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BACKGROUND Thyroid nodules with indeterminate cytology represent up to 30% of cases. Molecular testing is now highly recommended to improve management. This study aimed to evaluate the use of the Idylla™ NRAS/BRAF mutation test, a rapid and automated polymerase chain reaction (PCR) assay validated for fixed paraffin-embedded use, on residual thyroid liquid-based fine-needle aspiration (LB-FNA). METHODS Concordance between mutations detected by the Idylla™ assay and the gold-standard qPCR was assessed by splitting in two aliquots 31 BRAF or RAS mutated and 5 non-mutated LB-FNA samples. Samples were obtained either from simulated FNA after thyroidectomy or from FNA obtained during routine care. A third aliquot was used to assess the limit of detection of Idylla™ for five mutated samples. RESULTS The Idylla™ assay showed a sensitivity of 97% and a specificity of 83% as results were concordant for 34 out of 36 samples. One discordant sample concerned a BRAF p.K601E-mutation which is not detected by the Idylla™ cartridge. The other showed a false-positive NRAS p.A146T detection and a weak BRAF p.V600E detection. The limit of detection of the Idylla™ assay was not reached by the dilution assay. CONCLUSION Idylla™ NRAS/BRAF mutation testing can be performed on residual thyroid LB-FNA, using low DNA quantity input, thus not requiring a dedicated sample. The Idylla™ NRAS/BRAF assay offers a quick and easy first step for analyzing the main molecular alterations in indeterminate thyroid nodules, hence improving diagnostic management.

International audience; We present, for the first time, a new CV based technique to extract the Active Dopant Profile under the spacer in thin film FDSOI devices (CV-AJP). The methodology is successfully applied to FDSOI devices fabricated at 500°C for 3D sequential integration. It shows that the ION/ IOFF trade-off relies mainly on the chemical dopant introduction below the offset spacer, as the activation level obtained with thermal activation is found to be high enough. The LT device demonstrated in this work, already outperforms the literature. The active profile extraction also allows to draw guidelines for further device performance improvement: using a scaled SiCO spacer (5,5nm) allows to circumvent the negligible dopant diffusion at 500°C without dynamic performance penalty due to its low-k dielectric value.

The aim of this paper is to present the 3D-sequential integration and its main prospective application sectors. The presentation will also give a synoptic view of all the key enabling process steps required to build high performance Si CMOS integrated by 3D-sequential with thermal budget preserving the integrity of active devices and interconnects and will sketch a status and prospect on current low temperature device performance.

Objective: Somatostatin receptor type 5 (SST5) is inconsistently expressed by corticotroph tumors, with higher expression found in corticotropinomas havin g ubiquitin-specific protease 8 (USP8) mutations. Aims were to study the correlation between characteristics of corticotropinomas and SST5 expression/USP8 mutation status and to describe the response to pasireotide in five patients. Design: Retrospective cohort study. Methods: Clinico-biochemical, radiological and pathological data of 62 patients, operated for a functioning or silent corticotropinoma between 2013 and 2017, were collected. SST5 expression was measured by immunohistochemistry (clone UMB -4, Abcam, IRS > 1 being considered positive), and Sanger sequencing was performed on 50 tumors to screen for USP8 mutations. Results: SST5 expression was positive in 26/62 pituitary tumors. A moderate or strong IRS was found in 15/58 corticotropinomas and in 13/35 functioning corticotropinomas. Among functioning tumors, those expressing SST5 were more frequent in women (22/24 vs 9/15, P = 0.04) and had a lower grade (P = 0.04) compared to others. USP8 mutations were identified in 13/50 pituitary tumors and were more frequent in functioning compared to silent tumors (11/30 vs 2/20, P = 0.05). SST5 expression was more frequent in USP8mut vs USP8wt tumors (10/11 vs 7/19, P = 0.007). Among treated patients, normal urinary free cortisol levels were obtained in three patients (IRS 0, 2 and 6), while a four-fold decrease was observed in one patient (IRS 4). Conclusion: SST5 expression appears to be associated with functioning, USP8mut and lower grade corticotropinomas. A correlation between SST5 expression or USP8mut and response to pasireotide remains to be confirmed.

INTRODUCTION The cytological diagnosis of follicular-patterned thyroid lesions is challenging, especially since the World Health Organisation classification has recognised non-invasive follicular thyroid neoplasm with papillary-like features. These entities are often classified as indeterminate on cytology. Molecular testing has been proposed to help classify indeterminate nodules. RAS and K601E BRAF mutations are mostly encountered in follicular-patterned lesions, but their diagnostic value is not well established. Nuclear scores have also been proposed to help classify indeterminate lesions. OBJECTIVE To investigate the correlation between cytological features and histology and to assess nuclear scores in a series of indeterminate RAS or BRAF K601E positive thyroid nodules. METHODS The cytological parameters of 69 indeterminate RAS or BRAF K601E-positive thyroid nodules were evaluated. The Strickland and Maletta scores and a new nuclear score were assessed. Diagnosis of malignant, benign or indolent neoplasms was confirmed in each case by histology. Malignant and indolent nodules were considered surgical nodules, and adenomas non-surgical nodule. RESULTS Surgical nodules were associated with the presence of ground glass nuclei (P = .001), grooves (P

