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Objectif L’hypophosphatemie genetique lie a l’X (XLH), due aux mutations du gene PHEX, s’accompagne d’une production excessive de Fibroblast Growth Factor 23 (FGF-23), ayant pour consequence une fuite urinaire de phosphate avec des anomalies de la mineralisation osseuse. Les etudes epidemiologiques suggerent un lien entre FGF-23, obesite et syndrome metabolique. Toutefois, le retentissement metabolique du XLH n’a pas ete evalue. Methodes Etude prospective (CNIL2171036v0) comparant la prevalence du surpoids et de l’obesite chez des patients XLH adultes aux donnees de la population francaise. La tolerance au glucose et l’insulinosecretion ont ete evaluees par une hyperglycemie provoquee par voie orale (HGPO) et comparees aux resultats obtenus chez des temoins apparies sur l’âge, le sexe et l’IMC. Resultats Cent treize patients XLH (85F/28H), âge median 35,5 ans, porteurs de mutation PHEX, ont ete evalues. Leur IMC median etait de 25 kg/m2. Trente-huit (35,5 %, 29F) patients etaient en surpoids et 22 (20,5 %, 16F) patients etaient obeses. La prevalence de l’obesite en comparaison a la population generale etait plus importante chez les patients XLH (+ 20 %, 95 % CI [+6; + 33], p = 0,013), en particulier chez les sujets jeunes. Quatre (3,8 %) patients avaient un diabete et 10 (10,3 %) etaient classes comme intolerants au glucose lors de l’HGPO. Les aires sous la courbe de glycemie et d’insulinemie de 82 patients XLH et de 82 temoins etaient comparables. Discussion Les patients XLH ont un risque eleve de surcharge ponderale par rapport a la population francaise, sans retentissement sur le metabolisme glucidique.

La tomografia por emision de positrones con 18F-fluorodesoxiglucosa (18F-FDG) acoplada a la tomografia computarizada (18F-FDG PET-TC) ocupa, en lo que respecta a los canceres ginecologicos y mamarios, un lugar destacado en el estudio inicial de extension locorregional y metastasica. Esta tecnica proporciona datos relevantes en caso de recidiva y puede ser util para evaluar la respuesta terapeutica. En esta revision de las publicaciones se resumen los datos mas recientes respecto a la contribucion de esta prueba de imagen en la exploracion de los canceres de mama, ovario, cuello y cuerpo del utero en la evaluacion preterapeutica y el seguimiento de las pacientes. Las potencialidades y los limites en terminos de deteccion y caracterizacion de los canceres ginecologicos son motivo de discusion.

Background Chemoradiotherapy is the reference curative-intent treatment for nonresectable locally advanced non-small-cell lung carcinoma (NSCLC), with unsatisfying survival partially due to radiation resistance in hypoxic tissues, raising the question of targeted radiotherapy. Objective To evaluate the risk-benefit of radiotherapy boost on hypoxic tumors in NSCLC patients treated by curative-intent chemoradiotherapy in an open-label, nonrandomized, phase II clinical trial developed from 2012 to 2015 with a 3-year follow-up. Multicenter study performed in 15 French academic centers ( NCT01576796 ). Participants: eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. Seventy-nine patients underwent a run-in period, of which 54 were included. Twenty-four patients completed the study at 3 years. 18F-fluoromisonidazole (18F-MISO) positron emission tomography/computed tomography was performed to determine the hypoxic profile of patients (34 positive and 20 negative). Those with positive 18F-FMISO status and without organ-at-risk constraints (n = 24) received radiotherapy boost (70–84 Gy); the others received standard radiotherapy (66 Gy). Overall survival (OS), progression-free survival (PFS), and safety. Hypotheses tested were formulated before data collection. Results: fifty-four patients were evaluated, with a median age of 61 (41–76) years. OS and PFS rates at 1, 2, and 3 years were, respectively, 87%, 58.2%, and 48.5%, and 59.3%, 36.4%, and 28.8%. The median OS in the positive 18F-FMISO group was 25.8 months and was not reached at 3 years in the negative (P = 0.01). A difference was also observed for PFS (12 vs. 26.2 months, P = 0.048). By focusing on positive 18F-FMISO patients, no difference was observed in OS according to the dose, probably because of the small sample size (P = 0.30). However, the median OS seemed to be in favor of boosted patients (26.5 vs. 15.3 months, P = 0.71). In patients who underwent boost, no significant early or late toxicities were observed. Conclusions and relevance 18F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features. In the group of 18F-FMISO-positive patients, radiotherapy boost seems to improve the OS by 11.2 months. These results deserve further attention in a future clinical trial devoted to hypoxic patients to confirm boost efficacy.

