective study in five reference hospital centres.

AIM: One objective of Ophdiat, a telemedical network using digital non-mydriatic cameras in Ile-de-France, is to develop a comprehensive screening programme that provides access to annual fundus examinations to all diabetic patients. The aim of this study was to evaluate the benefits of this programme in a hospital setting. METHODS: A retrospective analysis of 500 case reports of diabetic patients hospitalized before and after Ophdiat setup was performed in five reference hospital centres. At each centre, 100 case reports (50 before, 50 after) of patients aged greater than 18 years, hospitalized for their annual check-up, with no known diabetic retinopathy (DR) before hospitalization and with the last fundus examination performed greater than 11 months previously, were randomly selected. The primary endpoint was the proportion of patients whose fundus examinations were performed during hospitalization; secondary endpoints were the number of cases of DR found and the time taken by ophthalmologists to make the diagnosis. RESULTS: The mean proportion of patients with fundus examinations was 50.4% and 72.4% before and after, respectively, Ophdiat (P<0.01). The prevalence of DR was 11.1% before and 12.7% after (not significant). The mean time taken by an ophthalmologist per diagnosis of DR was 0.90 half-day before and 0.32 half-day after Ophdiat. CONCLUSION: This evaluation shows that Ophdiat, combined with the availability of modern and effective devices, has improved DR screening in diabetology departments in hospitals. Additional human resources would certainly ensure more effective use of the system.

[Drawing up guidelines for the attendance of physical health of patients with severe mental illness]. / Elaboration de recommandations pour le suivi somatique des patients atteints de pathologie mentale sévère.

INTRODUCTION: Having a mental illness has been and remains even now, a strong barrier to effective medical care. Most mental illness, such as schizophrenia, bipolar disorder, and depression are associated with undue medical morbidity and mortality. It represents a major health problem, with a 15 to 30 year shorter lifetime compared with the general population. METHODS: Based these facts, a workshop was convened by a panel of specialists: psychiatrists, endocrinologists, cardiologists, internists, and pharmacologists from some French hospitals to review the information relating to the comorbidity and mortality among the patients with severe mental illness, the risks with antipsychotic treatment for the development of metabolic disorders and finally cardiovascular disease. The French experts strongly agreed on these points: that the patients with severe mental illness have a higher rate of preventable risk factors such as smoking, addiction, poor diet, lack of exercise; the recognition and management of morbidity are made more difficult by barriers related to patients, the illness, the attitudes of medical practitioners, and the structure of healthcare delivery services; and improved detection and treatment of comorbidity medical illness in people with severe mental illness will have significant benefits for their psychosocial functioning and overall quality of life. GUIDELINES FOR INITIATING ANTIPSYCHOTIC THERAPY: Based on these elements, the French experts propose guidelines for practising psychiatrists when initiating and maintaining therapy with antipsychotic compounds. The aim of the guidelines is practical and concerns the detection of medical illness at the first episode of mental illness, management of comorbidity with other specialists, family practitioner and follow-up with some key points. The guidelines are divided into two major parts. The first part provides: a review of mortality and comorbidity of patients with severe mental illness: the increased morbidity and mortality are primarily due to premature cardiovascular disease (myocardial infarction, stroke...).The cardiovascular events are strongly linked to non modifiable risk factors such as age, gender, personal and/or family history, but also to crucial modifiable risk factors, such as overweight and obesity, dyslipidemia, diabetes, hypertension and smoking. Although these classical risk factors exist in the general population, epidemiological studies suggest that patients with severe mental illness have an increased prevalence of these risk factors. The causes of increased metabolic and cardiovascular risk in this population are strongly related to poverty and limited access to medical care, but also to the use of psychotropic medication. A review of major published consensus guidelines for metabolic monitoring of patients treated with antipsychotic medication that have recommended stringent monitoring of metabolic status and cardiovascular risk factors in psychiatric patients receiving antipsychotic drugs. There have been six attempts, all published between 2004 and 2005: Mount Sinai, Australia, ADA-APA, Belgium, United Kingdom, Canada. Each guideline had specific, somewhat discordant, recommendations about which patients and drugs should be monitored. However, there was agreement on the importance of baseline monitoring and follow-up for the first three to four months of treatment, with subsequent ongoing reevaluation. There was agreement on the utility of the following tests and measures: weight and height, waist circumference, blood pressure, fasting plasma glucose, fasting lipid profile. In the second part, the French experts propose guidelines for practising psychiatrists when initiating and maintaining therapy with antipsychotic drugs: the first goal is identification of risk factors for development of metabolic and cardiovascular disorders: non modifiable risk factors: these include: increasing age, gender (increased rates of obesity, diabetes and metabolic syndrome are observed in female patients treated with antipsychotic drugs), personal and family history of obesity, diabetes, heart disease, ethnicity as we know that there are increased rates of diabetes, metabolic syndrome and coronary heart disease in patients of non European ethnicity, especially among South Asian, Hispanic, and Native American people. Modifiable risk factors: these include: obesity, visceral obesity, smoking, physical inactivity, and bad diet habits. Then the expert's panel focussed on all the components of the initial visit such as: family and medical history; baseline weight and BMI should be measured for all patients. Body mass index can be calculated by dividing weight (in kilograms) by height (in meters) squared; visceral obesity measured by waist circumference; blood pressure; fasting plasma glucose; fasting lipid profiles. These are the basic measures and laboratory examinations to do when initiating an antipsychotic treatment. ECG: several of the antipsychotic medications, typical and atypical, have been shown to prolong the QTc interval on the ECG. Prolongation of the QTc interval is of potential concern since the patient may be at risk for wave burst arrhythmia, a potentially serious ventricular arrhythmia. A QTc interval greater than 500 ms places the patient at a significantly increased risk for serious arrhythmia. QTc prolongation has been reported with varying incidence and degrees of severity. The atypical antipsychotics can also cause other cardiovascular adverse effects with, for example, orthostatic hypotension. Risk factors for cardiovascular adverse effects with antipsychotics include: known cardiovascular disease, electrolyte disorders, such as hypokaliemia, hypomagnesaemia, genetic characteristics, increasing age, female gender, autonomic dysfunction, high doses of antipsychotics, the use of interacting drugs, and psychiatric illness itself. In any patient with pre-existing cardiac disease, a pre-treatment ECG with routine follow-up is recommended. CONCLUDING REMARKS: Patients on antipsychotic drugs should undergo regular testing of blood sugar, lipid profile, as well as body weight, waist circumference and blood pressure, with recommended time intervals between measures. Clinicians should track the effects of treatment on physical and biological parameters, and should facilitate access to appropriate medical care. In order to prevent or limit possible side effects, information must be given to the patient and his family on the cardiovascular and metabolic risks. The cost-effectiveness of implementing these recommendations is considerable: the costs of laboratory tests and additional equipment costs (such as scales, tape measures, and blood pressure devices) are modest. The issue of responsibility for monitoring for metabolic abnormalities is much debated. However, with the prescription of antipsychotic drugs comes the responsibility for monitoring potential drug-induced metabolic abnormalities. The onset of metabolic disorders will imply specific treatments. A coordinated action of psychiatrists, general practitioners, endocrinologists, cardiologists, nurses, dieticians, and of the family is certainly a key determinant to ensure the optimal care of these patients.