Context. Somatostatin receptor type 5 (SST5), a target of pasireotide, is inconsistently expressed by corticotroph tumors. Somatic driver mutations in the ubiquitin-specific protease 8 (USP8) gene have been describes in 35% to 60% of corticotropinomas. SST5 expression has been found to be higher in USP8mut corticotropinomas. Objective. To study the correlation between clinical and biochemical characteristics of a large cohort of functioning and silent corticotroph tumor and SST5 expression or USP8 mutation status. To describe SST5 expression and the response to pasireotide in 5 patients. Design. Retrospective cohort study. Setting. University hospitals of Lyon. Patients. 62 patients operated for a corticotroph tumors between 2013 and 2017. Intervention. None. Main Outcome Measure. Clinical, biological, radiological and pathological data were evaluated depending on SST5 expression measured by immunohistochemistry (rabbit monoclonal antibody, clone UMB-4, Abcam). Membrane immune-positivity with an IRS>1 was considered positive. USP8 analysis was performed by Sanger sequencing in 50 tumors. Results. SST5 expression was positive in 26 (41.9%) pituitary tumors. A moderate or strong IRS was found in 24.2% of the cohort and in 32.5% of the functioning pituitary tumors. Compared to SST5-negative pituitary tumors, those expressing SST5 were more frequent in women (92.3% vs 55.6%; p=0.002), fewer were silent (7.7% vs 58.3%; p USP8 mutations were identified in 26% of the cohort and more frequent in functioning (n=11/30, 36.7%) compared to silent corticotroph tumors (n=2/20, 10%; p=0.05). SST5 expression was more frequent in USP8mut vs USP8neg tumors (58.8% vs 7.7%; p Among treated patients, normal urinary free cortisol (UFC) levels were obtained in 3 patients (IRS 0, 2, and 6) and a 4-fold decrease of UFC in one patient (IRS 4). Conclusion. SST5 expression seems to be associated with functioning, well-differentiated pituitary tumors and USP8 mutation. However, a correlation between SST5 expression or USP8mut and response to pasireotide treatment remains to be confirmed.

In this contribution, we report on the growth of Ge inside extremely thin 16-nm thick cavities through selective lateral growth of Ge on 300 mm silicon-on-insulator (0 0 1) substrates. We showed that the density of defects depends on the cavity shape, with extended defects such as micro-twins and stacking faults observed on the top surface along the 〈1 1 0〉 directions when the Si/Ge growth interface is along the 〈1 1 0〉 directions. The optimization of the cavity shape, by tuning the etching conditions, leads to a significant reduction of the defects in the Ge nanostructures, and this approach paves the road towards the co-integration of Si and Ge based devices.

International audience; Objective: The treatment of hypothalamus-invading craniopharyngiomas, based on pediatric experience, is subtotal resection (STR) with radiotherapy. This strategy sometimes leads to uncontrollable tumor progression. In adults, with the use of endoscopic endonasal surgery (EES), does removing the hypothalamic part of the tumor-whenever possible-compromise the outcome of the patients?Methods: We included adults with craniopharyngioma treated by a first EES in 2008-2016 by senior neurosurgeon (E.J.). Endocrine, ophthalmologic, and hypothalamic data were retrospectively collected, including body mass index (BMI), cognitive and social status, with a systematic follow-up interview. Magnetic resonance imaging scans were graded according to Puget classification: 0, no hypothalamic involvement; 1, hypothalamic displacement; and 2, hypothalamic involvement. Grade 2 tumors were separated into gross total resection (GTR) or STR.Results: We included 22 patients aged 18-79 years. Presenting symptoms were visual (14, 64%), endocrine dysfunction (10, 45%), BMI >30 (8, 36%), and cognitive/psychiatric impairment (9, 41%). Fourteen (64%) were grade 2 craniopharyngiomas. GTR was performed in 14 (64%) patients. Postoperatively, 12/14 (86%) cases improved visually, and 20 (91%) needed hormone replacement therapy. There was no difference in BMI evolution in the GTR versus STR group, cognitive status was stable or improved in all patients except 1; 4/8 patients with STR experienced progression needing adjuvant treatment versus no patient with GTR.Conclusions: EES GTR of grade 2 craniopharyngiomas does not cause major hypothalamic worsening, in contrast with children operated by cranial approaches. The surgeon's experience is key in deciding when to stop the dissection. Offering GTR whenever possible aims at avoiding tumor progression and radiotherapy.

For the first time, a comprehensive study going from the integration of 3D stacked nanosheets Gate-All-Around (GAA) MOSFET devices to SPICE modeling is proposed. Devices have been successfully fabricated on SOI substrates using a replacement high- $\kappa$ metal gate process and self-aligned-contacts. Back-biasing is herein efficiently used to highlight a drastic improvement of electrostatics in the upper GAA Si channels. Advanced electrical characterization of these devices enabled us to calibrate a new version of physical compact model (LETI-NSP) in order to assess the performance of ring oscillators for different configurations of GAA FETs integrating up to 8 vertically stacked Si channels.

