Periodic Report Summary 2 - π-NET (Pulmonary Imaging Network)
The members of the #-net (Figure 1) network have created a series of MRI-based tools for the early-diagnosis and follow-up of lung diseases. The investigational and therapeutic potential of these new techniques --and existing ones-- have been explored and developed. The sharing of expertise within the network has been key in finding solutions to some of the complex problems that lie in the frontiers of pulmonary imaging and has helped to make those solutions more integrated and comprehensive.
The scientific outcomes of #-net have been largely published in peer reviewed journals (sixty-one published articles, nine of which are a collaboration between two or more groups, twelve submitted manuscripts and six manuscripts in preparation), books (two chapters published by the early stage researchers) with an accumulated impact factor of 218.4. Sixty percent of the papers were published in first quartile journals. We have filed five patents, three of them with direct participation of our young researchers, who have had an active role in all the activities. Moreover we have presented 96 communications in scientific events, 29 papers were selected for oral presentation, and five of them being selected for some kind of award. Young researchers have generated 67% of the total impact factor of the network. Among the ESRs, five out of ten have already defended their theses. One ESR
has been hired by one of the pharmaceutical companies participating in the project (Boehringer Ingelheim, BI). The two contracted ERs have already found permanent positions. One of them as academic staff at the University of Montreal in Canada. The other, after a short post-doc stay in a research institution in New York, has been hired by AstraZeneca (AZ), the same pharmaceutical company and #-net partner where she was contracted initially.
#-net has provided training and carried out research relevant to the clinical and preclinical domains in the fields of MRI physics, radiology, molecular imaging, pulmonology, and therapeutic drug development. The networked nature of these efforts has stimulated close transnational interactions.
Some of the novel imaging solutions generated in the project are multiple breath washout (MBW) imaging and fractional ventilation maps, both based on the use of hyperpolarized gases, as well as new pulse sequences for proton lung imaging: Fourier Decomposition lung MRI, magnetization and
diffusion preparation for quantitative lung imaging, oxygen enhanced imaging and T1 mapping of the lungs, and ultrashort echo time sequences.
Multiple breath wash-out imaging has been developed as a quantitative and reproducible measure of lung ventilation. Fractional ventilation maps (see Figure 2 taken from Horn et al, NMR Biomed and J Appl Physiol 2014) has been assessed in treatment-response (bronchodilator) studies in asthma
population and in cystic fibrosis patients. Fourier Decomposition proton lung MRI from 1.5 to 7 T MRI allows to obtain ventilation/perfusion maps (Figure 3 and Kjørstad et al. Inv. Radiology under review) and these quantitative values are being tested in human studies with lung cancer human studies (under evaluation in Investigative Radiology). The magnetization and diffusion preparation sequences for quantitative functional and microstructural imaging of the human lung are being used in patients to assess pathological changes in lung microstructure (Fig 4 and Carinci et al, JMRI 2014). Oxygen enhanced imaging and T1 mapping of the lung of small animals have been used in very challenging applications (Zurek et al. MRM 2014) and ultrashort echo time sequences were exploited in a variety of applications (e.g. Bianchi et al, NMR Biomed 2012).
Since the lung is one of the most difficult organs to image using proton MRI, we have also explored new imaging modalities to amplify the lung signal using either molecular imaging approaches or Positron Emission Tomography (Figure 5, Groult et al, in preparation). The molecular imaging approaches include Gadolinium based contrast agents for MRI (Figure 4 and Bianchi et al. PNAS 2014) and hot spot imaging using other fluorescent agents.
Figure 1.Logo of the Pulmonary Imaging network (#-net). Figure 2. Single breath ventilation imaging (left panel) and fractional ventilation in an asthma patient. Figure 3. Fourier decomposition methods for new quantitative methods in pulmonary imaging. Ventilation (left panel), perfusion (middle) and V/Q panels. See how large vessels are visible in the perfusion map.
