ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research

Abstract Background NTRK1, NTRK2 and NTRK3 fusions are present in a plethora of malignancies across different histologies. These fusions represent the most frequent mechanism of oncogenic activation of these receptor tyrosine kinases, and biomarkers for the use of TRK small molecule inhibitors. Given the varying frequency of NTRK1/2/3 fusions, crucial to the administration of NTRK inhibitors is the development of optimal approaches for the detection of human cancers harbouring activating NTRK1/2/3 fusion genes. Materials and methods Experts from several Institutions were recruited by the European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) to review the available methods for the detection of NTRK gene fusions, their potential applications, and strategies for the implementation of a rational approach for the detection of NTRK1/2/3 fusion genes in human malignancies. A consensus on the most reasonable strategy to adopt when screening for NTRK fusions in oncologic patients was sought, and further reviewed and approved by the ESMO TR and PM WG and the ESMO leadership. Results The main techniques employed for NTRK fusion gene detection include immunohistochemistry, fluorescence in situ hybridization (FISH), RT-PCR, and both RNA-based and DNA-based next generation sequencing (NGS). Each technique has advantages and limitations, and the choice of assays for screening and final diagnosis should also take into account the resources and clinical context. Conclusion In tumours where NTRK fusions are highly recurrent, FISH, RT-PCR or RNA-based sequencing panels can be used as confirmatory techniques, whereas in the scenario of testing an unselected population where NTRK1/2/3 fusions are uncommon, either front-line sequencing (preferentially RNA-sequencing) or screening by immunohistochemistry followed by sequencing of positive cases should be pursued

ESONET LIDO Demonstration Mission: the Iberian Margin node.

The Gulf of Cadiz is one of two the test sites chosen for the demonstration of the ESONET - LIDO Demonstration Mission (DM) [1], which will establish a first nucleus of regional network of multidisciplinary sea floor observatories. The Gulf of Cadiz is a highly populated area, characterized by tsunamigenic sources, which caused the devastating earthquake and tsunamis that struck Lisbon in 1755. The seismic activity is concentrated along a belt going from this region to the Azores and the main tsunamigenic tectonic sources are located near the coastline. In the framework of the EU - NEAREST project [2] the GEOSTAR deep ocean bottom multi-parametric observatory was deployed for a one year mission off cape Saint Vincent at about 3200 m depth. GEOSTAR was equipped with a set of oceanographic, seismic and geophysical sensors and with a new tsunami detector prototype. In November 2009 the GEOSTAR abyssal station equipped with the tsunami prototype was redeployed at the same site on behalf of NEAREST and ESONET - LIDO DM. The system is able to communicate from the ocean bottom to the land station via an acoustic and satellite link. The abyssal station is designed both for long term geophysical and oceanographic observation and for tsunami early warning purpose. The tsunami detection is performed by two different algorithms: a new real time dedicated tsunami detection algorithm which analyses the water pressure data, and a seismic algorithm which triggers on strong events. Examples of geophysical and oceanographic data acquired by the abyssal station during the one year mission will be shown. The development of a new acoustic antenna equipped with a stand alone and autonomous acquisition system will allow the recording of marine mammals and the evaluation of environmental noise. ReferencesEGUPublishedVienna1.8. Osservazioni di geofisica ambientaleope

