The silent variants of pituitary tumors: demographic, radiological and molecular characteristics.

INTRODUCTION: Tumors of the anterior pituitary gland (PTs) are mostly benign tumors with a low prevalence, which has nevertheless increased with advances in brain radiology techniques. Nearly half of PTs are not associated with a clinical endocrine syndrome. These tumors have been indistinctly named non-functioning pituitary adenomas (NFPAs) or silent pituitary tumors (SPTs) and the mechanisms of silencing are not fully known. AIM: To study the frequency and characterize the silent variant of PTs in a large local series, and to assess their pituitary adenohypophyseal gene expression. METHODS: This observational, cross-sectional study was performed in a Pituitary Tumor Center of Excellence and involved 268 PTs. After identifying the different subtypes according to the immunohistochemical (IHC) expression of adenohypophyseal hormones, we studied their gene expression by RT-qPCR. RESULTS: We found that silent tumors were larger and more invasive, but not more proliferative than their functional counterparts. The RT-qPCR complements the IHC typification of PTs, reducing the proportion of null-cell subtype. Finally, some silent PT subtype variants showed lower specific adenohypophyseal hormone gene expression than their functional counterparts, which may contribute to the absence of endocrine manifestations. CONCLUSIONS: This paper highlights the importance of identifying the silent variant of the PTs subtypes. As expected, silent tumors were larger and more invasive than their functioning counterparts. However, there was no difference in the proliferation activity between them. Finally, the lower specific gene expression in the silent than in the functioning counterparts of some PTs subtypes gives insights into the silencing mechanisms of PTs.

Is Somatostatin Receptor and Dopamine Receptor profiling useful in the management of silent somatotroph tumors?

Silent somatotroph tumors (sSTs) are pituitary neuroendocrine tumors (PitNETs) which do not give rise to the clinical syndrome of acromegaly. Differently to their functioning counterparts, the adjuvant medical treatment with somatostatin analogues (SSAs) or dopamine receptors agonists (DAs) has been scarcely addressed in these tumors. As preliminary results of an ongoing research on silencing mechanisms involved in the pathogenesis of sSTs, we have characterized by qRT-PCR the expression of SSTRs and DRDs in a large series of 18 silent and 68 functioning STs. Although the expression of SSTR2 and SSTR5 was lower in sSTs than in functioning ones, we found a negative correlation between SSTR2 and the tumor size of the sSTs. Additionally, levels of expression of DRD2 were similar between the two subtypes suggesting a possible basis for the treatment of these tumors with SSAs and DAs.

Impact of circulating bacterial DNA in long-term glucose homeostasis in non-diabetic patients with HIV infection: cohort study.

In HIV-infected patients, the damage in the gut mucosal immune system is not completely restored after antiretroviral therapy (ART). It results in microbial translocation, which could influence the immune and inflammatory response. We aimed at investigating the long-term impact of bacterial-DNA translocation (bactDNA) on glucose homeostasis in an HIV population. This was a cohort study in HIV-infected patients whereby inclusion criteria were: patients with age >18 years, ART-naïve or on effective ART (<50 HIV-1 RNA copies/mL) and without diabetes or chronic hepatitis C. Primary outcome was the change in HbA1c (%). Explanatory variables at baseline were: bactDNA (qualitatively detected in blood samples by PCR [broad-range PCR] and gene 16SrRNA - prokaryote), ART exposure, HOMA-R and a dynamic test HOMA-CIGMA [continuous infusion of glucose with model assessment], hepatic steatosis (hepatic triglyceride content - 1H-MRS), visceral fat / subcutaneous ratio and inflammatory markers. Fifty-four men (age 43.2 ± 8.3 years, BMI 24.9 ± 3 kg/m2, mean duration of HIV infection of 8.1 ± 5.3 years) were included. Baseline HbA1c was 4.4 ± 0.4% and baseline presence of BactDNA in six patients. After 8.5 ± 0.5 years of follow-up, change in HbA1c was 1.5 ± 0.47% in patients with BactDNA vs 0.87 ± 0.3% in the rest of the sample p < 0.001. The change in Hba1c was also influenced by protease inhibitors exposure, but not by baseline indices of insulin resistance, body composition, hepatic steatosis, inflammatory markers or anthropometric changes. In non-diabetic patients with HIV infection, baseline bacterial translocation and PI exposure time were the only factors associated with long-term impaired glucose homeostasis.