Figure 4. Diffusion-enhanced proton MRI to quantify alveolar size. Figure 5. Multimodal MRI (using and optimized pulse sequence Ultra-short-echo time to enhance lung proton MRI signal intensity in the pulmonary parenchyma) and optical near-infrared fluorescence (bioluminescence) using an ultrasmall rigid platform.
Figure 6. Dual modality nanoparticles. Bovine seroalbumin-iron oxide nanoparticles labeled with 89Zr for PET-MRI. The figures summarize the clearance after intratracheal administration.
One of the objectives of the project has been the integration of high throughput molecular testing (RNA seq, metabolomics, etc.) and imaging techniques. In this regard, we have had the opportunity to make high impact contributions to the field. Published works carried out within the network have helped revise the clinical criteria for acute respiratory distress syndrome (ARDS) (Thille et al AJRCC 2013 and editorial in Chest 2014 and a patent from Cardinal et al. 2014) and improved the methodology to study different lung samples using metabolomic approaches (Naz et al, Anal Chemistry 2013 and Ferrarini et al Electrophoresis 2013).
Our research activity covers both the preclinical and clinical domain, and it has a strong translational drive. It strives to promote multiparametric analysis using different types of biomarkers, in order to find methods that provide earlier disease diagnosis and more accurate monitoring. In our quest for new biomarkers, our industrial partners have played a key role. They are mainly pharmaceutical (AZ, BI) and diagnosis (GE-Healthcare) companies who are interested in these technologies due to their capabilities for drug development research. MRI is especially attractive to them because being non-invasive and not relying on ionizing radiation, it fits well the longitudinal type of research needed for the development of drugs and testing of diagnostic techniques. Our industrial partners have been directly involved in the production of four publications, three of which were in collaboration with academic groups. Thus, the project has sparked and strengthened excellent cooperation among academic, clinical and industrial researchers in Europe and other places of the
world. This cooperation in the field of functional lung imaging has been facilitated by efficient communication among all the partners, achieved through a comprehensive group of on-site, virtual and transfer of knowledge activities. The web page of the network (http://www.pi-network.eu) has been an essential tool to canalize these training and research initiatives.
We are very happy that our scientific and training activities have provided us with the opportunity to bring positive economic and cultural change.
The scientific outcomes of #-net have been largely published in peer reviewed journals (sixty-one published articles, nine of which are a collaboration between two or more groups, twelve submitted manuscripts and six manuscripts in preparation), books (two chapters published by the early stage researchers) with an accumulated impact factor of 218.4. Sixty percent of the papers were published in first quartile journals. We have filed five patents, three of them with direct participation of our young researchers, who have had an active role in all the activities. Moreover we have presented 96 communications in scientific events, 29 papers were selected for oral presentation, and five of them being selected for some kind of award. Young researchers have generated 67% of the total impact factor of the network. Among the ESRs, five out of ten have already defended their theses. One ESR
has been hired by one of the pharmaceutical companies participating in the project (Boehringer Ingelheim, BI). The two contracted ERs have already found permanent positions. One of them as academic staff at the University of Montreal in Canada. The other, after a short post-doc stay in a research institution in New York, has been hired by AstraZeneca (AZ), the same pharmaceutical company and #-net partner where she was contracted initially.
#-net has provided training and carried out research relevant to the clinical and preclinical domains in the fields of MRI physics, radiology, molecular imaging, pulmonology, and therapeutic drug development. The networked nature of these efforts has stimulated close transnational interactions.
Some of the novel imaging solutions generated in the project are multiple breath washout (MBW) imaging and fractional ventilation maps, both based on the use of hyperpolarized gases, as well as new pulse sequences for proton lung imaging: Fourier Decomposition lung MRI, magnetization and
diffusion preparation for quantitative lung imaging, oxygen enhanced imaging and T1 mapping of the lungs, and ultrashort echo time sequences.
