All right, good morning, I think we're going to get started. Welcome to this session on innovative imaging techniques for ILD. The reason we put this session together is essentially for more than 30 years, pulmonologists have been relying almost exclusively on chest x-ray and CT scans as their imaging modalities of choice. Of course, the younger physicians in the audience, which is almost everybody younger than me, will point out the utility of now using point of care ultrasound, which is a new modality that really wasn't available when I trained. And that's really become the standard of care in ICUs nationwide. However, we are really failing to use the full spectrum of tools in the radiology toolkit. And so, with that in mind, we wanted to put together a session that sort of highlights some of the stuff that can be done with alternate technologies that the radiologists are really very, very familiar with. In order to do that, we've put together a really excellent panel, primarily of radiologists. I'm the only clinician here. So we have Dr. Jane Koh. She's the professor of radiology at NYU Langone Health. She's a former president of the Society of Thoracic Radiology, and she's exceptionally well-known for her work on ground glass nodules and for her exceptionally thoughtful approach to difficult topics in thoracic radiology, which she can really make very simple and easy to understand. So she will be talking today on photon counting, CT, in thoracic radiology. And then we're also lucky to have Dr. Jordi Brancano. He is a partner at HealthTime in Cordoba, Spain. And he's really a pioneer in chest MRI. And as you'll see, he really pushes the limits of what MRI can do. And as you'll see, his fusion of CT and MRI data are really spectacular. And he's going to be talking a bit about the utilization of MRI for imaging ILD. And then lastly, I'm Adrian Schifrin. I'm a pulmonologist in charge of the ILD program at Washington University in St. Louis. And I'm going to be showing you some preliminary data that we have on using PET-CT to monitor the molecular pathogenesis of interstitial lung disease, and specifically idiopathic pulmonary fibrosis. So what we're going to do is we're going to have all the speakers do their talks. If we do go a little bit long, we're apparently, there's no session directly after this. So all three of us are available to answer questions for as long as you'd like. And we're happy to extend it over if you would like to wait and ask us questions even after the session is over. So with that being said, I'd like to call Dr. Koh to talk to us about photon counting CT. Thank you very much. And good morning, everyone. It's really great to be here in Hawaii and to be part of this conference. And I'd like to thank the ACCP and Adrian for inviting me. So let's move on to our objectives, which are to touch on photon counting CT. We're going to touch on ILD and ultra-high res imaging, but also other thoracic applications that are thoracic related. First my disclosures out of a past research agreement with Siemens Health and Yours. And to explain our experience at NYU, our scanner has been installed for about a year and a half. It's at an outpatient site. It's very high volume. Our technologists are amazing in imaging with this scanner. And there's very limited literature pertaining to clinical practice. And you'll be hearing much more about this as the technology disseminates and there's more research. And I'd like to acknowledge the technical staff, our radiologists and radiographers, and our photon counting CT interest group and our thoracic radiologists. So our objectives are to review photon counting technology. We'll cover some basic concepts. We're going to also discuss current knowledge in terms of the thoracic applications. And we'll highlight the advantages and weaknesses in terms of the technology and also in terms of any ILD evaluation. And we'll provide some imaging examples. So first let's start off with physics principles and technology. And this is the basis for photon counting CT and dual energy imaging. You probably are well aware of that. So dual energy CT and photon counting CT are based on material de-differentiation or differentiation. It's been called multi-energy imaging and spectral. More recently we've been using the term multi-energy because we can evaluate multiple photon energies. Basically we can identify different components in an image that's acquired, say with contrast, and perform material differentiation. And this takes advantage of the fact that materials behave differently at different photon energies. And this is particularly true for high atomic number elements such as iodine in which if you have low and higher photon energies the attenuation of the iodine is by far much higher at lower photon energies than high. And this is because of the greater interactions that are photoelectric effect that particularly are the interactions that high atomic number elements interact with photons. So to be able to separate the photon energies we have to have technology. So let's move on to the current technology for the dual energy CT technology that preceded photon counting. There's a dual source configuration in which there are two x-ray sources which are run at different kilovolt potentials that determine the maximum photon energy. And there are two detectors. One is larger than the other so that's a trade-off. And there is a slight temporal resolution offset as the tubes are set differently on the gantry. The next technology is the single source rapid KVP switching technology in which there is one source and the beam flickers between low and high KVP in one detector. And there is a temporal resolution aspect and some dose aspects because of the dwell time being the determinant for image quality. The last is the multilayer detector which there is a single source but there are two layers to measure the low photon energies and the high photon energies. And there is some image quality aspects due to photon starvation. Now the basis for photon counting CT is a detector-based technology just like the photon multilayer dual energy CT scanner. The typical or the current configuration for the one CT scanner that is now able to perform photon counting imaging is this dual source CT in which the detector is a special semiconductor detector that is new technology that enables photon energies to be measured. It can be mounted and performed on both tubes because there are two detectors that are both the semiconductor. And therefore you can image at very high pitches and obtain the temporal resolution that is needed. And you can obtain multiple energy information and have the spatial resolution. So let's look at the two detectors. The photon counting detector is basically the photons hit the semiconductor and directly converts it to an electrical signal. There's no intermediate step and you can preserve photon energy. On the other hand, the traditional detector actually has photons that strike and have to be converted to light prior to be converted to an electrical signal. And this is what's in all our prior and currently used CT scanners. And there's wasted dose given these reflectors that are present and photon energy information is lost. And therefore that's why we have to image with different KVPs to obtain photon energy. So with that backdrop, let's start off with iodine evaluation. And we'll