ESONET LIDO Demonstration Mission: the East Sicily node

Off East Sicily (at 2100 m depth, 25 km off the harbour of Catania) a prototype of a cabled deep-sea observatory (NEMO-SN1) was set up and has been operational in real-time since 2005 (the cabled deep-sea multi-parameter station SN1, equipped with geophysical and environmental sensors and the cabled NEMO-OνDE, equipped with 4 broadband hydrophones). The Western Ionian Sea is one of the node sites for the upcoming European permanent underwater network (EMSO). Within the activities of the EC project ESONET-NoE some demonstration missions have been funded. The LIDO-DM (Listening to the Deep Ocean-Demonstration Mission) is one of these and is re- lated to two sites, East Sicily and Iberian Margin (Gulf of Cadiz), the main aims being geo-hazards monitoring and warning (seismic, tsunami, and volcanic) and bio-acoustics. The LIDO-DM East Sicily installation represents a fur- ther major step within ESONET-NoE, resulting in a fully integrated system for multidisciplinary deep-sea science, capable to transmit and distribute data in real time to the scientific community and to the general public. LIDO-DM East Sicily hosts a large number of sensors aimed at monitoring and studying oceanographic and environmental parameters (by means of CTD, ADCP, 3-C single point current meter, turbidity meter), geophysical phenomena (low frequency hydrophones, accelerometer, gravity meter, vector and scalar magnetometers, seismometer, abso- lute and differential pressure gauges), ocean noise monitoring and identification and tracking of biological acoustic sources in deep sea. The latter will be performed using two tetrahedral arrays of 4 hydrophones, located at a relative distance of about 5 km, and at about 25 km from the shore. The whole system will be connected and powered from shore, by means of the electro-optical cable net installed at the East Sicily Site Infrastructure, and synchronised with GPS. Sensors data sampling is performed underwater and transmitted via optical fibre link, with optimal S/N ratio for all signals. This will also permit real-time data acquisition, analysis and distribution on-shore. Innova- tive electronics for the off-shore data acquisition and transmission systems has been designed, built and tested. A dedicated computing and networking infrastructure for data acquisition, storage and distribution through the internet has been also created. The deployment and connection of the deep sea structures will be performed using the dedicated ROV and Deep Sea Shuttle handling facilities (PEGASO, owned by INGV and INFN). LIDO-DM constitutes the enhancement of the Western Ionian site in view of the EMSO Research Infrastructure.PublishedVienna1.8. Osservazioni di geofisica ambientaleope

Specific immunotherapy by the sublingual route for respiratory allergy

Specific immunotherapy is the only treatment able to act on the causes and not only on the symptoms of respiratory allergy. Sublingual immunotherapy (SLIT) was introduced as an option to subcutaneous immunotherapy (SCIT), the clinical effectiveness of which is partly counterbalanced by the issue of adverse systemic reactions, which occur at a frequency of about 0.2% of injections and 2-5% of the patients and may also be life-threatening. A large number of trials, globally evaluated by several meta-analyses, demonstrated that SLIT is an effective and safe treatment for allergic rhinitis and allergic asthma, severe reactions being extremely rare. The application of SLIT is favored by a good compliance, higher than that reported for SCIT, in which the injections are a major factor for noncompliance because of inconvenience, and by its cost-effectiveness. In fact, a number of studies showed that SLIT may be very beneficial to the healthcare system, especially when its effectiveness persists after treatment withdrawal because of the induced immunologic changes

CD47 plays a critical role in T-cell recruitment by regulation of LFA-1 and VLA-4 integrin adhesive functions

CD47 plays an important but incompletely understood role in the innate and adaptive immune responses. CD47, also called integrin-associated protein, has been demonstrated to associate in cis with β1 and β3 integrins. Here we test the hypothesis that CD47 regulates adhesive functions of T-cell α4β1 (VLA-4) and αLβ2 (LFA-1) in in vivo and in vitro models of inflammation. Intravital microscopy studies reveal that CD47(−/−) Th1 cells exhibit reduced interactions with wild-type (WT) inflamed cremaster muscle microvessels. Similarly, murine CD47(−/−) Th1 cells, as compared with WT, showed defects in adhesion and transmigration across tumor necrosis factor-α (TNF-α)–activated murine endothelium and in adhesion to immobilized intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion protein 1 (VCAM-1) under flow conditions. Human Jurkat T-cells lacking CD47 also showed reduced adhesion to TNF-α–activated endothelium and ICAM-1 and VCAM-1. In cis interactions between Jurkat T-cell β2 integrins and CD47 were detected by fluorescence lifetime imaging microscopy. Unexpectedly, Jurkat CD47 null cells exhibited a striking defect in β1 and β2 integrin activation in response to Mn(2+) or Mg(2+)/ethylene glycol tetraacetic acid treatment. Our results demonstrate that CD47 associates with β2 integrins and is necessary to induce high-affinity conformations of LFA-1 and VLA-4 that recognize their endothelial cell ligands and support leukocyte adhesion and transendothelial migration

Highly Pathogenic Avian Influenza Virus Subtype H5N1 in Africa: A Comprehensive Phylogenetic Analysis and Molecular Characterization of Isolates