In this contribution, we report on the growth of horizontal Ge nanowires inside extremely thin tunnels surrounded by oxide. This is achieved through selective lateral growth of Ge on silicon-on-insulator (001) substrates. The 16 nm high tunnels are formed by HCl vapor etching of Si followed by Ge growth in the same epitaxy chamber. First, the benefit of growing the Ge nanowires at high temperature was highlighted to homogenize the length of the nanowires and achieve a high growth rate. Afterwards, we showed that increasing the tunnel depth led to a significant reduction in the growth rate. Finally, transmission electron microscopy showed that no defects were present in the Ge nanowires. These results are encouraging for the planar co-integration of heterogeneous materials on Si.In this contribution, we report on the growth of horizontal Ge nanowires inside extremely thin tunnels surrounded by oxide. This is achieved through selective lateral growth of Ge on silicon-on-insulator (001) substrates. The 16 nm high tunnels are formed by HCl vapor etching of Si followed by Ge growth in the same epitaxy chamber. First, the benefit of growing the Ge nanowires at high temperature was highlighted to homogenize the length of the nanowires and achieve a high growth rate. Afterwards, we showed that increasing the tunnel depth led to a significant reduction in the growth rate. Finally, transmission electron microscopy showed that no defects were present in the Ge nanowires. These results are encouraging for the planar co-integration of heterogeneous materials on Si.

Context. Within the framework of the second-generation instrumentation of the Very Large Telescope Interferometer of the European Southern Observatory we have developed the four-telescope beam combiner in integrated optics. Aims. We optimized the performance of such beam combiners, for the first time in the near-infrared K band, for the GRAVITY instrument dedicated to the study of the close environment of the galactic centre black hole by precision narrow-angle astrometry and interferometric imaging. Methods. We optimized the design of the integrated optics chip and the manufacturing technology as well, to fulfil the very demanding throughput specification. We also designed an integrated optics assembly able to operate at 200 K in the GRAVITY cryostat to reduce thermal emission. Results. We manufactured about 50 beam combiners by silica-on-silicon etching technology. We glued the best combiners to single-mode fluoride fibre arrays that inject the VLTI light into the integrated optics beam combiners. The final integrated optics assemblies have been fully characterized in the laboratory and through on-site calibrations: their global throughput over the K band is higher than 55% and the instrumental contrast reaches more than 95% in polarized light, which is well within the GRAVITY specifications. Conclusions. While integrated optics technology is known to be mature enough to provide efficient and reliable beam combiners for astronomical interferometry in the H band, we managed to successfully extend it to the longest wavelengths of the K band and to manufacture the most complex integrated optics beam combiner in this specific spectral band.

International audience; This paper presents recent progress on Gate-All-Around (GAA) stacked-NanoWire (NW) / NanoSheet (NS) MOSFETs. Key technological challenges will be discussed and recent research results presented. Width-dependent carrier mobility in Si NW/NS and FinFET will be analyzed, and intrinsic performance and design considerations of GAA structures will be discussed and compared to FinFET devices with a focus on electrostatics, parasitic capacitances and different layout options. The results show that more flexibility can be achieved with stacked-NS transistors in order to manage power-performance optimization.

session 32: Process and Manufacturing Technology (32.2); International audience; For the first time, a low temperature (LT) FinFET process is demonstrated, using Solid Phase Epitaxy Regrowth (SPER), gate last integration and Self Aligned Contact (SAC). The LT devices exhibit performances close to those of the High Temperature Process Of Reference (HT POR). Several techniques of SPER doping are investigated and an innovative Double SPER (DSPER) process using two amorphization/recrystallization steps, is demonstrated. This DSPER process has the advantage of doping the bulk of the S/D junctions. This work opens the door to the fabrication of high-performance LT FinFETs for 3D sequential integration.

International audience; We present recent progress on vertically stacked-wires MOSFETs with a replacement metal gate process for CMOS scaling beyond FinFET technology. Key technological challenges (such as 3D integration process including inner spacer, mobility, and strain engineering) will be discussed in relation to recent research results.

Stacking N over CMOS devices using 3D Sequential CoolCube™ Integration has been shown promising for the scaling of 6T SRAMs. By transposing one pass-gate and one pull-down NMOS to the top layer, a cell footprint reduction of 27% could be obtained, leading to a 3D vias density over 108/mm2 achievable. In addition, we presented N-type devices fabricated below 630°C yielding quasi-equivalent performances as high temperature ones while fulfilling the PBTI and hot-carrier effects reliability requirements, comforting the viability of N over CMOS approach.

International audience; We report on vertically stacked horizontal Si NanoWires (NW) p-MOSFETs fabricated with a replacement metal gate (RMG) process. For the first time, stacked-NWs transistors are integrated with inner spacers and SiGe source-drain (S/D) stressors. Recessed and epitaxially re-grown SiGe(B) S/D junctions are shown to be efficient to inject strain into Si p-channels. The Precession Electron Diffraction (PED) technique, with a nm-scale precision, is used to quantify the deformation and provide useful information about strain fields at different stages of the fabrication process. Finally, a significant compressive strain and excellent short-channel characteristics are demonstrated in stacked-NWs p-FETs.

In this paper, the recent advances in low temperature process in view of 3D VLSI integration are reviewed. Thanks to the optimization of each low temperature process modules (dopant activation, gate stack, epitaxy, spacer deposition) and silicide stability improvement, the top layer thermal budget fabrication has been decreased in order to satisfy the requirements for 3D VLSI integration.