discuss high spatial resolution imaging and IOD. But this opens up a new frontier in terms of ability. And because of the high temporal resolution, because of the dual source technique. So this is a CT angiogram study performed for the aorta. And we can acquire one contrast acquisition. We can see the contrast but also generate, because of material differentiation, a virtual non-contrast image that allows high attenuation material that's not enhancing to be more readily discerned from the contrast-enhanced lumen. And this patient had aortic surgery and this was a pleasure placed at the site of cardiopulmonary bypass. And you can see on a prior EID detector, that's our typical CT scanner we utilize, is this pulsation artifact because of the poor temporal resolution. Now the temporal resolution affects the virtual non-contrast image and you can see how there is a pseudo high attenuation that can be misinterpreted as an acute intramural hematoma without this knowledge and therefore we don't use in the acute aorta situation the dual energy technique in the dual source configuration and the other scanner configurations because of the lack of temporal resolution. This is a photon counting CT image and you can see how we have the virtual non-contrast image and in the post-surgical aorta and post-endovascular repair aorta, it's very useful because you can avoid irradiating patients twice to obtain a pre-contrast image. From the post-contrast image, you can separate the image data into iodine and non-contrast imaging. And you can see where the stent is and you can evaluate for any endoleak and these are just reformats in the coronal plane and you can see the stent and you can nicely see on the iodine image the contrast leaking around the stent. This is a type 2 backflow endoleak going from the subclavian around the stent in the endovascular repair region with aneurysmal dilatation. And this was obtained with only a very small amount of contrast. We typically only utilize 50cc of contrast because it's a tight bolus because of the fast imaging and we can avoid giving about 150cc which is oftentimes used for CTA studies. So this is how we can minimize nephrotoxicity and we have utilized this technology. Here's another example, photon counting, post-aortic dissection repair, and you can see the virtual non-contrast nicely demonstrates a graft end. And this is a pitfall just to be aware that on the iodine image, something that's high atomic number and very high density can bleed into the iodine-only image and that's why you see bones. This is only iodine. There's no overlay of the iodine information with any anatomic non-contrast image. We can perform quantification and this is regional analysis of lymphadenopathy in patients with cancer and you can see how the iodine image which has been overlaid on top of a virtual non-contrast image shows areas of iodine attenuation that are higher in iodine intensity than necrotic areas. And with the technology, we can actually place variations of interest in different areas. You can see an area of contrast enhancement that is much higher in this area of the node as opposed to this area of the node and you can actually separate out the Hounsfield units attributed to the pre-contrast soft tissue, the iodine only, and then you can also generate the average Hounsfield units as if you were looking at a regular CT image. And you can calculate iodine density and you can see how the iodine density is much higher in this region than not. And it's been shown for the photon counting CT and phantom work to show that the root mean square error is the same as with EID and the pre-existing scanner technology. Now with nodule applications, we've always tried to perform this. However, there have been limitations due to variation in IV contrast injection. It depends on the phase of imaging. You have to have your technical parameters very, very consistent when you're imaging across and within the same patient. But this is the typical image that we would look at and this is for dual energy imaging, not photon counting, but the same principle. You can place a region of interest and this patient actually had Hounsfield units enhancement of 55. So that's a very avidly enhancing nodule. You can do 3D analysis. And this is something that is potential and can be maximized with photon counting technology because of the high temporal resolution. You don't have to worry so much about cardiac pulsation. So in terms of pulmonary embolism evaluation, this is a huge area in which image quality can be improved. Notice the relative motionless imaging. This is an acute PE and we can see the contrast in this expanded vessel distended by the embolus. And the patient was followed six months up on the photon counting CT scanner also. And notice how the vessel has completely structured down and has become occluded. And we have the temporal resolution to delineate these small bronchial artery quadrils and even heterogeneous enhancement within the embolus. So this is potentially a sign that can be evaluated. In terms of the value of looking at different photon energies, lower photon energies can be generated and made into images and have been shown to increase visibility of pulmonary embolism on images and also have been shown to improve diagnostic accuracy and confidence in terms of diagnosing pleura and pyema. And this is a patient who has breast cancer and had a mastectomy and we can see that there's a pectoral muscle soft tissue implant. And notice the subtle high attenuation that is more readily discernible from surrounding soft tissue than if performed with reconstructions with similar technique to an EID. This is actually a photon counting recon series that actually utilizes all the photon energies that's in the CT data. And this with the photon counting CT technology, you can isolate photons that are potentially only 60 keV. And basically the lower attenuation photon, sorry, the lower photon counting energy, photon energies actually enhance the iodine enhancement within this nodule. So let's move on to ultra high resolution imaging. This is actually something that is potentially extremely useful, particularly with quantitative methods and lung imaging. So what's the difference between ultra high spatial resolution imaging and standard? These are both available on the photon counting CT and what I showed you was the non-ultra high res images that we acquired in patients with CTA and other aspects. But what makes ultra high resolution acquisition different is that there's a different detector configuration. It's smaller, it's shorter, and the sub-pixels are read out independently as opposed to binned as with the standard photon counting acquisition. The reconstruction options are also different in which you can go down to 0.2 millimeter sections and you can even go down to 0.4 millimeter multi-energy data information. So like with PEs, we can actually recon and get those iodine and mono-energetic information just at 0.4. And similarly with the standard, we can get 0.4 millimeter sections. But so what's the difference? Well, it's the acquisition is the key. So let's take a look at what's been published in terms of ILD, which is very limited. But this was by Remy Jardin's group, who is a pioneer in dual energy imaging, and she evaluated 112 patients and compared a dual source CT that's very high generation CT scanner using the EID