Highly pathogenic avian influenza virus A/H5N1 was first officially reported in Africa in early 2006. Since the first outbreak in Nigeria, this virus spread rapidly to other African countries. From its emergence to early 2008, 11 African countries experienced A/H5N1 outbreaks in poultry and human cases were also reported in three of these countries. At present, little is known of the epidemiology and molecular evolution of A/H5N1 viruses in Africa. We have generated 494 full gene sequences from 67 African isolates and applied molecular analysis tools to a total of 1,152 A/H5N1 sequences obtained from viruses isolated in Africa, Europe and the Middle East between 2006 and early 2008. Detailed phylogenetic analyses of the 8 gene viral segments confirmed that 3 distinct sublineages were introduced, which have persisted and spread across the continent over this 2-year period. Additionally, our molecular epidemiological studies highlighted the association between genetic clustering and area of origin in a majority of cases. Molecular signatures unique to strains isolated in selected areas also gave us a clearer picture of the spread of A/H5N1 viruses across the continent. Mutations described as typical of human influenza viruses in the genes coding for internal proteins or associated with host adaptation and increased resistance to antiviral drugs have also been detected in the genes coding for transmembrane proteins. These findings raise concern for the possible human health risk presented by viruses with these genetic properties and highlight the need for increased efforts to monitor the evolution of A/H5N1 viruses across the African continent. They further stress how imperative it is to implement sustainable control strategies to improve animal and public health at a global level

ESONET LIDO Demonstration Mission: the Iberian Margin node.

The Gulf of Cadiz is one of two the test sites chosen for the demonstration of the ESONET - LIDO Demonstration Mission (DM) [1], which will establish a first nucleus of regional network of multidisciplinary sea floor observatories. The Gulf of Cadiz is a highly populated area, characterized by tsunamigenic sources, which caused the devastating earthquake and tsunamis that struck Lisbon in 1755. The seismic activity is concentrated along a belt going from this region to the Azores and the main tsunamigenic tectonic sources are located near the coastline. In the framework of the EU - NEAREST project [2] the GEOSTAR deep ocean bottom multi-parametric observatory was deployed for a one year mission off cape Saint Vincent at about 3200 m depth. GEOSTAR was equipped with a set of oceanographic, seismic and geophysical sensors and with a new tsunami detector prototype. In November 2009 the GEOSTAR abyssal station equipped with the tsunami prototype was redeployed at the same site on behalf of NEAREST and ESONET - LIDO DM. The system is able to communicate from the ocean bottom to the land station via an acoustic and satellite link. The abyssal station is designed both for long term geophysical and oceanographic observation and for tsunami early warning purpose. The tsunami detection is performed by two different algorithms: a new real time dedicated tsunami detection algorithm which analyses the water pressure data, and a seismic algorithm which triggers on strong events. Examples of geophysical and oceanographic data acquired by the abyssal station during the one year mission will be shown. The development of a new acoustic antenna equipped with a stand alone and autonomous acquisition system will allow the recording of marine mammals and the evaluation of environmental noise. Reference

Home parenteral nutrition provision modalities for chronic intestinal failure in adult patients:An international survey

Background & aims: The safety and effectiveness of a home parenteral nutrition (HPN) program depends both on the expertise and the management approach of the HPN center. We aimed to evaluate both the approaches of different international HPN-centers in their provision of HPN and the types of intravenous supplementation (IVS)-admixtures prescribed to patients with chronic intestinal failure (CIF). Methods: In March 2015, 65 centers from 22 countries enrolled 3239 patients (benign disease 90.1%, malignant disease 9.9%), recording the patient, CIF and HPN characteristics in a structured database. The HPN-provider was categorized as health care system local pharmacy (LP) or independent home care company (HCC). The IVS-admixture was categorized as fluids and electrolytes alone (FE) or parenteral nutrition, either commercially premixed (PA) or customized to the individual patient (CA), alone or plus extra FE (PAFE or CAFE). Doctors of HPN centers were responsible for the IVS prescriptions. Results: HCC (66%) was the most common HPN provider, with no difference noted between benign-CIF and malignant-CIF. LP was the main modality in 11 countries; HCC prevailed in 4 European countries: Israel, USA, South America and Oceania (p < 0.001). IVS-admixture comprised: FE 10%, PA 17%, PAFE 17%, CA 38%, CAFE 18%. PA and PAFE prevailed in malignant-CIF while CA and CAFE use was greater in benign-CIF (p < 0.001). PA + PAFE prevailed in those countries where LP was the main HPN-provider and CA + CAFE prevailed where the main HPN-provider was HCC (p < 0.001). Conclusions: This is the first study to demonstrate that HPN provision and the IVS-admixture differ greatly among countries, among HPN centers and between benign-CIF and cancer-CIF. As both HPN provider and IVS-admixture types may play a role in the safety and effectiveness of HPN therapy, criteria to homogenize HPN programs are needed so that patients can have equal access to optimal CIF care