[Hypoglycemia and insulinoma]. / Hypoglycémie et insulinome.

Insulinomas are rare causes of hypoglycemia. After having ruled out non insulinomatous causes of hypoglycemia in a patient in whom Whipple's triad is documented, hyperinsulinism must be demonstrated biochemically, either during a spontaneous hypoglycemic episode or, more often, during a supervised fast which may be prolonged up to 72 h. A mixed-meal test may also help to diagnose the very rare cases of postprandial hypoglycemia related to non insulinoma pancreatogenic hypoglycemic syndrome (NIPHS) or to some rare insulinomas. Only when diagnosis of hypoglycemic hyperinsulinism is made, the tumor localization process may be initiated. This may be difficult due to the small size of insulinomas (generally < 1 cm). Multimodal approach is necessary. The association of endoscopic ultrasound and CT-scan or MRI seems optimal. Octreoscan will be also performed. First results with a very new technique, the GLP-1 receptor imaging, are promising for localizing very small tumors. This localization aims to allow a sparing surgery; enucleation of benign tumors, if possible, allows a pancreatic tissue preservation in patients with quite normal survival.

Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults.

The V Consensus Group Meeting on 'Guidelines for Treatment of GH Excess and GH Deficiency in the Adult' was an international workshop held on February 20-22, 2006 in Santa Monica, California, USA. The principal aim of this meeting was to provide guidelines for the evaluation and treatment of adults with either form of abnormal GH secretion: GH excess or GH deficiency. The workshop included debates as to the choice of primary treatment, discussions of the targets for adequate treatment, and concluded with presentations on open issues germane to adult GH treatment including the role of GH in malignancies, the impact of longterm treatment on bone, and a cost-benefit analysis. The meeting was comprised of 66 delegates representing 13 different countries.