detector that we typically use and the photon counting CT at 0.2 millimeters. And they showed that there was higher noise, but there was higher visual qualitative scores. You could see much more bronchial divisions or bronchial divisions that were ninth as opposed to 10th, and the bronchial walls are sharper. And you had greater visualization of a large number of the findings that we associate with fibrotic ILD, and actually four patients who had non-fibrotic ILD were then reclassified as fibrotic with the ultra-high resolution imaging. So a potential way to impact ILD evaluation. So here are some scans. This is the typical CT single detector that was performed two years prior to this photon counting CT. And you can see the greater reticulation and greater detail and the more cystic areas are better clearly defined as truly cystic or traction bronchiolectasis. So this is one millimeter and 0.2, and it's still unclear whether the 0.2 is superior to the one, but from our experience, we believe that we can see much finer detail. And this is traction bronchiolectasis. This is the EID CT detector, the traditional technology, photon counting with similar section thickness, and you can see to much finer detail the bronchiolectasis, the architecture, and here the ultra-high res 0.2. Here is just how we can see normal anatomic structures on the EID. It's very hard to actually see the fissure, the minor fissure, and here you can see it to a better degree with photon counting CT, same section thickness. And you can see this fibrotic area, the better-defined walls, and all of this could potentially add to quantitative analysis and make this more accurate and precise. So in terms of emphysema, so here's ultra-high res image, one millimeter, and 12 months prior in EID, you can actually see and discern the emphysema better, even with the one millimeter section that is related to the acquisition of the photon counting CT. And here there are multiple areas. You can see a fine reticulation also to a better degree. In terms of emphysema, this was just comparing one to 0.2, and 0.2, the small lucencies can stand out better. So in terms of reconstruction algorithms, this is actually a huge aspect in terms of radiology investigation, because we have to understand what's the best way to evaluate this data or use this data and to visualize it. And this looked at multiple permutations of reconstruction algorithms and section thicknesses, and basically showed that maybe the 0.4 is the best section thickness, although there are some technical differences among preferences, among radiologists. And in general, the 0.2 was equivalent to 0.4 for these aspects, but the 0.4 millimeter actually proved to be a little bit better, not by direct comparison, but just in terms of performance of 0.4 compared to the standard one millimeter and 0.2 to the one. So in general, 0.4 and 0.2 are better than one millimeter sections. And this patient had a transplant with fibrotic left lung. And here you can see the right lung had these fine central alveolar ground glass nodules. And on the 0.2 millimeter sections, we can even see them better than the one millimeter, both photon counting. Here is high pitch, ultra high resolution imaging, and this is what we can perform without any tradeoff in terms of radiation dose and temporal resolution. The patients can be scanned in four second breath holds, which is a huge advantage in patients who are inherently short of breath. And we can obtain this high resolution data, and notice how you can see the small areas of traction bronchielectasis by far better defined in addition to the airway wall. So this patient had UIP with ultra high resolution imaging showing the traction bronchielectasis. So in terms of quantitative assessment, this is actually a very technical paper, but they looked at contrast CT and showed how the images are affected in terms of how you reconstruct the data. So if you reconstruct the data at very low photon energies, just to visualize the data at 40 monoenergetic, you will be impaired in terms of being able to see emphysema. So attention to technical details is really key for the radiologists when they actually implement any CT scanner. And basically, quantitation can be really underestimated, both visually and quantitatively, if you use the wrong photon energy to visualize the data. So this is just to show perhaps some potential application of ultra high resolution imaging, and that's just to improve quantitative analysis. This is not a photon counting CT, but where we are in terms of image analysis, we can perform cluster analysis and display connected voxels and identify the volume of the lung that actually has greater than a certain threshold in terms of contiguous vessels. And reconstruction algorithms and technical parameters, however, are hugely key. So just one take-home point is technical parameters are really essential to keep consistent across any CT scans that a patient receives to compare other patients. And here's just an example of emphysema quantification in blue areas, areas that are below the threshold of minus 950, and this is another patient with a different recon algorithm. Notice how there's all this noise. All this blue is noise, so we have to make sure that we utilize the right recon algorithm. Now, in terms of lung nodules, this is a huge area of investigation, and this is just to show even the difference between one millimeter and 0.2 millimeter sections with ultra-high res, and you get much finer detail that could potentially improve quantitative analysis and visualization of solid portions within a nodule that may prove beneficial and predictive. And phantom experience has shown that basically the accuracy in phantoms for photon-counting CT was better than the traditional CT detector, so for both ground glass and solid nodules. So in vivo, manuscripts will probably be ensuing in the near future. So lastly, I'll just wrap up with imaging and dose and just screening CT, and these are some of our screening CTs that are performed on the EID typical CT scanner and photon counting, and notice how there's a lower CT dose index and the image quality is comparable. And it's been shown by Inouye and colleagues that basically the image quality, sharpness, noise was better on screening CT. There was a little bit more artifact with photon-counting CT, but basically, it provided image quality that was better with less noise despite a lower radiation dose. And actually, at our institution, we've lowered from the targeted radiation exposure parameters, the photon-counting CT parameters to start off with just because of its greater efficiency, and here you can see lower CTDI, and you can see how the standard deviation, the image noise is lower for the photon-counting CT scanner as opposed to the traditional, so excellent image quality. And this just studied and basically showed how you can achieve equivalent image quality compared to the traditional technology. This was a dual-source scanner, and you can see that if you isolated only a portion of the image data from this acquisition, which was capable of performing, you get much better, higher image quality scores and equivalent dosing, so basically, the same performance at a third of the dose, and you can see the difference in the overall radiation exposure to the patient compared to a full-dose CT. So basically, you can look and see ILD at