In this paper, the energy process window of nanosecond (ns) laser annealing for junctions activation has been determined for several dopants (As, P, BF2). The different recrystallization states observed when tuning laser energy density are explained by numerical simulations. Within these conditions, the laser impact on the thermal stability of ULK/copper inter-tiers interconnections has been evaluated for a 28nm node backend metal 1 design rules technology both from morphological and electrical perspectives. This study highlights the interest of ns laser anneal for CoolCube™ 3D integration.

International audience; 3D sequential integration requires top FETs processed with a low thermal budget (500-600°C). In this work, high performance low temperature FDSOI devices are obtained thanks to the adapted extension first architecture and the introduction of mobility boosters (pMOS: SiGe 27% channel / SiGe:B 35% RSD and nMOS: SiC:P RSD). This first demonstration of n and p extension first FDSOI devices shows that low temperature activated device can match the performance of a device with state-of-the-art high temperature process (above 1000°C).

Les adenomes corticotropes expriment de maniere variable le recepteur de la somatostatine de type 5 (STTR5) qui est une cible du PASIREOTIDE, traitement medical de la maladie de Cushing. Objectifs Identifier les elements cliniques, biologiques ou radiologiques predictifs de l’expression de SSTR5. Patients et methodes Etude retrospective comportant 51 patients operes d’un adenome corticotrope aux hospices civils de Lyon entre 2013 et 2017. STTR5 a ete recherche par immunohistochimie (anticorps monoclonal de lapin Clone UMB4, fournisseur : Abcam, reference : ab109495). L’expression membranaire par plus de 1 % des cellules a ete consideree positive. Resultats Le sex-ratio etait de 2,4 (F/M = 36/15), l’âge moyen a la chirurgie de 43 ans, 30 (58,8 %) patients presentaient un macroadenome et 19 (37,2 %) un adenome corticotrope silencieux. STTR5 etait exprime par 23 (45 %) adenomes. Comparativement aux adenomes SSTR5 « negatifs », ceux exprimant STTR5 etait statistiquement associe a une maladie de cushing clinique (21/23 vs 11/28 ; p Conclusion L’expression de SSTR5 semble associee a des tumeurs bien differenciees et de bon pronostic.

Responses of GH-secreting adenomas to multimodal management of acromegaly vary widely between patients. Understanding the behavioral patterns of GH-secreting adenomas by identifying factors predictive of their evolution is a research priority. The aim of this study was to clarify the relationship between the T2-weighted adenoma signal on diagnostic magnetic resonance imaging (MRI) in acromegaly and clinical and biological features at diagnosis. An international, multicenter, retrospective analysis was performed using a large population of 297 acromegalic patients recently diagnosed with available diagnostic MRI evaluations. The study was conducted at ten endocrine tertiary referral centers. Clinical and biochemical characteristics, and MRI signal findings were evaluated. T2-hypointense adenomas represented 52.9% of the series, were smaller than their T2-hyperintense and isointense counterparts (PP=0.0001), invaded the cavernous sinus less frequently (P=0.0002), and rarely caused optic chiasm compression (PP=0.067) and presented higher IGF1 values (P=0.01). Although in total, adenomas had a predominantly inferior extension in 45.8% of cases, in men this was more frequent (PP=0.0067). Most adenomas (45.1%) measured between 11 and 20 mm in maximal diameter and bigger adenomas were diagnosed at younger ages (P=0.0001). The T2-weighted signal differentiates GH-secreting adenomas into subgroups with particular behaviors. This raises the question of whether the T2-weighted signal could represent a factor in the classification of acromegalic patients in future studies.

Summary Background Recurrence after treatment of stage I–II melanoma involves regional lymph nodes in about 50% of patients. A reliable method is needed to evaluate lymph node status (metastatic or not) in the case of palpable lymph nodes. Objectives To evaluate the efficiency of fine-needle aspiration biopsy (FNAB) in examining clinically detected suspicious lymph node in patients followed up after surgical removal of stage I–II melanoma. Patients and methods One hundred and twenty FNABs were performed in 67 patients with a suspicious node in an open study conducted in a French melanoma regional

La chirurgie transphenoidale reste a ce jour le seul traitement curateur dans l’acromegalie avec normalisation rapide de l’IGF-1. La selection de patients pouvant beneficier d’une chirurgie curatrice reste toutefois difficile. Objectifs (1) Evaluer les facteurs pronostiques de l’issue de la chirurgie dans l’acromegalie afin de mieux cibler les patients candidats a une chirurgie premiere. (2) Comparer les profils histologiques tumoraux des patients gueris vs. non gueris. Patients et methodes Etude retrospective monocentrique, de 63 patients acromegales operes de 2009 a 2015, par le meme chirurgien. Analyse des caracteristiques cliniques, biologiques pre- et postoperatoire a 3 mois, IRM preoperatoires (taille, invasion, signal T2) et histologiques (classification pronostique, granulation). Resultats Trois mois apres la chirurgie, le taux de remission defini par la normalisation de l’IGF-1 et/ou de GH/HGPO p p p Discussion La taille et le caractere invasif de la tumeur semblent etre les meilleurs facteurs pronostiques de l’issue chirurgicale.