Biological markers of fertility (inhibin-B) in HIV-infected men: influence of HIV infection and antiretroviral therapy.

OBJECTIVES: Inhibin B (IB) levels and the IB: follicle-stimulating hormone (FSH) ratio (IFR), biomarkers of global Sertoli cell function, show a strong relationship with male fertility. The aim of the study was to examine the prevalence of impaired fertility potential in HIV-infected men and the influence of antiretroviral therapy (ART) on fertility biomarkers. METHODS: A cross-sectional study with sequential sampling was carried out. A total of 169 clinically stable patients in a cohort of HIV-infected men undergoing regular ambulatory assessment in a tertiary hospital were included. The mean [± standard deviation (SD)] age of the patients was 42.6 ± 8.1 years, all were clinically stable, 61.5% had disease classified as Centers for Disease Control and Prevention (CDC) stage A, and were na?ve to ART or had not had any changes to ART for 6 months (91.1%). Morning baseline IB and FSH concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) and an electrochemiluminescent immunoassay (ECLIA), respectively. A multivariate logistic regression model was used to identify factors associated with impaired fertility, defined as IB < 119 pg/mL or IFR < 23.5. RESULTS: The mean (± SD) IB level was 250 ± 103 pg/mL, the median [interquartile range (IQR)] FSH concentration was 5.1 (3.3-7.8) UI/L and the median (IQR) IFR was 46.1 (26.3-83.7). The prevalence of impaired fertility was 21.9% [95% confidence interval (CI) 16.3-20.7%]. Negative correlations of body mass index and waist: hip ratio with FSH and IB levels were observed (P < 0.01), while a sedentary lifestyle and previous nevirapine exposure were associated with a decreased risk of IB levels ≤ 25th percentile in multivariate analysis. Only older age, as a risk factor, and sedentary lifestyle, with a protective effect, were independently associated with impaired fertility in multivariate analysis. CONCLUSIONS: Global testicular Sertoli cell function and fertility potential, assessed indirectly through serum IB levels and IB: FSH ratio, appear to be well maintained in HIV-infected men and not damaged by ART.

Safety of long-term treatment with Pegvisomant: analysis of Spanish patients included in global ACROSTUDY.

PURPOSE: To evaluate the long-term safety of Pegvisomant (PEG) in the Spanish cohort of ACROSTUDY. METHODS: As of July 2013, 199 Spanish patients were included in ACROSTUDY, a global non interventional safety PEG surveillance study. Patients were observed for safety, biochemical outcome and magnetic resonance imaging evaluations. RESULTS: PEG was administered during an average period of 6.7 ± 2.1 years and a mean daily dose of 15.5 ± 7.5 mg. 48.2% of patients received PEG monotherapy. 90.9% of patients had received other medical treatment before PEG start. 195 adverse events (AEs) were reported in 88 patients (44.2%), and serious AEs were described in 31 patients (15.6%). There were no cases of liver tests >10 ULN, or permanent liver damage. Tumor size changes were locally reported in 61 cases (33.5%), with increases observed in 11 patients (6%). In acromegalic patients with diabetes mellitus a decrease in fasting serum glucose value was reported, reaching statistical significance after 1 and 4 years of treatment (-24.6 and -25.9 mg/dl, p = 0.04). After 60 months, normal or lower limit of normal (LLN) IGF-I levels were found in 67.9% of patients. 85.5% of patients showed an IGF-I normal or

Harlequin sign due to an upper thoracic paravertebral lesion. A systematic review of the literature.