better, at least conserving image quality and diagnostic accuracy with a third of the dose. So I'd like to just touch upon where we're heading, and basically, we'll see how this impacts quantification, radiomics, and AI, but really working on how we can integrate this into everyday practice, and this will all be learned more in the future. So I'd like to conclude, and thank you for your attention and learning about this new technology. It's really new, but there's a huge potential for obtaining multi-energy information with high temporal resolution that may help in multiple factors, both vascular work, ILD, and other organ systems with dose reduction. And in the future, we'll really define the role in where this technology can play in patient care. So with that, I'd like to thank you for your attention. Dr. Jordi Brancano to discuss MRI. So thank you very much, Irene, for the invitation and for the introduction. I'm Jordi Brancano. I have nothing to disclose. And today we're going to review the potential role of chest MRI in ILG as well as differentiating different imaging techniques, findings, and potential prognostic biomarkers in ILG. We know that intestinal lung diseases group are a generous group of entities that have in common the diffuse parenchymal damage of the peripheral interstitium of the ovarian walls that ultimately lead to progressive interstitial fibrosis and respiratory failure. UIP and SIP are the most common imaging, the most common entities. And we also do know that high-resolution CT is the first imaging modality due to the extraordinary accuracy for detecting certain features like bronchiectasis, honeycombing, reticulation, and growth-relapse capacities. Not only can it outstand qualitatively but also can yield some quantitative information and we can obtain several biomarkers that help us to not only grade the severity but also to monitor the disease with prognostic implications. The main disadvantages of high-resolution CT is that it's a technique that uses ionizing radiation and this could be a concern especially in patients that needs close follow-up in young patients or women. And also, it cannot differentiate with conventional CT. We cannot differentiate inflammatory growth-relapse capacities rather than fibrotic growth-relapse capacities. On the other side, MRI, we know that it's a technique that doesn't use ionizing radiation that could be interesting in those patients that require multiple follow-ups in young individuals, in women, or in pregnant patients. However, the application of MRI in the lung is complex because the lung has inner and low proton density and air-tissue interfaces leading to a feline homogeneity's inner low to signal-to-noise ratio and artifacts. And also, it's technically complex to use because of the presence of cardiac and respiratory motion and lung acquisition techniques, although with deep learning acquisition and reconstruction strategies, we're going to reduce it. But what I do think is the major advantage of MRI in the test is this. We can apply a general morphological protocol and we could tailor this protocol to the patient needs and to the facial pathology of the lung disease that we are evaluating by adding different functional capabilities. In ILD, we are going to start in the morphological protocol with balanced stage-to-stage preprecision techniques that is a spoil-grind echo sequence that it's very rapid and fast to acquire. It provides a rapid test evaluation. It's great for detecting pulmonary embolism or thrombosis and has a reasonably good accuracy for detecting interstitial lung disease. The second sequence that we are going to rely on our morphological protocol are T2-weighted imaging that we are going to use to evaluate fluid, mucosal, and bronchial thickening. We could differentiate pulmonary infiltrates and detect it according to the high T2 content due to inflammation. And in non-collaborative patients, we could apply T2-weighted imaging with propeller readout and respiratory navigation that help us to obtain high-quality images in those non-collaborative patients and has been shown to be very useful for the detection of pulmonary nodules. With T2-weighted imaging, we could differentiate inflammatory versus fibrotic tissue, making some ratio compared to the skeletal muscle. And we can go one step forward and apply T2 relaxometry maps in order to differentiate the T2 values between grungus opacity, reticulation, and honeycombing. And this has been correlated also to the progression of fibrosis. The third imaging technique, morphological imaging technique, we are going to include in our protocol is the ultra-short echo-time imaging, the ultra-short T. It's a real game-changer in the evaluation of lung parenchyma and relies on two things. First, it's a hardware frequency pulse. It uses hardware frequency pulse that helps us to non-selectively excite the lung parenchyma and also a rapid gauge space readout, which helps us to increase the signal-to-noise ratio and also to have high spatial resolution. The main pros of this technique is that we offer full chest coverage with isotropic resolution and by implementing respiratory navigation and cardiac triggering, we can go up on signal averaging and more radial projections that increases the signal-to-noise ratio, optimizing the visualization of lung parenchyma. The main disadvantages is that it's long acquisition, I think, usually five, six minutes, and we can have some respiratory motion in the lung basis. Another thing to take into account is that it is quite a tendency for some techniques contrary to higher resolution CT, and this could be a matter of concern when we are evaluating smaller-wage disease. Overall, the ultra-short T has a good overall diagnosis for ILD, with great observer agreement, but in some studies, when we focus to specific features inside ILD, some authors have mentioned that it's inferior to high-resolution CT for the evaluation of reticulation, bronchiectasis, ground glass capacities, or honeycombing. However, other groups focusing specifically on IPF have shown that the diagnostic accuracy of ultra-short T, 3D ultra-short T, compared to CT was similar in reticulation, honeycombing, and contraction bronchiectasis. The first functional technique that we could add on in our MR protocol for interstitial lung disease is ventilation imaging. We can use oxygen-enhanced MRI that relies on the paramagnetic effect of oxygen, and by alternating inhaled oxygen with pure high-flow oxygen. It's a relatively cheap and safe technique, but on the other side, it has low signal-to-noise ratio and long acquisition times. We can also do hyperpolarized gas MRI that rely on the administration of air-space contrast based on Shannon and helium. It's high-cost. It's technically complex, but provides quantitative assessment of lung ventilation and lung microstructure. Both of them do not assess perfusion, only ventilation. It's been shown that oxygen-enhanced MRI can detect lower percentage of oxygen alteration peaks in patients with ILD compared to healthy controls, and this has been correlated with pulmonary function tests. Also, it could be a marker of functional loss and disease severity, and could monitor progression. On the other side, Shannon MRI accounts for the different absorption rate of the Shannon between tissue, plasma, and red blood cells, and we could quantify these peaks, tissue plasma