Aim of the study: Primary hyperparathyroidism usually affects elderly patients. Juvenile primary hyperparathyroidism is rare, and raises diagnostic and pronostic problems. The aim of this retrospective study on 24 patients is to establish clinical, histological, and therapeutic features of juvenile primary hyperparathyroidism. Patients and methods: From 1986 to 2001, 673 patients were treated for primary hyperparathyroidism in our department. Twenty four patients were younger than 30 years old (3,5%). There were 14 women and 10 men. Mean age was 23 year (14–30). Clinical manifestations, pathologics findings and postoperative results were studied. Results: Sixteen patients presented a sporadic form of primary hyperparathyroidism with a single adenoma. Clinical manifestations were renal symptoms in 11 cases and acute hypercalcemia syndrome in 2 cases. Seven patients had a NEM I syndrome: parathyroid lesions were 6 hyperplasia and one adenoma. A 27 years old woman presented a recurrent familial isolated hyperparathyroidism. She was operated on 10 years before and at reoperation parathyroid carcinoma was found. Nineteen patients were cured after a post operative follow up ranging from 3 to 168 months. One patient had an asymptomatic hypercalcemia recurrence. Two patients presented permanent hypoparathyroidism treated whith calcitriol and calcium. Conclusion: Sporadic forms represent majority of cases of juvenile hyperparathyroidism. Renal manifestations are usual. Nevertheless, multiple endocrine neoplasia type 1 has to be evocated.

Introduction L’invasion du sinus caverneux (CS) par une tumeur hypophysaire est le facteur pronostique principal limitant les chances de resection chirurgicale complete. L’identification preoperatoire de cette invasion permettrait d’adapter la strategie therapeutique a chaque patient. Objectif Les objectifs de notre etude etaient d’evaluer la valeur pronostique de la classification radiologique revisitee de KNOSP et la correler aux resultats postoperatoires. Methodes Evaluation retrospective de notre serie chirurgicale de macroadenomes hypophysaires operes entre septembre 2012 et janvier 2016 par voie endoscopique trans-sphenoidale. Les images IRM preoperatoires ont ete retrospectivement interpretees selon la nouvelle classification KNOSP en 5 grades (1, 2, 3A, 3B, 4). La constatation peroperatoire de l’invasion des SC a ete retrouvee sur les comptes rendus operatoires. La remission postoperatoire precoce (RPOP) etait evaluee a 3 mois postoperatoire radiologiquement (absence de residu) et biologiquement (absence d’hypersecretion) pour les tumeurs secretantes. Resultats Cent quatre-vingt-onze tumeurs ont ete inclues (127 gonadotropes et non fonctionnelles et 64 secretantes), 17,2 % presentaient une invasion du SC. La frequence de l’invasion peroperatoire des SC ainsi que la RPOP etait correlees aux grades de la nouvelle classification KNOSP. Les taux d’invasion etait respectivement de 1,3 % ; 8,3 % ; 22,1 % ; 55,3 % ; 88,9 % et 100 % et les taux de RPOP de 78,1 % ; 78,7 %, 72,2 % 47,4 % ; 14,3 % et 10 % pour les grades 0 ; 1 ; 2 ; 3A ; 3B et 4 respectivement. Conclusion Cette etude valide la valeur pronostique de cette nouvelle classification radiologique dans la prediction des taux RPOP des tumeurs hypophysaire.

Gravity is one of the second-generation instruments of the Very Large Telescope Interferometer that operates in the near infrared range and that is designed for precision narrow-angle astrometry and interferometric imaging. With its infrared wavefront sensors, pupil stabilization, fringe tracker, and metrology, the instrument is tailored to provide a high sensitivity, imaging with 4-millisecond resolution, and astrometry with a 10µarcsec precision. It will probe physics close to the event horizon of the Galactic Centre black hole, and allow to study mass accretion and jets in young stellar objects and active galactic nuclei, planet formation in circumstellar discs, or detect and measure the masses of black holes in massive star clusters throughout the Milky Way. As the instrument required an outstanding level of precision and stability, integrated optics has been chosen to collect and combine the four VLTI beams in the K band. A dedicated integrated optics chip glued to a fiber array has been developed. Technology breakthroughs have been mandatory to fulfill all the specifications. This paper is focused on the interferometric beam combination system of Gravity. Once the combiner concept described, the paper details the developments that have been led, the integration and the performance of the assemblies.