INTRODUCTION: Harlequin syndrome (HS) is an uncommon condition affecting the sympathetic nervous system, characterized by asymmetrical flushing and sweating impairment, which can affect the face or half of the body. When the dysfunction results from external factors like damage or compression, it's referred to as Harlequin Sign. Our objective was to document an exceedingly rare presentation of Harlequin Sign caused by a T3-T4 paravertebral mass and conduct the first systematic literature review on this subject. METHODS: We conducted a systematic review of English-language studies using PubMed, Scopus, and Embase databases. We excluded abstracts, posters, congenital and idiopathic Harlequin Syndrome cases, as well as iatrogenic and secondary Harlequin Sign cases related to pathologies other than upper thoracic lesions. RESULTS: We employed the PRISMA protocol and reviewed 1,538 papers, identifying 8 single case reports describing the Harlequin sign resulting from upper thoracic paravertebral lesions. The mean age of the patients was 41.25 years, with 6 (75 %) being female. The average time from onset to presentation was 8 months, and all patients (100 %) exhibited hemifacial flushing, while 4 (50 %) also had hemifacial anhidrosis. Stress or exercise exacerbated these symptoms in 50 % of cases. Additionally, 3 patients (37.5 %) presented with associated Horner Syndrome. The most commonly used diagnostic tool was a CT scan (50 %), revealing an average tumor diameter of 3.95 cm, with 50 % of cases located at T2-T3. Diagnosis indicated 57 % of cases as schwannomas and 29 % as lung adenocarcinoma (Superior Sulcus). Unfortunately, surgical treatment resolved symptoms in only 25 % of patients. CONCLUSIONS: Hemifacial or hemibody autonomic symptoms should raise concern for paraspinal lesions in the thoracic spine. In addition to the first comprehensive review on this topic, we present a rare case of a T3/4 paraspinal schwannoma causing Harlequin Syndrome successfully managed with neurosurgical intervention.

Impact of vitamin D insufficiency on insulin homeostasis and beta cell function in nondiabetic male HIV-infected patients.

OBJECTIVES: Vitamin D is thought to play a role in glucose homeostasis and beta cell function. Our aim was to examine the impact of plasma 25-hydroxyvitamin D [25(OH)D] upon in vivo insulin sensitivity and beta cell function in HIV-infected male patients without diabetes. METHODS: A cross-sectional study was carried out involving a cohort of HIV-infected patients undergoing regular assessment in a tertiary hospital. Eighty-nine patients [mean (± standard deviation) age 42 ± 8 years] were included in the study: 14 patients were antiretroviral therapy (ART)-naïve, while 75 were on ART. Vitamin D insufficiency (VDI) was defined as 25(OH)D < 75 nmol/L; insulin sensitivity was determined using a 2-h continuous infusion of glucose model assessment with homeostasis (CIGMA-HOMA), using the trapezoidal model to calculate the incremental insulin and glucose areas under the curve (AUCins and AUGglu, respectively). Beta cell function was assessed using the disposition index (DI). Abdominal visceral adipose tissue (VAT) and hepatic triglyceride content (HTGC) were measured by magnetic resonance imaging (MRI) and 1-H magnetic resonance spectroscopy. Multivariate linear regression analysis was performed. RESULTS: VDI was associated with insulin resistance (IR), as indicated by a higher CIGMA-HOMA index (odds ratio 1.1) [1.01-1.2]. This association was independent of the main confounders, such as age, Centers for Disease Control and Prevention (CDC) stage, ART, lipodystrophy, body mass index, VAT:subcutaneous adipose tissue ratio and HTGC, as confirmed by multivariate analysis (B = 12.3; P = 0.01; r² = 0.7). IR in patients with VDI was compensated by an increase in insulin response. However, beta cell function was lower in the VDI subpopulation (33% decrease in DI). CONCLUSIONS: VDI in nondiabetic HIV-positive male patients is associated with impaired insulin sensitivity and a decrease in pancreatic beta cell function.

Development of a molecularly imprinted polymer-matrix solid-phase dispersion method for selective determination of ß-estradiol as anabolic growth promoter in goat milk.