peak and red blood cell peak. In IPF, it's been shown that there is a reduced red blood cell peak compared to tissue plasma peak, and this has been correlated with pulmonary function tests, and also, it's sensitive to changes during time. We can modify the acquisition technique and apply 3D ultra-short EEG to hyperpolarized gas MRI in order to shorten the echo time on optimizing lateral noise ratio. Also, we can provide whole lung coverage and reduce cardiac motion sensitivity. In UIP pattern, it has been shown that there's an increased barrier gas ratio and reduced red blood cell ratio here in the periphery and basal of the lungs as a reflection of gas diffusion blockade compared to the homogeneous enhancement in healthy individuals. And we can make another type of acquisition. Most hyperpolarized gas and oxygen MRI rely on multi-nuclear capabilities or on technically complex technique, but on the other side, we can use non-contrast ventilation perfusion imaging without the need of multi-nuclear imaging, without the need of respiratory gating or cardiac triggering, and this technique accounts for changes in the lung density ventilation and perfusion secondary to oscillation of the MR signal. It's based on balanced state of respiratory and echo, and you could see that what we have here is we shorten the echo time in order to increase the temporal resolution, but also we do shorten the repetition time in order to decrease filson homogeneities. After the acquisition of this dynamic technique in free breathing without cardiac triggering, we can separate the respiratory and perfusion components of this signal, and after the application of non-region registration methods, we can obtain ventilation and perfusion-weighted imaging that we could do assess not only qualitatively, but also quantitatively. The first described technique using this approach was Fourier decomposition that relies on 2D balanced state-state preposition images with three images per second of temporal resolution. There's been another evolution of this technique, that is peripheral MRI, that what do accounts for, they fix the face component signal change, so we can increase more the temporal resolution, we can apply 3D spoiler and echo for full chest coverage, and for assessing ventilation and perfusion imaging. There's no reference about the use of this technique in ILD, but there's initial data in COPD, in asthma, in chronic thromboembolic pulmonary hypertension and lung transplantation that it's feasible and reproducible, and also allows us to assess treatment monitoring of those patients. The other scenario I want to discuss here is the value of MRI in lung cancer in patients with interstitial and lung disease. We do know that lung cancer is the second most common malignancy in general population, and is the first cause of cancer-related death in the US. Also we know that lung cancer is a non-complication in ILD, and it's very prevalent in IPF patients, even higher than in general population or in COPD patients. Not only that, also there's a cumulative incidence over the years with associated post-prognosis. There are several features that are very important to keep in mind when we are dealing with patients with lung cancer in ILD, different from general population. First of all, scamosal carcinoma is the most common subtype. Also these patients would have more frequently lung cancer in the periphery and the lower lobes, near or within IPF areas, and the mass or no may compress the honeycombic areas. So there are different scenarios where MRI could be very, very useful. First of all, we need to differentiate lung cancer from UIP areas in order to avoid the underestimation of the tumor size. We do need also early diagnosis, because if we have a patient with ILD and lung cancer, usually has associated functional impairment and worse prognosis. Also those patients have higher risk of percutaneous thoracic needle biopsy. So we need a good imaging modality that help us to characterize those lesions noninvasively. And also we know that there's a higher prevalence of reactive lymph nodes in patients with ILD, that is known, a well-known false positive from PET-CT. Among the different functional techniques that has been shown in MRI and has been applied in lung cancer, the first of them is diffusion-weighted imaging. Diffusion-weighted imaging analyzes the Brownian motion of water molecules inside biological tissues, reflecting tissue cellularity and architecture. And this cannot only be applied qualitatively, but also we could analyze the signal decay over time and differentiate patients and obtain a quantitative marker that is the apparent deficient coefficient. Therefore, patients with lesions with high signal decay over time will have higher IDC in absence of restriction. Also we could analyze perfusion-weighted imaging by the tracking of contrast over time using 3D T1 grain ecosequences. And we can analyze it not only qualitatively, but also quantitatively by the obtention of time-intensity curves. And depending on the time-intensity curves, we could differentiate and characterize lesions. Therefore, malignant tissues, we're going to have typically very steep slope with or without washout, whereas benign lesions are going to have or known or minimal enhancement or progressive low steep enhancement. In the calculation of pulmonary nodules, we do know that MRI is better than PET-CT for differentiating benign than malignant pulmonary nodules by the combination of diffusion-weighted imaging and perfusion-weighted imaging. And this is how we do apply it. This is a patient that has restrictive behavior on the pulmonary nodules, hyper-intense on high B-value, hyper-intense on ADC map indication restriction, and therefore, tumoral origin. And also we could see here that as a time-intensity curve with steep enhancement and plateau indicating malignancy. And we also know that in diffusion-weighted imaging, the higher the signal intensity at the most of the regenerative is, it's associated with worse prognosis and it's correlated not only with the ADC value, but also with the standard object value. And in lung cancer staining, it's very useful as well because we could differentiate central lung neoplasm from peripheral post-restrictive pneumonitis. And this is due to the non-restrictive behavior of peripheral post-restrictive pneumonitis with higher diffusion values compared to central neoplasms. And this could also be applied in patients with ILD. Moreover, we could differentiate active inflammatory lesions from tumoral ones because we know that active inflammatory lesions can have time-intensity curves similar to tumoral ones, but active inflammatory lesions are going to be non-restrictive behavior on diffusion-weighted imaging compared to tumoral ones. It's a consolidation on the right lung that has restrictive behavior, hyper-intense on the ADC map indicating tumoral origin. Moreover, the combination of diffusion-weighted imaging with perfusion imaging help us to differentiate and to characterize invasion of adjacent structure, not only the chest wall, but also the medicinal structure. Another scenario that we have to keep in mind is that although diffusion-weighted imaging may have similar sensitivity to PET-CT for discriminating benign and malignant, if not, it has higher specificity, and this is due to the lower false positives, secondary to discrimination