Resume Le retard staturoponderal lie a un deficit en GH (hormones de croissance) ou en insulin-like growth factor 1 (IGF1) est frequemment associe chez l’adulte a des valeurs basses de la densite minerale osseuse (DMO), a une osteoporose et une augmentation du risque de fractures (Tritos et al., 2011 [1] ; Wuster et al., 2001 [2] ; Bex et Bouillon, 2003 [3] ). En revanche, le risque de fracture chez les enfants presentant un deficit en GH ou IGF1 n’a pas ete clairement evalue jusqu’a ce jour (Hogler et Shaw, 2010 [4] ). Nous presentons le cas d’une jeune fille âgee de 21 ans, porteuse d’un syndrome associant un retard psychomoteur et staturoponderal (–4 DS) severe depuis l’enfance, un dysmorphisme facial et une epilepsie, chez qui des troubles de la marche et une perte de force motrice sont apparus recemment, sans antecedent traumatique. La scintigraphie osseuse a permis de reveler de multiples foyers hyperfixants evocateurs de fissures ou fractures des os corticaux, et le bilan hormonal a mis en evidence un deficit en IGF1. Ce cas nous permet d’evoquer le role de la GH et de l’IGF1 dans le developpement osseux et de rappeler les principes a respecter lors de la mesure de la densite osseuse par absorptiometrie (DXA) chez l’enfant.

The synthesis of three molecules containing a fluorocarbon chain (either C(6)F(13), C(8)F(17) or C(10)F(21)), a sugar moiety (derived from lactobionic acid) and a chelate (derived from DTPA) is reported. These molecules (C(6)F(13)-Gal-DTPA, C(8)F(17)-Gal-DTPA or C(10)F(21)-Gal-DTPA) have been dispersed in water and their critical micellar concentration (CMC) as well as their size were determined. Their interaction with serum was weak as evaluated by time resolved fluorimetry of europium complexes. The presence of sugar on the surface of the nanoparticles was confirmed by the agglutination test using ricin. Conditions of pH and concentrations were optimised for in vivo studies. Finally, the nanoparticles formed with C(10)F(21)-Gal-DTPA have been complexed with (99m)Tc and injected to rats in order to follow their biodistribution by scintigraphy while following their stability by transmission electronic microscopy. A majority of the compound was found in the liver post-bolus injection.

The particular status of radiopharmaceuticals, together with the positioning of nuclear medicine in multidisciplinary approach of oncology, lead to real difficulties for conception, validation and granting of clinical trials which are necessary for demonstrating clinical interest of new compounds, for diagnosis as well as for therapeutic use. This article is a presentation of some recent clinical trials conducted in nuclear medicine in France, showing its dynamism but also pointing out some encountered difficulties. These experiences could lead to reflexion in order to improve the clinical research performances, taking into account a scientific and regulatory context more and more constraining.

Resume Le cas clinique rapporte est celui d’une petite fille de deux ans, ayant beneficie d’une transplantation hepatique dans le cadre d’une atresie des voies biliaires, adressee pour douleurs abdominales postoperatoires. La scintigraphie hepatobiliaire realisee avec l’acide iminiodiacetique-(99mTc) (IDA) a permis de mettre en evidence une fuite biliaire au niveau de l’anastomose chirurgicale. Ce cas clinique reprend certains aspects importants de la methodologie de la scintigraphie hepatobiliaire, peu connue et peu utilisee en France notamment en pediatrie, et illustre l’interet des acquisitions tardives dans les situations litigieuses.