[Endocrine tumors of the pancreas (EPTs) in multiple endocrine neoplasia (MEN1): up-date on prognostic factors, diagnostic procedures and treatment]. / Les tumeurs endocrines du pancréas lors de la néoplasie endocrinienne multiple type 1 (NEM1): actualités sur les facteurs pronostiques, l'imagerie et le traitement.

Endocrine pancreatic tumors (EPTs) are uncommon tumors, representing 1-2% of all pancreatic neoplasms. They are categorized on the basis of their clinical features into functioning and non-functioning tumors. EPTs may be part of the multiple endocrine neoplasia type 1 (MEN 1), an autosomal dominant syndrome due to inactivating germline mutation of the menin gene. Somatic mutations of menin are present in about 20% of sporadic neoplasms, particularly gastrinomas and insulinomas. 30-75% of patients with MEN1 have EPTs. The most prevalent are the gastrinomas (20-60%), then the insulinomas (5-10%), the glucagonamas and VIPomas (6-10%), whereas the nonfunctioning EPTs are present in 20-40% of patients. The most important biochemical screening marker for EPTs is chromogranin A, as it increases in 50-80% of patients. The most important negative prognostic factors are the presence of metastases, the gross invasion of adjacent organs, the angioinvasion, the perineural invasion and an immunopositivity for Ki-67 > 2%. Among the different imaging techniques, echoendoscopy, computed tomography (CT) and magnetic resonance imaging (MRI) are indicated for the detection of the primary tumor, but (III)In-octreotide scintigraphy has the highest sensitivity for detecting metastases. The choice of treatment is still debated and is different when the tumor occurs as a part of the MEN syndrome. The surgical treatment is the first choice for insulinomas and is more controversial for gastrinomas. The medical treatment includes somatostatin analogues (SA), chemotherapy and interferon-alpha (IFN-alpha). SA seem to improve the symptoms and have an antiproliferative effect, the most striking effect being seen in patients with VIPomas. Chemotherapy, which is generally proposed as a combination of streptozotocin (STZ) and 5-fluorouracil (5-FU) or doxorubicin, is indicated when the tumors tend to grow. Interferon-alpha (IFN-alpha) stimulates the immune system, blocks the tumor cells in the G1/S-phase of the cell cycle, inhibits protein and hormone synthesis and inhibits angionenesis. Treatment with IFN has been shown to produce symptomatic response in 40-60% of patients, a biochemical response in 30-60% and tumor shrinkage in 10-15%.

Drug treatment of hyperprolactinemia.

Medical treatment of hyperprolactinemia is based upon use of dopamine agonists (DA): bromocriptine, lisuride, quinagolide and cabergoline. In over 80% of cases, these drugs induce normal prolactinemia and ovulatory cycles. In resistant cases, the DA should be changed. Tolerance may occasionally be poor, particularly with bromocriptine, which appears less well-tolerated than quinagolide and than cabergoline above all. In the event of intolerance to a given DA, another should be tried. In patients with macroprolactinoma treated with DA, MRI monitoring should be carried out after 3 months of treatment to verify tumor size reduction, then after 1 year, yearly for the next 5 years and once every 5 years if adenoma size is stable. In cases of microprolactinoma, control under treatment is pointless. MRI may be performed after 1 year and then after 5 years. Once normal prolactin levels have been achieved, attempts may be made to stop the treatment. When a prolonged treatment is interrupted, especially with cabergoline, progressive increase in serum prolactin and return of hyperprolactinemia symptoms are seen in only around 20-30% of cases, particularly when residual adenoma exists after prolonged treatment. Nevertheless, prolactin levels should continue to be monitored after discontinuation of DA, possibly with MRI monitoring, since prolactin levels may rise again after a number of months or years. When normal prolactin levels have been achieved with DA, another solution consists in reducing the dose or dosing frequency of DA in steps to the lowest effective dose consistent with maintenance of normal prolactin levels and stable adenoma size. For drug-induced hyperprolactinemia, where the causative medication cannot be withdrawn, it is often pointless and possibly even dangerous to administer a DA. It is therefore necessary to check for absence of pituitary adenoma and where necessary, begin treatment with sex steroids so as to ensure satisfactory impregnation with sex steroids and avoid osteoporosis. For macroprolactinoma, the first-line treatment is drug therapy with DA. At present, there is no evidence to suggest that prior treatment with DA can modify the outcome of surgery. With microprolactinoma, DA treatment offers a good first-line therapeutic option but surgery may also be useful. DAs for microprolactinoma may be withdrawn after menopause.