of reactive lymph nodes compared to tumoral lymph nodes. The last scenario I want to discuss with you is the evaluation of pulmonary hypertension related in ILD. We know that it's common in under-recognized condition. This mainly occurs in IPF, but that's been shown to be occurring up to one-third of patients with a non-specific interstitial pneumonia and 44% of chronic HP, and it has prognostic implications with high morbidity and mortality. Also, the mechanisms are not fully understood and has been linked to the destruction of the lung parenchyma, hypoxic pulmonary vasoconstriction, increased pulmonary vascular resistance, or arterial remodeling, and MRI provides a great arsenal for evaluating patients with pulmonary hypertension. We know that cNA imaging MRI is the gold standard for the evaluation of cardiac volume and function, and indeed, we can also evaluate the interventricular septal power in patients with pulmonary hypertension. Moreover, we can go one step further and analyze the regional function with myocardial filter tagging. Moreover, we can discriminate between replacement fibrosis and interstitial fibrosis, which are non-prognostic indicators in patients with pulmonary hypertension, and also we can dive into the pulmonary arterial hemodynamics, obtaining not only quantitative markers for the pulmonary artery itself, but also for the capillary with the pulmonary transient time. And we have to keep in mind that it's important to differentiate patients with adverse remodeling compared to a normal adaptive response. Patients with adverse remodeling in pulmonary hypertension are going to show high right ventricle volumes, low right ventricle mass, and low right ventricle function, and the detection of adverse remodeling and not maladaptive response has been linked to increased major cardiac events. Specifically, in patients with ILD, it's been shown that there is a reduction of the right ventricle end diastolic volume, right ventricle end systolic volume, and right ventricle education fraction, and this has been linked to poor prognosis. We can go do another different approach for evaluation of pulmonary hemodynamics and apply four different techniques. With this, we cannot only assess conventional functional parameters of the pulmonary arterial hemodynamics, but also we can assess several complex parameters like vorticity, elicity, and wall shear stress. Moreover, we can adjust the motion of the cardiac pulse in order to be aware of and precisely quantify pulmonary regurgitation, or we can apply novel techniques like kinetic energy particle tracing in order to have another view of the interventricular cardiac hemodynamic. In pulmonary hypertension, it's been shown that there is a reduce of pulmonary vorticity and elicity in patients with COPD, and this has been linked to poor right ventricular function and increased pulmonary arterial stiffness. Moreover, we can, with kinetic energy and particle tracing, separate the different components of the intracardiac flow into direct flow that enters and exits the same heartbeat, delayed, retained, and residual flow that resides in the left ventricle for at least two cardiac cycles. And this has been shown that in patients with pulmonary hypertension, the amount of right ventricle direct flow in green, it's decreased compared to other subjects, but also the amount of residual volume, it's increased in patients with pulmonary hypertension compared to healthy subjects. This is an example of our own clinic with a patient with pulmonary hypertension secondary to chronic thromboembolic disease, and you could see there's an increased component of the residual volume indicating adverse remodeling. And this pattern of decreased direct flow and increased residual volume has been linked not only to poor ventricular function, but also to poor pulmonary artery hemodynamics. So hopefully in this, I've been able to show you that chest MRI may provide consistent morphological findings, especially with 3D ultrasound, which can be very useful, especially in the follow-up of patients of interstitial lung disease. Although there's only initial data, we could provide significant functional information even without airspace or IV contrast. We could, I want you to keep in mind that chest MRI could be an alternative to PET-CT for lesion characterization and tumoral staging in patients with ILD and lung cancer. And finally, we have to look at the cardiac side and remember that MRI is an important tool for right ventricle analysis for identifying adverse right ventricle remodeling, myocardial fibrosis, and pulmonary artery hemodynamics. Thank you very much. Thank you. All right. Thank you, Jordi. I'm going to have to try and beat those cool images. So again, thank you for attending the session. I'm going to be talking about PET-CT imaging in idiopathic pulmonary fibrosis. And the goal today is I wish to share with you how PET-CT scanning could be used as a non-invasive molecular assessment tool in the diagnosis of idiopathic pulmonary fibrosis and following it over time. So PET-CT scanning or positron emission tomography is a non-invasive and most importantly functional imaging technique for detecting and quantifying radioactivity in vivo. It uses intravenous radio tracers to demonstrate the distribution of radioactivity either within tissues or with organs after allowing for dissemination of that radio tracer. Now radio tracers really consist of two components. The first is a ligand targeting molecule which is specific to either a process or a pathway within the body and it is this ligand targeting that results in a characteristic distribution of the radio tracer within the body. The second is a positron emitting tag or radio isotope tag as shown in red here which is used to track that distribution of the targeting agent within the body. So how does PET scanning work? So it uses positron emitting radio isotopes and these are radio isotopes that undergo beta positive decay which really results in the production of a neutrino and a positron which is the green E positive particle shown in the diagram. When that positron interacts with an electron basically both particles undergo annihilation with the resulting release of energy in the form of gamma rays that can then be picked up by gamma cameras to form an image. Now the problem with PET scan data is it can be reconstructed and displayed in either two or three dimensions. The problem is the physiologic information which is provided by PET scanning which is fantastic, is limited significantly by the poor spatial resolution as you can see in this figure over here. So in order to improve the results PET imaging is often combined with CT imaging as you can see in these two figures over here allowing for a correlation of the functional PET data with the anatomical CT data to help us understand the results significantly better. Now most of us are familiar with PET CT imaging in patients with cancer where it's used for staging. This uses a radio tracer that is known as 18 fluorodeoxyglucose and this is actually a radio tracer without a specific ligand targeting component. Here it's a carrier free 18F labeled glucose analog which will localize in tissues with altered glucose metabolism. So in fact it is very nonspecific in nature, the opposite of what we're kind of looking for because it's going to result in accumulation of the radiation in any tissue