Small clinical trials are trials in which the number of patients does not enable the objective of the study to be appropriately met with the usual methodological rules. This situation is common in the case of rare diseases, in paediatrics, in certain cancer pathologies or when the number of patients exposed to the treatment needs to be limited. The principal methodological problems are initially identified, and the classical methods (controlled, randomised, double-blind trial using parallel groups, crossover trial, factorial design, trial performed with several measures repeated over time, add-on design, randomised withdrawal design or early-escape design) and more uncommon methods (sequential approaches, meta-analyses, the ‘N of 1’ method and other methods that facilitate decision making or modelling) are then discussed. Subsequently, recommendations are made to ensure that the results obtained are not a matter of chance, and to increase the level of proof.

The effect of amiloride, a sodium channel blocker, has been evaluated in a multicenter randomized double-blind placebo-controlled trial in cystic fibrosis patients more than 5-years-old (n = 137) whose forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV(1)), and forced mid-expiratory flow (FEF(25-75)) were not below 50%, 50%, and 30% of reference values, respectively. Patients were randomly allocated to two parallel groups. Sixty-four patients were chronically colonized with Pseudomonas aeruginosa; they received either amiloride or placebo as a nebulized solution three times daily for 6 months. Routine treatments were continued. Patients chronically colonized with Pseudomonas received nebulized colimycine twice a day for a month during the third and sixth months of treatment. Bronchopulmonary exacerbations were treated in the usual way. The effects of the amiloride treatment were assessed at the end of the 6-month treatment period. The effects on FVC and secondarily on FEV(1), FEF(25-75), the number of days on antibiotic therapy, the Shwachman score, a nutritional index (weight/height(2)), the change in sputum bacterial flora, and nocturnal cough were assessed. For the patients not chronically colonized with Pseudomonas, the effect of the treatment was also evaluated by counting chronic colonizations with pathogens appearing during the trial period. The present study failed to demonstrate any significant benefit of amiloride over placebo on FVC, FEV(1), and the other secondary endpoints in the studied population. Neither the chronically colonized, nor the noncolonized patients benefited. The confidence intervals of the differences between treatment groups indicated small differences that were most likely of no clinical significance. Complementary analyses taking into account the gender, the type of mutation, the subpopulations whose FVC and FEV(1) were below 80% of normal values at the beginning of the study, and also patients less than 10 years old, did not show any statistically or clinically significant improvements following amiloride therapy.

The aim of this work was to assess the effect of a high-dose (10 million units, MU) short-duration (14 weeks) interferon-α2b (IFN-α2b) regimen in relapsers compared with the standard IFN regimen of 3 MU three times weekly (t.i.w.) for 6 months. Fifty-eight non-cirrhotic patients (who had relapsed after previous treatment with IFN) with chronic hepatitis were randomized: 29 to the high-dose, short-duration regimen and 29 to the standard regimen. By the end of IFN therapy, in the high-dose, short-duration group alanine aminotransferase (ALT) normalization was observed in 23 (79%) of 29 patients, and undetectable hepatitis C virus (HCV) RNA in eight (28%) vs 25 (86%) and 11 (38%) of the 29 patients in the standard group, respectively (P = NS). At the end of the 72-week follow-up, in the high-dose, short-duration group a sustained ALT normalization was observed in two (7%) patients, and undetectable HCV RNA in 0 (0%) vs five (17%) and four (14%) patients in the standard group (P = NS). There was less fibrosis improvement in the high-dose, short-duration group (two of 26 patients, 8%) than in the standard group (eight of 25 patients, 32%) (P = 0.04). Tolerance to IFN was good and similar in the two groups. In conclusion, in IFN relapsers, high-dose, short-duration treatment with IFN-α has no advantage when compared to a 6-month treatment with 3 MU IFN t.i.w.

