Etude pilote par PET/CT de la réponse à l'ipilimumab dans le traitement du mélanome métastatique.

0 Abstract L'incidence du mélanome est en nette augmentation en Europe et aux Etats-Unis. La Chirurgie peut être curative au stade précoce de la maladie,la radiothérapie se pratique À visée palliative, les chimiothérapies n'ont montré que peu d'effet. Les progress actuels se font via l'immunothérapie. Des traitements par l'interleukine-2 et l'interféron-α se sont montrés efficaces chez certains patients, mais leur utilisation est limitée par leur forte toxicité. Depuis 2011, en Suisse, une nouvelle molécule a été mise sur le marché, l'ipilimumab (Yervoy®). Il s'agit d'un anticorps! monoclonal humain dirigé contre le CTLA4. Il en résulte une activation non spécifique du système immunitaire. Une étude randomisée de phase IIIa été conduite au Etats-Unis. Elle démontre une augmentation de la survie chez les patients atteints de melanoma métastatique traits par ipilimumab, sans traitement préalable des métastases. Le but de cette etude est de determiner s'il est possible, par le biais de l'imagerie PET-CTau 18F-FDG, de prédire la réponse individuelle au traitement par ipilimumab, afin d'optimiser la prise en charge de ces patients. 0.1 Méthode Les patients atteints de mélanome métastatique sont exposés au traitement d'ipilimumab selon les recommandations de Bristol-Myers Squibb. Puis ils effectuent des PET-CT au F-18-FDG selon! le! protocole (CER 400/11, annexé) de l'étude. Les images sont!analysées selon les critères PERCIST (PETResponse Criterias In Solid Tumors) et le TLG (Total Lesion Glycolysis) est calculé. Parallèlement, des prises de sang sont effectuées et les échantillons sont analysés à l'institut Ludwig (LICR, Unil) selon les critères imRC qui determinant la réponse immunologique au traitement. 0.2 Résultats Nous notons une discrépance dans les résultats. Lorsque nous observons une maladie stable avec les critères immunologiques imRC, nous observons une maladie progressive avec lescritères PERCIST. 0.3 Discussion - Conclusion Nous n'avons pu faire entrer que cinq patients dans l'étude, dont trois étaient vivants à trois mois, ce qui a restreint le nombre de données analysables. Les discrépances que nous observons dans nos résultats pourraient être dues au fait que le PET-CT au 18FDG ne nous permet pas de différencier l'activité tumorale de l'activité inflammatoire péri-tumorale. Ce biais pourrait être à l'avenir prévenu en utilisant du 18FLT, un marqueur plus sélectif des cellules tumorales.L'analyse desimages avec les critères de total-lesion glycolysis a été impossible au vu du nombre de lésions que présentaient certains patients. Les critères PERCIST exigent un protocole d'acquisition très strict. La corrélation entre les images, les données immunologiques et la clinique mérite d'être suivie sur le long terme, car il pourrait y avoir une réponse positive plus tardive du traitement par ipilimumab.

Distinction of males of the Lutzomyia intermedia (Lutz & Neiva, 1912) species complex by ratios between dimensions and by an artificial neural network (Diptera: Psychodidae, Phlebotominae)

The females of the two species of the Lutzomyia intermedia complex can be easily distinguished, but the males of each species are quite similar. The ratios between the extra-genital and the genital structures of L. neivai are larger than those of L. intermedia s. s., according to ANOVA. An artificial neural network was trained with a set of 300 examples, randomly taken from a sample of 358 individuals. The input vectors consisted of several ratios between some structures of each insect. The model was tested on the remaining 58 insects, 56 of which (96.6%) were correctly identified. This ratio of success can be considered remarkable if one takes into account the difficulty of attaining comparable results using traditional statistical techniques.

Appendices for Complex Needs - The Nursing Response to Children and Young People with Complex Physical Healthcare Needs (PDF 708 KB)

Appendices to Complex Needs Report

Complex Needs - The Nursing Response to Children and Young People with Complex Physical Healthcare Needs (PDF 832 KB)

Departmental review of nursing services in order to ensure that they are facilitated to fully support and respond to children with complex needs and their families, and for them to work in partnership with other professions and agencies.

Cutaneous leishmaniasis caused by members of Leishmania braziliensis complex in Nayarit, State of Mexico

An epidemiological study was carried out in the northern Mexican state, Nayarit. Fourteen patients with possible cutaneous leishmaniasis skin lesions gave positive Montenegro skin tests. Biopsies were taken from the skin ulcer and analyzed by polymerase chain reaction (PCR) with specific primers for the Leishmania mexicana complex; however all biopsies were not amplified. PCR carried out with specific primers for the L. braziliensis complex resulted in the amplification of all patient DNA. DNA from 12 out of 14 biopsies gave positive amplification with primers species specific for L. (Viannia) braziliensis and hybridized with a species specific L. (V.) braziliensis probe. These results demonstrate the presence in Nayarit of at least two members of the L. braziliensis complex. Most of the cutaneous lesions were caused by L. (V.) braziliensis and two by another species belonging to the L. braziliensis complex. As far as we are aware, this is the first report of L. (V.) braziliensis in Nayarit. The main risk factor associated with the contraction of this disease in Nayarit is attributed to working on coffee plantations.