with high glucose utilization which for cancer is kind of useful if you're looking for meds but it may not be useful for other purposes. Now the accumulation of the radio tracer is measured in what are known as standardized uptake values or SUV and the benefit of using this is that it removes the variability introduced by patients of different sizes, in other words different heights, different weights, different body mass index and the amount of injected radio tracer. So different amounts of radio tracer in different patients. So the idea is to standardize the readings between different patients getting different doses of medicine. Now I am not a radiologist, I'm a pulmonologist. My primary area of interest is interstitial lung disease and in particular one of the conditions we see most frequently is idiopathic pulmonary fibrosis. Now as most of you in the audience will know it's a devastating lung disease. It has a median survival of around two and a half to three years and a five year survival of as low as 20%. There are only two currently FDA approved drugs, nantenonib and profenadone and they have a limited impact on both disease progression and patient survival. Now there is currently no good way to predict individual patient responses to specific therapy nor to monitor the molecular or cellular response to treatment. Although clinically we use both high resolution CT and pulmonary function testing, these tests are both indirect measures of disease outcome. And so developing a non-invasive technique that can actively address these challenges can both improve patient care as well as drug development. Now at Wash U I'm fortunate to work with a number of people, specifically Steve Brody who have an interest in CCL2 and CCR2 signaling. So CCL2 is a monomeric cytokine belonging to the CC motif chemokine family. And this chemokine family are also known as beta chemokines. And the reason they're named this way is they have adjacent cysteine amino acids near their amino terminus, hence the CC designation. There've been at least 27 of these described in mammals, but the one that we follow at Wash U is the CCL2. Now this is a very potent chemokine for monocytes and was actually first described as a protein called monocyte chemotactin protein 1. CCL2 binds with very high affinity to the CC chemokine receptor type 2, which is very creatively named CCR2. And this CCL, CCR2 signaling is best known for its role in regulating monocyte recruitment and polarization during the inflammation produced by any kind of tissue injury. Now this CC motif chemokine family has been extensively studied in models of pulmonary fibrosis. So what we do know is that elevated levels of CCL2 are found in the BAL and serum of patients with idiopathic pulmonary fibrosis. And these elevated CCL2 levels direct the egress of CCR2 positive monocytes from the bone marrow into the serum to be targeted to the injured fibrosing lung. Once they get into the lung, they undergo differentiation to become monocyte derived alveolar macrophages. And it is these macrophages that recruit the pro-fibrotic cells in lung fibrosis, which are known as fibrocytes. And these are the cells that produce the abundant collagen resulting in a fibrotic lung. In addition, we know that CCR2 knockout mice have markedly attenuated lung fibrosis in a number of different pro-fibrotic animal models. So the picture from the paper here by Murat El shows intratracheal installation of bleomycin in mice that are either wild type or deficient in CCR2. And you can see that they're followed out to days 14 and 21. And the knockout mice show significantly reduced fibrosis, both by trichrome staining, as you can see here, is reduced compared to the wild type. And also by looking at hydroxyproline measurements, which are a measure of collagen deposition within the lung. So based on all this information, we wanted to look and see if PET would be a viable method of looking at IPF. And fortunately, a number of members of our group at Washington University were involved in the development of a peptide-based radio tracer, which I've shown here. It's the same one we showed before. And this recognizes the first extracellular loop, otherwise known as ECL1 or extracellular loop 1, of CCR2 and allows for quantification of CCR2 positive inflammatory cell burden using PET scanning. And because of this, we hypothesized that this radio tracer, known as 64CU, which is copper DOTA-ECL1, which I'll refer to as ECL1, could detect an increase in CCR2 response associated with idiopathic pulmonary fibrosis. And this could potentially be used to monitor disease activity. So the first thing we did was we wanted to see if these CCR2 positive cells, these alveolar macrophages, localized to perifibrotic regions in bleomycin-induced lung injury. And so what we did was we took CCR2 positive GFP knock-in mice. So these are mice that express GFP wherever there's CCR2 and allow us to stain the GFP to localize the CCR2. They were given intranasal bleomycin, and we were able to track the CCR2 cells during fibrosis on days 14 through 28. And as you can see in figure A over here and figure B, we were able to show a dramatic increase in the number of CCR2 positive cells in the lungs at day 14 and day 28. And here are the counts shown over here. Although by day 28, the counts had decreased, however, they were still statistically significantly greater than those at day zero. What we've shown in figure C is we were able to track the CCR2 cell numbers and map them with fibrosis as quantified by modified Ashcroft scoring. So in other words, over here we have an Ashcroft score of zero, indicating no fibrosis, and a score there of seven, indicating high fibrosis. And what we were able to show was that CCR2 counts were exceptionally low in areas of normal lung, as shown by a score of zero, and increased significantly on both days 14 and 28 in areas of high fibrosis with the highest Ashcroft scores. In addition, we were able to show that the cells, CCR2 cells, were abundant in the regions surrounding the remodeled fibrotic parenchyma, which is supportive of a role for CCR2 cells in the pro-fibrotic lung niche. We then wanted to examine the application of the ECL1 radio tracer PET in the bleomycin model. And as shown again in figure A over here and figure D, the uptake of the radio tracer at day two was not significantly different from day zero. But by day 14, the uptake of the radio tracer was remarkably increased, and this persisted until day 28, although again, there was a slight decrease in the signal compared to day 14. What we were also able to show, if you look at figure B over here, was that the molecular specificity of the ECL1 radio tracer for detection of CCR2 was very good, and this was demonstrated by the lack of signal when compared to day 14 in CCR2 knockout mice. So in other words, if you had no CCR2, you got no signal. In addition, the specificity of the radio tracer was confirmed by decreased uptake in mice that were injected with non-radioactive ECL1, which then acted as a competitive blocking agent for the radioactive ECL1. So you can see the signal here, looks very similar to the signal at day zero, and this was confirmed when we were doing counts. So we know that perfenadone treatment results in a reduction in fibrosis in a number of animal models of fibrosis, including that induced by bleomycin, radiation, and graft versus