Objectifs Les histiocytoses langerhansiennes (HL) et non langerhansiennes sont des maladies inflammatoires caracterisees par une infiltration tissulaire d’histiocytes. Les objectifs de l’etude etaient de caracteriser par TEP/TDM au 18 F-FDG sur le plan metabolique des sujets atteints d’histiocytose, ceci au moment du diagnostic puis dans le suivi therapeutique. Materiels et methodes Cent vingt-sept bilans initiaux et 457 de suivi ont ete compares a l’imagerie morphologique (TDM et IRM). La reponse metabolique au traitement (41 patients sous interferon-α, 13 sous vemurafenib et 7 sous infliximab) a ete estimee sur les fixations les plus intenses, par le rapport SUV max (initial–final)/initial. Resultats La sensibilite et la specificite de la TEP/TDM au 18 F-FDG par rapport a l’imagerie morphologique etaient comprises, respectivement, entre 33 a 100 % et entre 60 a 100 %, selon le type d’histiocytose et le site lesionnel analyse. Exprimee en pourcentage d’examens, la TEP/TDM au 18 F-FDG initiale comparativement a l’imagerie morphologique a identifie plus de lesions des os longs (93 % vs 86 %), pleuropulmonaires (43 % vs 33 %) et des sinus paranasaux (50 % vs 45 %). La TEP/TDM au 18 F-FDG de suivi a identifie 17 reponses metaboliques complete ou partielle sous interferon-α (RC + RP = 41 % ; mediane de suivi 24 mois), une reponse complete et 8 reponses partielles sous vemurafenib (RC + RP = 62 % ; mediane de suivi 12 mois), enfin une reponse partielle sous infliximab (mediane de suivi 15 mois). Conclusions Les resultats de cette large etude retrospective suggerent que la TEP/TDM au 18F-FDG permet de mieux caracteriser certaines localisations d’histiocytose et qu’elle se revele tres utile dans l’evaluation de la reponse metabolique de cette maladie aux traitements immunomodulateurs.

Objective: Morphological changes affecting small arteries are recognized surrogates of end-organ damage due to aging and/or hypertension. However, the corresponding structural modifications of the wall of microvessels are poorly known. Here, using adaptive optics (AO) infrared imaging, we analyzed the vascular microstructures in subjects with various degree of hypertensive retinopathy. Methods: The wall-to-lumen ratio (WLR) of the superotemporal artery was measured in 40 normotensive or treatment-naïve hypertensive subjects using a semi-automated procedure. Areas of focal vascular damage were also analyzed. Results: Intra- and interobserver reproducibility was high (ICC over 0.8 for all parameters measured). In treatment-naïve subjects, the WLR of the superotemporal artery (mean ± SD 0.31 ± 0.08) was independently correlated with diastolic blood pressure (p

Objectifs L’hypoxie tumorale est responsable d’une chimio- et radioresistance. La TEP au F-Miso permet d’etudier l’hypoxie tumorale in vivo. Notre objectif a ete d’etudier prospectivement des pts atteints d’un cancer pulmonaire non a petites cellules stade III qui devaient beneficier d’une radio-chimiotherapie (RCT) a visee curative. L’analyse de l’hypoxie par TEP-FMiso a ete realisee par 3 experts via le reseau SFMNnet et les volumes FDG et F-Miso ont ete definis de maniere centralisee. Les patients ayant une TEP-F-Miso positive ont beneficie d’un complement de dose de RT sur les volumes hypoxiques. Nous presentons les resultats preliminaires. Materiels et methodes Les patients ont beneficie d’une TEP-FDG avant et apres la CT d’induction. Les patients qui avaient une TEP-FDG positive apres la CT d’induction ont eu une TEP-F-Miso. Si la TEP-F-Miso etait positive, les patients ont eu une delineation des volumes cibles FDG et F-Miso, transmis ensuite au radiotherapeute local, qui prescrivait un boost a la dose maximale sur les zones hypoxiques. Si la TEP-F-Miso etait negative, les patients avaient une RCT standard de 66 Gy. Les examens ont ete recales, puis differents volumes cibles ont ete definis par seuillage relatif pour le FDG (40, 50, 60, 70, 80, 90 % des SUVmax) et par seuillage absolu pour le Fmiso (SUV a 1,4). Les volumes des traceurs ont ete compares (Dice et Jaccard). La tolerance et le controle local (RECIST1.1) ont ete evalues a 3 et 1 an post-RT. Resultats Soixante-dix-neuf patients (60a) ont ete inclus. Cinquante-quatre patients sur 79 evaluables en pre-RT ont beneficie d’une TEP-F-Miso. Trente-quatre patients sur 54 (62 %) avaient au moins 1 lesion hypoxique et 20/54 etaient non hypoxiques. Vingt-quatre patients sur 34 (70 %) hypoxiques ont pu beneficier d’une augmentation de dose de 70 a 86 Gy. Aucune toxicite grade 4 n’a ete observee et seulement 1 toxicite grade 3. Le SUVmax Fmiso etait de 2,6 pour les patients hypoxiques et de 1,5 pour les patients normoxiques (p Conclusions Les resultats preliminaires de l’etude multicentrique RTEP5 montrent que la realisation d’un complement de dose de RT basee sur la TEP-F-Miso est faisable. Aucune toxicite grade 4 n’a ete observee et le controle local des patients ayant eu une augmentation de dose est de 59 % a 3 mois. Les sous-volumes les plus hypermetaboliques et les volumes hypoxiques sont deux zones tumorales distinctes.