Multiple breath wash-out imaging has been developed as a quantitative and reproducible measure of lung ventilation. Fractional ventilation maps (see Figure 2 taken from Horn et al, NMR Biomed and J Appl Physiol 2014) has been assessed in treatment-response (bronchodilator) studies in asthma
population and in cystic fibrosis patients. Fourier Decomposition proton lung MRI from 1.5 to 7 T MRI allows to obtain ventilation/perfusion maps (Figure 3 and Kjørstad et al. Inv. Radiology under review) and these quantitative values are being tested in human studies with lung cancer human studies (under evaluation in Investigative Radiology). The magnetization and diffusion preparation sequences for quantitative functional and microstructural imaging of the human lung are being used in patients to assess pathological changes in lung microstructure (Fig 4 and Carinci et al, JMRI 2014). Oxygen enhanced imaging and T1 mapping of the lung of small animals have been used in very challenging applications (Zurek et al. MRM 2014) and ultrashort echo time sequences were exploited in a variety of applications (e.g. Bianchi et al, NMR Biomed 2012).
Since the lung is one of the most difficult organs to image using proton MRI, we have also explored new imaging modalities to amplify the lung signal using either molecular imaging approaches or Positron Emission Tomography (Figure 5, Groult et al, in preparation). The molecular imaging approaches include Gadolinium based contrast agents for MRI (Figure 4 and Bianchi et al. PNAS 2014) and hot spot imaging using other fluorescent agents.
Figure 1.Logo of the Pulmonary Imaging network (#-net). Figure 2. Single breath ventilation imaging (left panel) and fractional ventilation in an asthma patient. Figure 3. Fourier decomposition methods for new quantitative methods in pulmonary imaging. Ventilation (left panel), perfusion (middle) and V/Q panels. See how large vessels are visible in the perfusion map.
Figure 4. Diffusion-enhanced proton MRI to quantify alveolar size. Figure 5. Multimodal MRI (using and optimized pulse sequence Ultra-short-echo time to enhance lung proton MRI signal intensity in the pulmonary parenchyma) and optical near-infrared fluorescence (bioluminescence) using an ultrasmall rigid platform.
Figure 6. Dual modality nanoparticles. Bovine seroalbumin-iron oxide nanoparticles labeled with 89Zr for PET-MRI. The figures summarize the clearance after intratracheal administration.
One of the objectives of the project has been the integration of high throughput molecular testing (RNA seq, metabolomics, etc.) and imaging techniques. In this regard, we have had the opportunity to make high impact contributions to the field. Published works carried out within the network have helped revise the clinical criteria for acute respiratory distress syndrome (ARDS) (Thille et al AJRCC 2013 and editorial in Chest 2014 and a patent from Cardinal et al. 2014) and improved the methodology to study different lung samples using metabolomic approaches (Naz et al, Anal Chemistry 2013 and Ferrarini et al Electrophoresis 2013).
Our research activity covers both the preclinical and clinical domain, and it has a strong translational drive. It strives to promote multiparametric analysis using different types of biomarkers, in order to find methods that provide earlier disease diagnosis and more accurate monitoring. In our quest for new biomarkers, our industrial partners have played a key role. They are mainly pharmaceutical (AZ, BI) and diagnosis (GE-Healthcare) companies who are interested in these technologies due to their capabilities for drug development research. MRI is especially attractive to them because being non-invasive and not relying on ionizing radiation, it fits well the longitudinal type of research needed for the development of drugs and testing of diagnostic techniques. Our industrial partners have been directly involved in the production of four publications, three of which were in collaboration with academic groups. Thus, the project has sparked and strengthened excellent cooperation among academic, clinical and industrial researchers in Europe and other places of the
world. This cooperation in the field of functional lung imaging has been facilitated by efficient communication among all the partners, achieved through a comprehensive group of on-site, virtual and transfer of knowledge activities. The web page of the network (http://www.pi-network.eu) has been an essential tool to canalize these training and research initiatives.
We are very happy that our scientific and training activities have provided us with the opportunity to bring positive economic and cultural change.