host models of lung fibrosis. So to study the effects of perfenadone, mice were given intranasal bleomycin at day zero, and then from day 10 were separated into two groups, one that was fed regular chow, and the other that was fed chow that was laced with perfenadone, and the data were followed out to day 28. As you can see in these trichrome stained sections over here in figure I, there was a significant reduction in the amount of fibrosis in the perfenadone-treated mice when compared to those that were not treated. And again, this was confirmed by Ashcroft scoring, where the Ashcroft score went down significantly in the mice treated with perfenadone compared to those that weren't. A nice effect that we also noticed was that there was a significant reduction in the counts of CCR2 positivity in the mice that got the perfenadone along with the chow. We then looked at whether we could study the treatment effect of perfenadone on pet uptake in these bleomycin-treated mice, and what we can see in both the pet images as well as the SUV uptake was that there was a decrease in ECL1 radiotracer pet signal both visually and when confirmed by actual counts. And these observations indicate that the radiotracer is able to quantify changes in CCR2 cells associated with treatment, and suggests that there may be potential for monitoring therapeutic response in actual patients with idiopathic pulmonary fibrosis. So next we wanted to determine whether the ECL1 radiotracer will actually recognize CCR2 in human fibrotic lung tissue. And so what we did was we took explants from patients being transplanted for idiopathic pulmonary fibrosis, and we did serial sections with trichrome staining, immunostaining for CCR2, and then we also did, excuse me, autoradiography with the radiotracer to look for uptake. And what we were able to find is that when we overlaid images as shown by these boxes here, that the zones of high and low activity of CCR2 staining correlated very high with the zones of high and low tracer signal, indicating that CCR2 cells are able to be detected ex vivo by the tracer in human tissue. Once again, we were able to demonstrate the radiotracer specificity shown by loss of activity in the tissues that were pre-stained with non-radioactive ECL1, again, resulting in competitive binding. So then we wanted to see if we could actually take this into real human subjects. And so we were able to recruit six healthy volunteers, three men and three women, all of whom had normal lung function, and they received intravenous ECL1 radiotracer and then underwent serial PET CT scans over a period of 42 hours. And what we were able to show by dosimetry analysis is that there was trivial uptake in the lungs, but dramatic uptake in the liver, kidneys, and the bladder. No clinical adverse effects were identified in any of the patients given the radiotracer. So the last step we took was to evaluate whether the ECL1 radiotracer uptake would be beneficial in four patients with idiopathic pulmonary fibrosis. And as you can see in figure A, which are sagittal sections, and figure B, which are posterior coronal sections. So those are sections taken posterior to the middle of the chest in a coronal projection. We were able to show that the radiotracer uptake was significantly increased in patients with idiopathic pulmonary fibrosis when compared to a healthy control. And you can see that that increase was predominantly subplural, but there was a fair amount of variation between the patients with idiopathic pulmonary fibrosis. The next step that we did was we looked at lung uptake determined by the maximal SUV in order to compare values from the fibrotic sections of the lung shown in orange and the non-fibrotic sections of the lung shown in yellow in order to see if we could actually discriminate between fibrotic areas and non-fibrotic areas. And after correlation for tissue density, the maximal SUV in the fibrotic regions was approximately four to six times higher than that in the non-fibrotic regions and similar higher than those in the healthier controls, showing us that we have the power to discriminate between fibrotic and non-fibrotic lesions even within patients with idiopathic pulmonary fibrosis. So where do things stand right now? So at this point, we believe that we've shown a temporal and spatial relationship between CCR2 positive monocyte macrophages and fibrotic lung regions in both preclinical fibrotic models and fibrotic human tissue. We've verified the feasibility of non-invasive PET imaging to quantify CCR2 cells in the same preclinical models. We've confirmed the safety of quantifying CCR2 cells in IPF patients using this COPPA64 DOTA ECL1 PET tracer. And we demonstrated the sensitivity of the technique to detect a difference between areas of fibrosis and non-fibrotic lung within the same lung in patients with IPF. So at this point, our conclusions are that we're encouraged that subsets of patients with fibrotic lung disease could be identified as those who might benefit from perfenidone therapy, and that the responses to therapy could be monitored and tracked over time, although it's very, very early days and significant further validation would be required at this point in time. So with that, I'd like to thank the vast amount of people who are involved in this project, most specifically Steve Brody, but also to Corey Levine, who's one of our colleagues in cardiology, who's really the expert on the CCR2 probe. And with that, I'd like to thank you, and we'll open the floor to any questions. Yes, ma'am. Hi. Gloria Wesney, Morehouse School of Medicine. So I deal pretty much on the clinical level, trying to identify interstitial lung disease as early as possible. And so one of my concerns is with IPF. I mean, we still don't know why it is what, a heterogeneous presentation. Would this help us get to that answer, and would that be helpful? The short answer is I'm not sure if PET scanning would be the answer. As I mentioned earlier, it has exceptionally poor spatial resolution. And so I think, if anything, heterogeneity might be an enemy to this technique in terms of detecting it early. Now, with a photon-counting CT may be beneficial. I'll let Dr. Koh speak to that. But we can certainly, with photon counting, detect diseases earlier and with much improved spatial resolution that we can with PET CT. Or I can give you this one. Yes. I think with the CT technology in general, not just photon counting, but it's very promising with photon counting that you can get such fine detail. We actually pick up a lot of subclinical disease. So it's kind of hard to know whether what we're seeing is subclinical disease. That's how we started discovering these interstitial lung abnormalities that actually have been shown to increase in about half the patients. So I think there's promise. And I think with photon counting, even more to pick up something early, particularly if there's intervention that's developed, I think, from our medical colleagues to actually treat the disease early. So I think it goes hand-in-hand, and it's very exciting. Any other questions? All right. Thank you all for attending. Thank you.

innovative imaging techniques

intermediate lung disease

ILD

traditional imaging modalities

alternative technologies in radiology

photon counting CT

chest MRI

ventilation imaging

PET-CT

idiopathic pulmonary fibrosis

Idiopathic Lung Disease