Objectif L’objectif de cette etude est d’evaluer le module de reconstruction Oncoflash® pour diminuer le temps d’acquisition des images planaires de scintigraphies aux recepteurs de la somatostatine (SRS) indiquees avant la realisation d’une TEMP selon les guidelines EANM. Patients et methodes Soixante et onze acquisitions SRS consecutives chez 59 patients ont ete prospectivement effectuees entre janvier en decembre 2013. Les acquisitions ont ete realisees en mode dynamique de deux images de 7 min 30. Celles-ci sont sommees pour creer une image de 15 min non traitee, et une image de 7 min 30 est traitee par le module Oncoflash® (Siemens, Erlangen, Allemagne). Chaque serie d’images a ete interpretee en aveugle et independamment par 3 medecins nucleaires (2 seniors et 1 junior). La qualite d’acquisition (bonne ou mauvaise), l’interpretation globale de l’examen (positif, non conclusif ou negatif) et le grade de la lesion la plus fixante (selon Krenning) ont ete enregistres. Le taux de discordance forte (examen negatif vs positif ; ecart ≥ 2 grades de fixation) pour l’analyse des 2 series d’images ont ete evaluees. La variabilite inter-observateur a ete evaluee par l’indice Kappa de Cohen (k). Resultats une mauvaise qualite d’image a ete evaluee pour, respectivement, 19,7 % (42/213) et 18,3 % (39/213) des images reconstruites selon le protocole conventionnel et avec Oncoflash® (p = 0,711). Les taux de discordance forte pour l’interpretation globale et la lesion la plus fixante etaient, respectivement, de 2,8 % (6/213) et 1,4 % (1/72). La variabilite inter-observateur retrouvait des valeurs de k comprises entre 0,51 et 0,61 pour les images de 15 min et entre 0,56 et 0,62 pour les images de 7 min 30, avec notamment un accord fort entre les lecteurs seniors. Conclusion Nos resultats suggerent la possibilite d’utilisation du module Oncoflash® pour la reconstruction des images planaires de SRS permettant une diminution par un facteur 2 du temps d’acquisition sans alteration significative de la qualite de l’image ou repercussion majeure sur l’interpretation de l’examen avant la realisation de la TEMP.

Interferon-alpha (IFN) monotherapy results in sustained virological clearance in a minority of patients with chronic hepatitis C. The aim of this study was to assess the effect of a reinforced regimen combining ribavirin and high-dose IFN for 48 weeks compared with a nonreinforced regimen combining a standard IFN regimen and ribavirin for 24 weeks in nonresponders with chronic hepatitis C. A total of 231 patients with chronic hepatitis C and previous nonresponse to IFN monotherapy were randomized. The reinforced group (n = 114) received IFN-2b 6 million units (MU) thrice weekly (TIW) and ribavirin for 48 weeks, and the nonreinforced group (n = 117) received IFN-2b 3 MU TIW and ribavirin for 24 weeks. The main outcome measure was a sustained virological response, defined as negative serum hepatitis C virus (HCV)-RNA 24 weeks following the end of treatment. This endpoint was determined in 98 patients of the reinforced group and 105 patients of the nonreinforced group. At the end of follow-up, a sustained virological response was observed in 29 of the 98 patients (29.6%) in the reinforced group vs 16 of the 105 patients (15.2%) in the nonreinforced group (P = 0.014). In multivariate analysis, factors associated with a sustained virological response were treated with a reinforced regimen [odds ratio (OR) 2.9; P = 0.06] and genotype 2 or 3 (OR 8.8; P < 0.0002). A total of 160 patients had paired biopsies before and after treatment. Histological activity improvement was observed in 32 of 80 patients (40%) and fibrosis worsening in 26 of 80 patients (33%) in the reinforced group vs 13 of 80 (16%) and 19 of 80 (24%) in the nonreinforced group (P = 0.30 and 0.20, respectively). Hence in nonresponders, a high-dose 48-week regimen of IFN and ribavirin combination was more effective than a regimen with interferon at lower dose and ribavirin for 24 weeks only.