A simple, fast, and sensitive method for determination of 17 ß-estradiol (E2) in goat milk samples has been developed by combining selective molecularly imprinted matrix solid-phase dispersion (MIP-MSPD) and liquid chromatography with diode-array detection (DAD). The molecularly imprinted polymer was synthesized by use of 17ß-estradiol as template molecule, methacrylic acid as functional monomer, ethylene glycol dimethacrylate as crosslinker monomer, azobisisobutyronitrile as initiator, and acetonitrile as porogen, and was used as selective solid support for matrix solid-phase dispersion. The selected dispersant had high affinity for E2 in the goat milk matrix and the extract obtained was sufficiently clean for direct injection for HPLC analysis without any interferences from the matrix. The proposed MIP-MSPD method was validated for linearity, precision, accuracy, decision limit (CCα) and detection capability (CCß), in accordance with European Commission Decision 2002/657/EC criteria. Linearity ranged from 0.3-10 µg g(-1) (correlation coefficient r(2) > 0.999). Mean recovery of E2 from goat milk samples at different spiked levels was between 89.5 and 92.2%, with RSD values within 1.3-2%. CCα and CCß values were 0.36 and 0.39 µg g(-1), respectively. The developed MIP-MSPD method was successfully applied to direct determination of E2 in goat milk samples.

Disposable electrochemical sensor combined with molecularly imprinted solid-phase extraction for catabolites detection of flavan-3-ol in urine samples.

Polyphenols are bioactive substances of vegetal origin with a significant impact on human health. The assessment of polyphenol intake and excretion is therefore important. In this work, a new electrochemical approach based on molecularly imprinted polymer extraction and preconcentration, combined with a disposable carbon screen-printed sensor and adsorptive transfer differential pulse voltammetry detection has been proposed for quantifying of 4-hydroxyphenylacetic acid (4-HPA), which is a biomarker of flavan-3-ols intake, and other phenolic acids. The simple experimental performance has allowed the rapid data collection with relevant information about the profile of catabolites extracted. The method was validated over a concentration range of 10-200 mg L-1, R2 > 0.999. In the optimized conditions, the recovery value was 94% with RSD 8%. The limits of detection and quantification were 2.38 mg L-1 and 7.21 mg L-1, respectively. The method was validated by means of a chromatographic method, being the differences between the values of the 4-HPA concentrations obtained by both methods under 1%. The proposed method showed high recoveries, low detection limit, and good accuracy, providing a fast, reliable, and cheap procedure to quantify phenolic metabolites in urine, and representing therefore a good and interesting alternative method. Also, the procedure offers other advantages, including the miniaturization, the low use of organic solvents, the ability to analyse small volumes of samples, in situ analysis and simple instrumentation requirement.

[The return of the statisticians. On the value of statistics in clinical neuropsychology]. / El regreso de los estadisticos. Sobre el valor de la estadistica en neuropsicologia clinica.

There was a time when clinicians looked down on any decision-making that did not depend on their own judgement. Statisticians laughed at such naivety, as they were fully aware of the extent to which the heuristics that guide human decisions are capable of error, even in the most highly trained individuals. More than 60 years after the beginning of this conflict, the two standpoints have still not been adopted in clinical psychology or in neuropsychology. This work defends the practical application of statistics in clinical decision-making and shows that even intuitive-type judgement is somehow based on applying the basic use of statistical concepts, without neglecting the fact that statistical instruments have sometimes been misused. To this end, this study compares the opinions offered by some clinicians in sentence form with the bibliography consulted, which spans the period from the earliest works by the clinical psychologist Paul Meehl to the present day. We have no intention whatsoever of imposing an opinion, but instead of discussing the advantage of adopting an approach that uses mathematical knowledge to support clinical decision-making. Attention is also drawn to the need for multidisciplinary teams in the special units of our hospitals.