Aims/hypothesis. Non-alcoholic steatohepatitis is frequent in Type II (non-insulin-dependent) diabetes mellitus and can lead to fibrosis and cirrhosis. The interindividual variability in the occurrence of non-alcoholic steatohepatitis suggests, however, a genetic modulation. Microsomal triglyceride transfer protein (MTP) is necessary for the assembly and secretion of VLDL and when the protein is not functional, such as in abetalipoproteinaemia, a steatohepatitis occurs. We therefore assessed the association between a functional polymorphism in the promoter region of MTP gene (–493 G/T) and the biological features of steatohepatitis in Type II diabetic patients. Methods. We studied 271 patients with Type II diabetes. Determination of –493 G/T polymorphism was made by PCR-RFLP. Increased liver enzymes were used as surrogates of liver steatosis and alanine aminotransferase concentration was the outcome variable for the multivariate analysis. Liver ultrasonography was available for a subgroup of patients with newly diagnosed diabetes. Results. The proportion of patients with increased alanine aminotransferase was higher in GG than in GT and TT subgroups (23 %, 11 % and 6 %, respectively, p = 0.01). Additionally, patients with high alanine aminotransferase concentrations were more likely to be young (p = 0.01), male (p = 0.001), obese (p = 0.04) and have low HDL-cholesterol (p = 0.01). In multivariate analysis, the MTP genotype was independently associated with alanine aminotransferase concentration (p = 0.0023) as well as sex and body mass index but not HDL-cholesterol. Conclusion/interpretation. The –493 G/T MTP gene polymorphism is associated with biological surrogates of steatohepatitis in patients with Type II diabetes. The G allele which is responsible for a decrease in MTP gene transcription is prone to increase the intrahepatic triglycerides content, conferring by this a genetic susceptibility for steatohepatitis. [Diabetologia (2000) 43: 995–999]

Resume But de l’etude : Le but de cette etude prospective etait d’evaluer les benefices et les contraintes de la cervicotomie, de l’abord electif et de la videochirurgie dans le traitement de l’hyperparathyroidie primaire (HPT 1). Patients et methodes : Au cours de l’annee 1998, 66 patients ont ete operes pour HPT 1 dans le meme centre. Il s’agissait de 48 femmes et 18 hommes (âge moyen : 58 ans, extremes : 21–84). Aucun n’avait de forme familiale ou de neoplasie endocrinienne multiple. L’intervention a ete realisee par cervicotomie ( n : 32), par abord electif lateralise ( n = 8), par videochirurgie ( n = 25). Un adenome mediastinal a ete enleve par cervicotomie et un autre par thoracoscopie gauche. Le dosage rapide de la parathormone (PTH) etait effectue 20 minutes apres exerese de l’adenome. La calcemie etait dosee a la 24 e et 48 e heure et deux mois apres l’intervention. Resultats : L’examen anatomopathologique a trouve un adenome double et 65 adenomes uniques. L’exerese a ete suivie dans tous les cas d’une chute significative de la PTH. Dans le groupe traite par chirurgie video-assistee, il y a eu 11 conversions en cervicotomie (44 %) et une paralysie recurrentielle. A la fin de l’etude, tous les patients sauf un etaient normocalcemiques. Conclusion : Ce travail confirme la faisabilite de la chirurgie video-assistee dans l’hyperparathyroidie. Elle necessite un reperage preoperatoire de l’adenome et un dosage rapide peroperatoire de la PTH. Elle permet de reduire la taille de la cicatrice et evite la sternotomie pour l’exerese des adenomes mediastinaux. L’abord electif a un interet comparable a celui de la videochirurgie et une plus grande simplicite. La cervicotomie conserve une place de choix en cas de cervicotomie anterieurement, de thyroidectomie associee, de non reperage de l’adenome par l’imagerie et chez les sujets âges moins concernes par des preoccupations esthetiques.

Introduction Les inhibiteurs de tyrosine kinase (ITK) sont maintenant indiques en premiere intention dans les formes agressives et symptomatiques de cancer medullaire de la thyroide (CMT) avance. Cependant, le recours a la chimiotherapie peut se justifier chez les patients non repondeurs ou presentant des contre-indications aux ITK. Objectifs Rapporter l’effet d’une chimiotherapie par 5-Fluorouracile (5-FU) et dacarbazine chez 4 patients traites entre 2011 et 2014 pour un CMT avance et rapidement progressif. Methodes La reponse tumorale a ete evaluee selon les criteres RECIST 1.0. La methylation du promoteur de MGMT a ete analysee par pyrosequencage. Resultats Deux patients ont presente une reponse objective prolongee (reduction tumorale de 50 % et 55 % respectivement, maintenue pendant 12 mois pour les deux patients), accompagnee d’une amelioration spectaculaire de l’etat general et d’une diminution de 79 % et 86 % de la calcitonine serique. Une reponse partielle a ete obtenue chez un 3e patient et le 4e a ete non repondeur. Pour l’ensemble des 4 patients, la survie sans progression mediane a ete de 8,5 mois (3–12) et la survie globale mediane de 13,5 mois (5–27). Une diminution de la calcitonine a 3 mois etait associee a la presence d’une reponse tumorale. Le statut MGMT n’etait pas un facteur predictif de reponse. Aucun effet secondaire majeur n’a ete observe. Conclusion Le taux de reponse etait eleve dans cette petite serie (75 %). L’association 5-FU-Dacarbazine peut constituer une alternative aux ITK. Les facteurs predictifs de reponse au traitement restent a identifier.

Resume Nous presentons le cas d’une patiente de 75 ans avec une tumeur vasculaire splenique nodulaire decouverte fortuitement. L’exploration TDM, echographique conventionnelle et avec produit de contraste rejeterent l’angiome splenique typique. La patiente est finalement splenectomisee. L’examen anatomopathologique montre un hemangiome capillaire thrombose. L’arsenal radiologique ne permet pas toujours d’affirmer le diagnostic d’hemangiome splenique, du fait de la localisation splenique, des remaniements tumoraux, et lorsque la taille est importante. L’imagerie ne peut alors exclure une lesion maligne.