The risk of hip fracture is higher among persons living in long-term care than among persons living at home. The aim of this study was to explain the difference in risk between the two types of residence by identifying differences in the respective risk factor profiles. Information from the Mediterranean osteoporosis (MEDOS) study questionnaire was used for statistical analyses of 107 non-demented female cases and 225 neighbourhood controls matched for age, sex, and residential area. The statistical analyses incorporated adjustments of the risk estimates by unconditional multivariate logistic regression. Urban background, activity, and morbidity were found to differ between the two types of residence. The detected differences in risk factor profiles were, however, not considered to be sufficient as an explanation for the difference in risk of fracture.

A combination of low-dose aspirin with anticoagulants may provide better protection against thromboembolic events compared to anticoagulants alone in high-risk patients with atrial fibrillation.Evaluation of the preventive efficacy against nonfatal thromboembolic events and vascular deaths of the combination of the oral anticoagulant fluindione and aspirin (100 mg) in patients with high-risk atrial fibrillation.A multicenter, placebo-controlled, double-blind, randomized trial was conducted at 49 investigating centers in France. Atrial fibrillation patients with a previous thromboembolic event or older than 65 years and with either a history of hypertension, a recent episode of heart failure or decreased left ventricular function were included in the study. Patients were treated with fluindione plus placebo (i.e. anticoagulant alone) or fluindione plus aspirin (i.e. combination therapy), with an international normalized ratio target of between 2 and 2.6. The combined primary endpoint was stroke (ischemic or hemorrhagic), myocardial infarction, systemic arterial emboli or vascular death. The secondary endpoint was the incidence of hemorrhagic complications.The 157 participants (average age 74 years; 52% women; 42% with paroxysmal atrial fibrillation) were followed for an average of 0.84 years. Three nonfatal thromboembolic events were observed (1 in the anticoagulation group, 2 in the combination group) and 6 patients died (3 in the anticoagulation group, 3 in the combination group), none of them from a thromboembolic complication. However, 3 deaths were secondary to severe hemorrhagic complications (1 in the anticoagulation group, 2 in the combination group). Nonfatal hemorrhagic complications occurred more often in the combination group (n = 10, 13.1%) compared to the anticoagulation group (n = 1, 1.2%) (p = 0.003).The combination of aspirin with anticoagulant is associated with increased bleeding in elderly atrial fibrillation patients. The effect on thromboembolism and the overall balance of benefit to risk could not be accurately assessed in this study due to the limited number of ischemic events.

A combination of low-dose aspirin (A) and anticoagulation (AC) may provide better protection against thromboembolic events compared with AC alone in high-risk patients with atrial fibrillation (AF).We performed a multicentric placebo-controlled double blind-trial to test the preventive efficacy against thromboembolic events of the addition of aspirin (A) (100 mg) or placebo (P) to anticoagulant treatment in patients with high-risk atrial fibrillation. A total of 157 patients were included, with atrial fibrillation and previous thromboembolic event or older than 65 years with either a history of hypertension, a recent episode of heart failure or a left ventricular dysfunction. All patients received fluindione (F) and P or F and A, with an INR target between 2 and 2.6. The primary endpoint was a combined endpoint of stroke (ischaemic or haemorrhagic), myocardial infarction, systemic arterial emboli or vascular death.The study had to be stopped prematurely owing to a too low recruitment rate. During follow-up (0.84 years) 3 non-fatal thromboembolic events were recorded (1P, 2A) and 6 patients died (3P, 3A), none of them from a thromboembolic complication. However, 3 deaths were secondary to severe haemorrhagic complications (1P, 2A). Non-fatal haemorrhagic complications occurred more often in group A (n = 10, 13.1 pour cent) compared with group P (n = 1, 1.2 pour cent), p = 0.003.The FFAACS study was not able to show any therapeutic benefit from the addition of aspirin to anticoagulant in patients with high-risk AF. Such a combination increased the incidence rate of bleeding complications, which therefore greatly reduces its potential overall benefit.