TITLE: El regreso de los estadisticos. Sobre el valor de la estadistica en neuropsicologia clinica.Hubo un tiempo en que los clinicos despreciaban cualquier toma de decisiones que no dependiera de su propio juicio. Los estadisticos se reian de tal ingenuidad, conociendo lo falible de los heuristicos que guian las decisiones humanas, incluso en los individuos mas entrenados. Tras mas de 60 años del inicio del enfrentamiento, ambas posturas aun no se han asimilado en psicologia clinica ni en neuropsicologia. El presente trabajo respalda la aplicacion practica de la estadistica en la toma de decisiones clinica y muestra que incluso el juicio de tipo intuitivo descansa de algun modo en la aplicacion del uso basico de conceptos estadisticos, sin obviar que en ocasiones se ha hecho mal uso de las herramientas estadisticas. Para ello contrasta las opiniones ofrecidas por algunos clinicos en forma de frase con la bibliografia consultada, que se extiende desde los primeros trabajos del psicologo clinico Paul Meehl hasta la actualidad. Lejos de querer imponer una opinion, se comenta la ventaja de asumir un enfoque que aproveche los conocimientos matematicos como apoyo a la toma de decisiones clinica. Finalmente se comenta la necesidad de equipos multidisciplinares en las unidades especiales de nuestros centros hospitalarios.

Why don't corticotroph tumors always produce Cushing's disease?

OBJECTIVE: Silent corticotroph tumors are a pituitary neuroendocrine tumor subtype of corticotroph lineage that do not clinically express Cushing's disease. The silencing of this type of tumor is not fully understood. The aim of the present study was to delve into the lack of secretory activity, studying the post-transcriptional and post-translational regulation of POMC/ACTH in a series of molecularly identified functioning and silent corticotroph tumors. DESIGN: We analyzed 24 silent corticotroph, 23 functioning corticotroph and 25 silent gonadotroph tumors. METHODS: We used Sanger sequencing, quantitative real-time PCR and Western blot to analyze genetic alterations in POMC, gene expression of TBX19, NEUROD1, POMC, PCSK1, PCSK2, CPE and PAM and protein expression of POMC, PC1/3, PC2, CPE and PAM. RESULTS: We found different polymorphisms in the POMC gene of corticotroph tumors, some of them related to deficiency of proopiomelanocortin. Silent corticotroph tumors showed lower PC1/3 gene and protein expression than functioning ones, especially compared to micro-functioning corticotroph tumors (all P < 0.05). Moreover, we found a positive correlation between PC2 and CPE gene and protein expression (rho ≥ 0.670, P < 0.009) in silent corticotroph tumors compared with functioning ones. CONCLUSIONS: By studying the post-transcriptional and post-translational processing of POMC and ACTH, respectively, in a large series of silent and functioning corticotroph tumors, we found that the lack of secretory activity of these tumors is related to an impaired processing of POMC and a high degradation of ACTH, with the macro-functioning corticotroph tumor behaving as an intermediate state between micro-functioning and silent corticotroph tumors.

Structure of the RCK domain from the E. coli K+ channel and demonstration of its presence in the human BK channel.

The intracellular C-terminal domain structure of a six-transmembrane K+ channel from Escherichia coli has been solved by X-ray crystallography at 2.4 A resolution. The structure is representative of a broad class of domains/proteins that regulate the conductance of K+ (here referred to as RCK domains) in prokaryotic K+ transporters and K+ channels. The RCK domain has a Rossmann-fold topology with unique positions, not commonly conserved among Rossmann-fold proteins, composing a well-conserved salt bridge and a hydrophobic dimer interface. Structure-based amino acid sequence alignments and mutational analysis are used to demonstrate that an RCK domain is also present and is an important component of the gating machinery in eukaryotic large-conductance Ca2+ activated K+ channels.

Outcome of pregnancy in a hypothyroid woman with resistance to thyroid hormone treated with triiodothyronine.

Epidemiological and research data have shown the significant role of maternal thyroid hormone in fetal neurologic development. It has been suggested that maternal hypothyroxinemia is potentially damaging for the neurodevelopment of the fetus, independently of T3 levels. We present a pregnant woman with resistance to thyroid hormone and iatrogenic hypothyroidism who was treated with triiodothyronine during the whole pregnancy. Even though maternal hypothyroxinemia was severe the children showed a normal neuropsychological development.

An isolated pituitary metastasis as presentation of a differentiated hepatocellular carcinoma mimicking a nonfunctioning macroadenoma.