Introduction L’evaluation preoperatoire du risque de malignite des nodules thyroidiens repose sur l’echographie et la cytoponction, au terme desquels 30 % sont classes indetermines. Objectif Construire un test moleculaire dont les performances seront evaluees en association avec le resultat cytologique et adaptees au contexte clinique dans le but d’affiner le diagnostic preoperatoire des nodules thyroidiens. Materiel et Methodes Dans cette etude prospective, le materiel de cytoponction des nodules possedant un diagnostic histologique etait analyse par une puce transcriptomique de 20 genes construits lors d’un travail anterieur. L’ajustement d’un modele de regression logistique a permis de selectionner les 7 genes les plus pertinents pour construire un predicateur combine, integrant egalement le resultat Bethesda. Ses performances ont ete optimisees pour differentes prevalences de malignite ainsi qu’en ponderant les consequences d’eventuelles erreurs diagnostiques (ratios benefice-risque). Ce modele a ete compare a la classification Bethesda seule en evaluant l’aire sous la courbe ROC (ASC). Resultats Sept cent vingt-deux cytoponctions ont ete incluses, 128 ont beneficie du test moleculaire dont 46 nodules malins. Le predicateur combine presentait dans notre cohorte (prevalence de 36 %) une sensibilite de 76 % et une specificite de 95 %. L’ASC du test combine etait significativement superieure a celle de la classification Bethesda seule (p = 0,004). Pour une prevalence de 7 %, nous obtenions une specificite maximale de 100 % et sensibilite plus basse de 47,8 %. Conclusion Ce test moleculaire, evalue en association avec la cytologie et optimise selon le contexte clinique, presente une excellente specificite et pourrait contribuer a une amelioration de l’evaluation preoperatoire des nodules thyroidiens.

An integrated optical circuit (IOC) combining all the detection functions of a standard magneto-optical reading head (MO reading, focus and tracking control) is presented. The reading function is achieved by mean of a patented interferometric circuit. For tracking control, the well-known push-pull method has been applied and adapted to integrated optics. For focus control, an original method based on multimode interference, using the benefits of integrated optics has been successfully tested. The implemented technology is based on a silicon substrate with a silicon nitride core between two silica cladding layers (Si-SiO/sub 2/-Si/sub 3/N/sub 4/-SiO/sub 2/). This technology is a low cost technology that is well adapted for mass production. The optical components of the circuits are made by standard "hard contact" photolithography and reactive ion etching. Several wafers with about 50 devices have been processed and characterised. In particular, the detection signals have been compared with the detection signals delivered simultaneously by a standard commercial MO drive. This experiment demonstrates the feasibility of an integrated detection device for a MO drive.

Gravity aims at enhancing infrared imaging at VLTI to significantly improve our understanding of the physical processes related to gravitation and accretion within compact objects. With its fiber-fed integrated optics, infrared wavefront sensors, fringe tracker, beam stabilization and a novel metrology concept, GRAVITY will push the sensitivity and accuracy of astrometry and interferometric imaging far beyond what is offered today. Four telescopes will be combined in dual feed in the K band providing precision astrometry of order 10 micro-arcseconds, and imaging with 4- milliarcsecond resolution. The fringe tracker and the scientific instrument host an identical integrated optics beam combiner made by silica-on-silicon etching technology that is put inside a cryogenic vessel and cooled down to 200K to reduce thermal background and increase sensitivity. This paper gives the design of the integrated beam combiner and of its fibered array that allows feeding the combiner with stellar light. Lab measurement of spectral throughput and interferometric performance for beam combiners made by Flame Hydrolysis Deposition and by Plasma-Enhanced Chemical Vapor Deposition (PECVD) are given. The procedure to glue together the beam combiner and its fibered array is described as well as the tests to validate the performance and the ageing effects at low temperature. Finally the thermal analysis and the eigen-frequency study of the whole device are presented.

Through Silicon Vias (TSV) is a very promising technology in advanced packaging, for the replacement of wire bonding. This technology is becoming mandatory for fully integrated products such as SiP, SoP, 3D components integration (e.g memory stacking), or MEMS structure packaging. Different alternatives are currently investigated such as via-first or via-last. Into the via-first family two different approaches can be considered. The TSV's can be done before the FEOL (pre-process approach) or in-between the FEOL and the BEOL (mid process approach). Each solution has advantages and drawbacks depending on the final application in particular. In a first part of this paper the tungsten mid-process TSV technology will be presented and briefly compared to the copper mid-process approaches. Then, the process of the tungsten TSV fabrication will be detailed and morphological characterizations will be presented. We will focus on two specific parts of the process which have been specifically optimized for the tungsten TSV technology: the low temperature insulation oxide and the tungsten deposition-etch back sequence to fill the vias. The results of those optimizations will be presented and discussed. Last, we will introduce the electrical test vehicle used in this work and present the main results regarding via resistances. Some specific recommendations will by proposed in term of design and integration rules in relation with the process constraints.