The effect of amiloride, a sodium channel blocker, has been evaluated in a multicenter randomized double-blind placebo-controlled trial in cystic fibrosis patients more than 5-years-old (n = 137) whose forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV(1)), and forced mid-expiratory flow (FEF(25-75)) were not below 50%, 50%, and 30% of reference values, respectively. Patients were randomly allocated to two parallel groups. Sixty-four patients were chronically colonized with Pseudomonas aeruginosa; they received either amiloride or placebo as a nebulized solution three times daily for 6 months. Routine treatments were continued. Patients chronically colonized with Pseudomonas received nebulized colimycine twice a day for a month during the third and sixth months of treatment. Bronchopulmonary exacerbations were treated in the usual way. The effects of the amiloride treatment were assessed at the end of the 6-month treatment period. The effects on FVC and secondarily on FEV(1), FEF(25-75), the number of days on antibiotic therapy, the Shwachman score, a nutritional index (weight/height(2)), the change in sputum bacterial flora, and nocturnal cough were assessed. For the patients not chronically colonized with Pseudomonas, the effect of the treatment was also evaluated by counting chronic colonizations with pathogens appearing during the trial period. The present study failed to demonstrate any significant benefit of amiloride over placebo on FVC, FEV(1), and the other secondary endpoints in the studied population. Neither the chronically colonized, nor the noncolonized patients benefited. The confidence intervals of the differences between treatment groups indicated small differences that were most likely of no clinical significance. Complementary analyses taking into account the gender, the type of mutation, the subpopulations whose FVC and FEV(1) were below 80% of normal values at the beginning of the study, and also patients less than 10 years old, did not show any statistically or clinically significant improvements following amiloride therapy.

High serum levels of the soluble interleukin 2 receptor (sIL-2R) have been reported in patients with chronic hepatitis C. The aims of this study were to determine the evolution of sIL-2R considered as an indicator of activation of T cells in patients with hepatitis C virus (HCV) treated with IFN-alpha and to correlate sIL-2R serum levels with parameters reflecting ongoing liver disease and with outcome of interferon treatment.In a case-control study, we studied patients enrolled in a multicenter randomized clinical trial which had demonstrated the benefit of a reinforced regimen of interferon alpha. Each of the 26 sustained virological responders (SVR) was paired for treatment regimen with two non-responders (NR).Prior to treatment, higher levels of sIL-2R were found in the sera of 78 patients compared with healthy controls (3791+/-210 pg/ml versus 956+/-88 pg/ml (p0.001)). In the 78 patients after 4 weeks of treatment, the levels of sIL-2R were higher than pretreatment levels (4308+/-206 pg/ml (p0.01)). In the NR, levels of sIL-2R increased significantly after 4 weeks of treatment compared with pretreatment levels (p0.01), and levels of sIL-2R at week 72 were not significantly different from those at pretreatment. Conversely, in the SVR, levels of sIL-2R at week 4 did not significantly increase compared to pretreatment values, and thereafter gradually decreased. At week 72, levels of sIL-2R were significantly lower than before treatment (p0.001). The difference between levels of sIL-2R at week 4 and before initiation of treatment (delta s IL-2R) was smaller in the SVR than in the NR (142+/-219 pg/ml versus 704+/-107 pg/ml (p0.02). The disappearance of HCV RNA from the serum at week 4 showed a sensitivity of 92% (95% confidence interval 86-98) and a specificity of 60% (95% confidence interval 49-71), delta sIL-2R had a sensitivity of 42% (95% confidence interval 31-53) and a specificity of 81% (95% confidence interval 79-90) for the prediction of a sustained virological response 6 months after stopping treatment. The disappearance of HCV RNA from serum at week 4 and delta sIL-2R were independent and early predictive factors for a sustained virological response 6 months after stopping treatment.At week 4, delta sIL-2R may be a more specific parameter than the disappearance of HCV RNA for assessing total, and hence more sustained, elimination of HCV infection 6 months after stopping treatment.