The differential diagnosis of sellar masses may be complex. Metastatic disease constitutes 1% of all pituitary lesions and sometimes mimics the clinical-radiological presentation of pituitary adenoma. The definitive diagnosis usually relies on histology, but occasionally even histological features of pituitary metastasis may resemble those of adenomas. We present a patient initially diagnosed with pituitary adenoma, but whose clinical course finally revealed pituitary metastasis of a hepatocellular carcinoma. The existing literature on this topic is reviewed.

Protocolo asistencial clínico-psicológico para el tratamiento del tabaquismo con citisina / Clinical-psychological care protocol for the treatment of smoking with cytisine

Citisina es un tratamiento farmacológico del tabaquismo que ha sido introducido recientemente en nuestro país. Los estudios realizados con el mismo durante los últimos años muestran que es un tratamiento eficaz y seguro utilizado a dosis decrecientes durante un periodo de 25 días. Sus específicas características de dosis y tiempo de duración hacen recomendable que se diseñe un protocolo asistencial clínico-psicológico para ser desarrollado durante la utilización de citisina. Un grupo multidisciplinario de profesionales sanitarios expertos en tabaquismo han consensuado un protocolo que recomiendan para llevar a cabo en aquellos pacientes a los que se prescriba citisina como fármaco para dejar de fumar. (AU)

Cytisine is a smoking cessation medication that has appeared recently in Spain. It is effective and safe for helping smokers to quit using for 25 days. Its specific characteristicis in doses and duration recommends to desing a protocol clinical-psychological. A multidisciplinary group of health professionals experts on smoking cessation has designed a protocol to develop with patients who are receiving cytisineas medication for smoking cessation. (AU)

[Prognostic morbidity and mortality factors in hospital enteral nutrition: prospective study]. / Factores pronósticos de morbi-mortalidad en nutrición enteral hospitalaria: estudio prospectivo.

OBJECTIVE: To determine the prognostic factors that may best for see the outcome of an enteral nutritional intervention and to assess the assistance quality of a nutrition unit. SETTING AND SUBJECTS: Patients that required enteral nutrition during hospital admission at a third level center. INTERVENTIONS: Observational prospective study in which 160 patients were included by means of consecutive sampling, for a 6-months follow-up period. Underlying pathology, disability degree, nutritional assessment, type of enteral nutrition, complications, nursing care, and clinical course of patients were determined. RESULTS: severe caloric and protein hyponutrition was diagnosed in 48.4 and 52.9% of patients; stress degree was moderate in 52.2% and severe in 36.5%. In 88.2% of patients variation of protein parameters was unchanged or improved, with a 0.26 g/dL increase in albumin levels and 2.4 m/dL in prealbumin (p < 0.05). Multivariate analysis adjusted for plasma albumin at admission showed that besides this biochemical parameter, a severe stress degree, a decreased alertness level, and worsening of protein variation during admission are independent prognostic mortality factors during an enteral nutritional intervention in the hospitalized patient (p < 0.05). CONCLUSIONS: alertness level, degree of caloric hyponutrition, stress degree, plasma albumin levels, and variation of protein parameters during nutritional support are independent prognostic factors for the nutritional intervention outcomes. The development of global monitoring systems of assistance activity and quality of Nutrition Units is paramount in order to improve the efficiency of enteral nutritional support at the hospital setting, to advance in patients care and promote the development of nutritional therapy.

Synthesis of a molecularly imprinted polymer for the isolation of 1-hydroxypyrene in human urine.