Comparison between computational alanine scanning and per-residue binding free energy decomposition for protein-protein association using MM-GBSA: application to the TCR-p-MHC complex.

Recognition by the T-cell receptor (TCR) of immunogenic peptides (p) presented by Class I major histocompatibility complexes (MHC) is the key event in the immune response against virus-infected cells or tumor cells. A study of the 2C TCR/SIYR/H-2K(b) system using a computational alanine scanning and a much faster binding free energy decomposition based on the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) method is presented. The results show that the TCR-p-MHC binding free energy decomposition using this approach and including entropic terms provides a detailed and reliable description of the interactions between the molecules at an atomistic level. Comparison of the decomposition results with experimentally determined activity differences for alanine mutants yields a correlation of 0.67 when the entropy is neglected and 0.72 when the entropy is taken into account. Similarly, comparison of experimental activities with variations in binding free energies determined by computational alanine scanning yields correlations of 0.72 and 0.74 when the entropy is neglected or taken into account, respectively. Some key interactions for the TCR-p-MHC binding are analyzed and some possible side chains replacements are proposed in the context of TCR protein engineering. In addition, a comparison of the two theoretical approaches for estimating the role of each side chain in the complexation is given, and a new ad hoc approach to decompose the vibrational entropy term into atomic contributions, the linear decomposition of the vibrational entropy (LDVE), is introduced. The latter allows the rapid calculation of the entropic contribution of interesting side chains to the binding. This new method is based on the idea that the most important contributions to the vibrational entropy of a molecule originate from residues that contribute most to the vibrational amplitude of the normal modes. The LDVE approach is shown to provide results very similar to those of the exact but highly computationally demanding method.

Effect of a second bloodmeal on the oesophagus colonization by Leishmania mexicana complex in Lutzomyia evansi (Diptera: Psychodidae)

Migration and colonization of the oesophagus by Leishmania mexicana parasites were enhanced after digestion of a second bloodmeal intake in Lutzomyia evansi. This event has epidemiological significance since it affects the infection susceptibility of this sand fly species, which is a proven vector of L. chagasi in Colombian and Venezuelan visceral leishmaniasis foci. Also, it may explain the host seeking behaviour displayed by some partially bloodfed flies found inside houses.

Complex and real Hausdorff operators

Vegeu el resum a l'inici del document del fitxer adjunt.

Relation between intraoperative EMG values and final pedicle screw position as seen on CT images

Introduction: Intraoperative EMG based neurophysiological monitoring is increasingly used to assist pedicle screw insertion. We carried out a study comparing the final screw position in the pedicle measured on CT images in relation to its corresponding intraoperative muscle compound action potential (CMAP) values. Material and methods: A total of 189 screws were inserted in thoracolumbar spines of 31 patients during instrumented fusion under EMG control. An observer, blinded to the CMAP value, assessed the horizontal and vertical 'screw edge to pedicle edge' distance perpendicular to the longitudinal axis of the screw on reformatted CT reconstructions using OsiriX software. These distances were analysed with their corresponding CMAP values. Data from 62 thoracic and 127 lumbar screws were processed separately. Interobserver reliability of distance measurements was assessed. Results: No patient suffered neurological injury secondary to screw insertion. Distance measurements were reliable (paired t-test, P = 0.13/0.98 horizontal/vertical). Two screws had their position altered due to low CMAP values suggesting close proximity of nerve tissue. Seventy five percent of screws had CMAP results above 10mA and had an average distance of 0.35cm (SD 0.23) horizontally and 0.46cm (SD 0.26) vertically from the pedicle edge. Additional 12% had a distance from the edge of the pedicle less than 0mm indicating cortical breach but had CMAP values above 10mA. A poor correlation between CMAP values and screw position was found. Discussion: In this study CMAP values above 10mA indicated correct screw position in the majority of cases. The zone of 10-20mA CMAP carries highest risk of a misplaced screw despite high CMAP value (17% of screws this CMAP range). In order to improve accuracy of EMG predictive value further research is warranted including improvement of probing techniques.

Genetic variability in Brazilian populations of Biomphalaria straminea complex detected by simple sequence repeat anchored polymerase chain reaction amplification

Biomphalaria glabrata, B. tenagophila and B. straminea are intermediate hosts of Schistosoma mansoni, in Brazil. The latter is of epidemiological importance in the northwest of Brazil and, due to morphological similarities, has been grouped with B. intermedia and B. kuhniana in a complex named B. straminea. In the current work, we have standardized the simple sequence repeat anchored polymerase chain reaction (SSR-PCR) technique, using the primers (CA)8RY and K7, to study the genetic variability of these species. The similarity level was calculated using the Dice coefficient and genetic distance using the Nei and Li coefficient. The trees were obtained by the UPGMA and neighbor-joining methods. We have observed that the most related individuals belong to the same species and locality and that individuals from different localities, but of the same species, present clear heterogeneity. The trees generated using both methods showed similar topologies. The SSR-PCR technique was shown to be very efficient in intrapopulational and intraspecific studies of the B. straminea complex snails.