Our aim was to assess and compare the long-term effect of interferon at standard (6 months) and reinforced dose and duration regimens in chronic hepatitis C.A multicentre institutional trial included 244 previously untreated patients with chronic hepatitis C, without cirrhosis, who were randomly allocated to either standard (3 MU thrice a week for 24 weeks; n=120) or reinforced (6 MU daily for 12 days, 6 MU thrice a week for 22 weeks, 3 MU thrice a week for 24 weeks; n=124) regimens. The main endpoint was sustained ALT response at 72 weeks (18 months); secondary end-points were virological (branched DNA and PCR) and histological responses (incidence of cirrhosis) at month 18.Sustained ALT response was observed in five patients (4%, 95% confidence interval 0-8%) in the standard group and in 21 patients (18%, 95% confidence interval 11-25%), from the reinforced group (p=0.002), in agreement with virological response in 21 (81%) patients. Cirrhosis at month 18 was observed in ten (10%) patients in the standard group and one (1%) in the reinforced group (p=0.004).The standard regimen of interferon, in chronic hepatitis C, confers a minimal sustained response rate at 18 months and may not prevent the occurrence of cirrhosis. Reinforced regimens allow sustained response to be reached in a limited number of patients and reduce the risk of cirrhosis during 18 months of follow-up.

The somatostatin analog octreotide has been demonstrated to improve optic tract compression caused by pituitary macroadenomas within hours of its administration and/or reduce tumor size in some patients. We report the results of a prospective multicenter study of the effects of octreotide on visual function and tumor size in patients with nonfunctioning pituitary adenomas or gonadotropin-secreting adenomas.Twenty-four patients with visual defects caused by histologically confirmed macroadenomas were administered octreotide via continuous subcutaneous infusion, as follows: 100 micrograms the 1st day and, if necessary, 200 micrograms the 2nd and then 100 or 200 micrograms three times daily if visual function improved. Vision was assessed after 4 days, 1 month, and 2 months, including tumor size evaluation. Visual improvement was defined by a net gain of at least 2/10 in acuity and/or of more than 20% of the surface of one isopter (a reduction in tumor volume ofor = 20% of the initial measurement); opposite changes were defined as deterioration.Visual improvement was noted in 13 of 24 patients, 10 of 23 patients and 9 of 22 patients, and was not noted in 11 of 24 patients, 14 of 23 patients, and 13 of 22 patients after 4 days, 1 month, and 2 months, respectively. After 2 months, three adenomas had shrunk, three had not changed in size, and one had increased; visual function improved in the seven patients with these adenomas. Octreotide was discontinued in 13 patients for lack of efficacy.The incidence of visual improvement and tumor shrinkage noted in this study was higher than previously reported. Our data suggest that early onset of visual improvement might help in deciding which patients profit from octreotide. However, concomitant gain in visual acuity with deterioration in visual fields or visual improvement with an increase (moderate) in tumor size can occur.

This round table discussion was devoted to describing the present status of clinical trials in the hospital setting, analysing common difficulties in conducting quality clinical research, and proposing realistic solutions to solve or attenuate those difficulties. This analysis was performed on five critical topics: personnel, laboratory tests and investigations, drug supplies, source documents and investigator's procedures.

Therapeutic trials conducted in Alzheimer's disease have benefited from the standardization of diagnostic criteria based on internationally recognized scales (DSM III-R, NINCDS-ADRDA) which ensure more valid inclusions. Well specified exclusion criteria are also of the utmost importance, in particular depression, vascular dementia and concomitant psychotropic drugs. Cognitive and/or functional scales allow an appreciation of the severity of the disease. Due to the heterogeneity of Alzheimer's disease stratification methods on identified prognostic factors i.e. aphasia, extrapyramidal symptoms should be performed. Selection of responders during an enrichment phase has still to be discussed. Multicentric studies become imperative because of the large number of patients required and the difficulties in selecting the adequate patients. These raise the issues of investigators' experience, coordination and between center variability.

The tolerability of four doses of intravenous nicardipine (0.03, 0.08, 0.11, and 0.15 mg/kg/h) was assessed in this randomized multicenter, parallel-group study. Fifty-two patients with Hunt and Hess grade I-III aneurysmal subarachnoid hemorrhage were treated with intravenous nicardipine beginning within 4 days of bleeding, for a mean duration of 12.6 days; this treatment was followed by administration of oral nicardipine 90–120 mg until day 30. Hypotension was the main side effect, and it occurred only in the two groups that received the highest doses. However, it was possible to continue nicardipine in all cases at lower doses or even without modification, and hypotension was never responsible for any deleterious clinical effect.