In the last decades, the assessment of polycyclic aromatic hydrocarbons' exposure has generated great interest and 1-hydroxypyrene (1-OHP) has been commonly used as a biological indicator of exposure to PAHs in many studies in environmental and occupational health. In this research, a molecularly imprinted polymer (MIP) was synthesised by precipitation polymerisation using 1-OHP as template, methacrylic acid (MAA) as functional monomer, ethylene glycol dimethacrylate (EGDMA) as cross-linker, and acetonitrile as porogen. MIP was used as solid-phase extraction (SPE) material for sample pretreatment and isolation of 1-OHP and posterior detection in a reversed-phase HPLC-FLD. Various parameters including washing solvent, elution solvent and volume affecting the extraction efficiency of the polymer have been evaluated to achieve the isolation of 1-OHP from urine samples and to reduce non-specific interactions. Cross-selectivity was studied in the presence of other structural analogues of the 1-OHP as hydroxyphenantrene isomers. The method was validated over a concentration range of 0.15-2.00 µg L(-1), R(2)>0.998. Recovery values were in the range of 78-90% and RSD <6.7%. The limits of detection and quantification were 0.05 µg L(-1) and 0.17 µg L(-1), respectively. In our knowledge, it is the first time that this methodology is applied for analysing urinary hydroxypyrene and it has been demonstrated that this specific MISPE-HPLC-FLD method offers a fast and simple alternative to determine 1-OHP in human urine samples.

Efficacy of the new long-acting formulation of lanreotide (lanreotide Autogel) in the management of acromegaly.

Lanreotide Autogel is a new long-acting aqueous preparation of lanreotide for the treatment of acromegaly and is administered by deep sc injection from a small volume, prefilled syringe. The aim of this study was to evaluate the efficacy and safety of this new long-acting formulation in a large population of acromegalic patients previously responsive to lanreotide 30 mg, im (sustained release microparticle formulation). Lanreotide Autogel was administered by deep sc injection every 28 d to 107 patients (54 males and 53 females; mean age, 54 +/- 1.2 yr). All patients had been treated with lanreotide (30 mg) for at least 3 months before study entry and had a mean GH level less than 10 ng/ml after at least 4 subsequent im injections every 14 d (48%), 10 d (32%), or 7 d (20%). Treatment was switched from lanreotide 30 mg injected every 14, 10, or 7 d to 60, 90, or 120 mg lanreotide Autogel, respectively, every 28 d. After three fixed dose injections of lanreotide Autogel, mean lanreotide levels were similar to those obtained at steady state with lanreotide 30 mg. During lanreotide Autogel treatment, the control of acromegalic symptoms was comparable with that previously achieved during lanreotide 30 mg treatment. After 3 injections of lanreotide Autogel, mean GH (2.87 +/- 0.22 ng/ml) and IGF-I (317 +/- 15 ng/ml) values were comparable with those recorded at the end of lanreotide 30 mg treatment (GH, 2.82 +/- 0.19 ng/ml; IGF-I, 323 +/- 16 ng/ml). GH levels below 2.5 ng/ml and age-/sex-normalized IGF-I were achieved in 33% and 39% of patients during lanreotide 30 mg and lanreotide Autogel treatment, respectively. Diarrhea, abdominal pain, and nausea were reported by 38%, 22%, and 18% of patients during lanreotide 30 mg treatment and by 29%, 17%, and 9% of patients, respectively, during lanreotide Autogel treatment. In conclusion, this clinical study shows that lanreotide Autogel is at least as efficacious and well tolerated as lanreotide 30 mg. This new long-acting lanreotide formulation, lanreotide Autogel, which is administered from a small volume, prefilled syringe by deep sc injection, is therefore likely to improve the acceptability of medical treatment for patients requiring long-term somatostatin analog therapy.

Genetic and clinical analysis in 10 Spanish patients with multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN 1) is characterised by the combination of tumours of the parathyroid, endocrine pancreas and anterior pituitary glands. In 1988 the MEN 1 gene was mapped to chromosome 11q13 and it was cloned in 1997. This gene contains 10 exons and extends across 9 Kb of genomic DNA; it encodes for a product of 610 amino acid named menin whose function is unknown. We have studied 10 unrelated MEN 1 kindreds by a complete sequencing analysis of the entire gene; mutations were identified in nine of them: five deletions, one insertion, two nonsense mutation and a complex alteration consisting of a deletion and an insertion that can be explained by a hairpin loop model. Two of the mutations have been previously described; the other seven were novel, and they were scattered throughout the coding sequence of the gene. As in previous series, no correlation was found between phenotype and genotype.