Through Silicon Via (TSV) is a very attractive solution for 3D stacking. One of the main concerns regarding the TSV technologies is the resulting stress build up inside the silicon substrate that induces warpage or expansion at the wafer level, crystalline defects in the neighboring silicon of the TSV and finally can impact performances and reliability of CMOS device as well. In this work, we show results on how the stress is built up in the substrate during the fabrication of via-first polysilicon TSVs and the influence of some of the specific process steps. Then, simulated data will be presented and compared to experimental findings. Then, stress release during back side processing is demonstrated by wafer expansion and cracks of the thinned wafer depending on the glue material used. We also present characterizations of silicon defects by chemical revelation around the TSV structures after back side processing. The impact of thin wafer expansion on TSV electrical performances will be then presented. Finally we show that with the optimization of some key process steps, stress induced in polysilicon via-first technology may be acceptable for IC integration.

Through Silicon Via (TSV) is a one of the more important bricks for 3D stacking and offer different integration approaches. The via-last approach has been first introduced into production. Yet the via-first approach is also currently actively investigated since it has some advantages particularly the use of high conformal deposition materials for isolation and filling of the TSVs enabling higher density of connections or high voltage operations required for certain final product applications. We will show results on process development and integration of 70µm deep annular TSVs using tungsten as filling material on a dedicated test chip vehicle. First the complete process flow will be presented. Then, process development work and issues will be addressed. At first we will present developments on the annular trenches opening aiming at favorable slopes and minimum roughness. Deep RIE TSV etching process will be illustrated. For the isolation of the TSV a comparison between SACVD and DHDP deposition oxide will be then discussed. A special focus will be done on W filling sequence using multiple deposition and etch-back steps with different deposition process recipes and a final Chemical Mechanical Polishing (CMP) planarization of the TSVs. The backside process is also presented with the optimization of the back-lapping and CMP process to obtain a stress free silicon surface with no degradation of the TSVs as well as a minimum topology enabling a good back side contact. Backside interconnection is also presented featuring RDL (redistribution Layer) and die-to-wafer attach with bumps technology. Then electrical characterizations will be presented. A specific test vehicle was designed to study the TSV density and proximity impact with different number of rings and ring width TSV designs. Daisy chains, specific structures to measure TSV resistance similar to Kelvin structures, interdigitated chains to measure via leakage, and special structures to stress at very high voltage (up to 1000V), were designed. The electrical results from those specific structures will be discussed.

In this paper a low temperature 'via-last' technology will be presented. This technology has been especially developed for CMOS image sensors wafer level packaging. In the first part of this paper, the design of the TSV will be presented and a first approach of a design rule definition for TSV will be introduced. The alignment strategy will be also presented, and specific patterns to succeed front side to back side alignment will be described. In a second part the steps of the Through Silicon Vias (TSV) technology will be briefly presented: glass wafer carrier bonding onto the silicon substrate, silicon thinning and backside technology including specific steps like double side lithography, silicon deep etching, silicon side wall insulation, vias metallization and final bumping. Then, morphological characterizations of the via-last technology will be presented and discussed. Finally, electrical characterization including vias continuity, single via electrical resistance, insulation layer leakage current and breakdown voltage have been measured and will be discussed. A picture obtained with the TSV CMOS Image Sensor (TSV CIS) will be also shown.

In this paper a low temperature dasiavia-lastrdquo technology will be presented. This technology has been especially developed for CMOS image sensors wafer level packaging. In the first part of this paper, the steps of the through silicon vias (TSV) technology will be presented: glass wafer carrier bonding onto the silicon substrate, silicon thinning and backside technology including specific steps like double side lithography, silicon deep etching, silicon side wall insulation, vias metallization and final bumping. In a second part, the design of the TSV will be presented and a first approach of a design rule definition for TSV will be introduced. Morphological and electrical characterizations of the via-last technology will then be showed and discussed. Finally, a picture obtained with the TSV CMOS image sensor (TSV CIS) will be presented.

In this paper a low temperature 'via-last' technology will be presented. This technology has been especially developed for CMOS image sensors wafer level packaging. The design rules of the vias will be briefly described and then, the steps of the technology will be presented : glass wafer carrier bonding onto the silicon substrate, silicon thinning and backside technology including specific steps like double side lithography, silicon deep etching, silicon side wall insulation, vias metallization and final bumping. Morphological and electrical characterizations of the vias-last technology will be showed and discussed. Finally, a picture obtained with the TSV CMOS Image Sensor (TSV CIS) will be presented.

In this paper a new 'via-first' technology which is compatible with CMOS high temperature steps will be presented. This technology is based on filling high aspect ratio trenches with doped polysilicon and thinning the silicon after active device bonding onto a wafer carrier. The initial morphological requirements are described and different designs of TSV are presented. The complete technology for TSV achievement is described in detail and electrical results obtained with different vias geometries are presented and compared to initial calculations. Finally, several reflows experiments have been performed on these vias and electrical measurements have been achieved again and compared to initial results.

In this paper a new 'via-first' technology which is compatible with CMOS high temperature steps will be presented. This technology is based on filling high aspect ratio trenches with doped polysilicon and thinning the silicon after active device bonding onto a wafer carrier. The initial morphological requirements are described and different designs of TSV are presented. The complete technology for TSV achievement is described in detail and the morphological characterization results are discussed. Finally, electrical results obtained with different vias geometries are presented and compared to initial calculations.