Joe O'Sullivan: Thanks. Okay, welcome back everybody. This is the final hurdle. Final stretch. We've got a fantastic lineup. We've kept some of our best speakers util last, so I hope you're going to enjoy this. First of all, I think one of the best known, one of our most favorite nuc meds, the President of the EANM Congress, Stefano Fanti, man of many talents is going to tell us about how to interpret and confirm lesions positive on PSMA PET, but no-correlation CT. Stefano, over to you.

Stefano Fanti: Well, good morning everybody. Thanks for the fantastic presentation. It's truly a honor to be here in this incredible event. I'm sincerely thankful to Silke and Aurelius, not only for inviting me, but for arranging, organizing, creating this event, which is, to every extent, the event on prostate cancer. So we sincerely thank you for that. Having said that, these are my disclosure. I'm sorry, this will not be a lecture, this will be a rush. Very sorry about that. Let's start. Disclosure. The main disclosure is that I'm proudly a nuclear medicine physician, so get ready for a presentation strongly biased by the fact that I'm a nuclear medicine physician.

When I read the title, well I was a little bit puzzled. Essentially, I recognized my ignorance, and that's led me to a good point, because by a classical philosophical point of view is the first step to wisdom. But then I ask some help to my wife because she is a philosophy of science and we'll come back on that. Now, this is a structure on my letter starting from how to interpret PSMA imaging and how to confirm the findings, and then moving to a philosophical question, why confirming those findings, and finally, some suggestion about what to do in clinical practice.

First, how to interpret. This is very simple to address. There are guidelines. We have procedure guidelines, but we also have guidelines for reporting with the fine nation of the score. So just use them, adhere to them, and you can do properly your job. Don't forget every imaging matters. There's limitation. Don't expect 100% accuracy of any practice in medicine, you always have this in mind. So, wrong and mistakes are always around the corner.

Now, how to confirm your findings. Well, clearly correlative imaging, and we know. We have a number of alternative imaging from x-rays, CT, MRI, and in some cases, ultrasound as well. When you are going to use them, well, it depends on the site and type of findings. So if it's about the axial skeleton, MRI is fantastic. In some cases you may use CT, for example, lymph node. You may also use ultrasound. So for example, enlarged lymph node in this gentleman, one is clearly positive at CT, so you have already a confirmation. In some few cases, you can also use ultrasound. That's a very strange case of splenic hemangioma confirmed by ultrasound in a patient with a prostate cancer.

But, in some cases, correlative image will not have any help, will be useless. So how can you do in those cases? In few cases, it's about the nature of what you see. So you need to put a needle, you need to perform a biopsy, like in this, again, unusual case of a patient with a lymphoma as well as a prostate cancer.

But what you do if you have a patient like this gentleman with three hotspots and negative CT counterpart? Well, you cannot pretend to put a needle at every lesion. It's not feasible at all. It's not practical. And, of course, in this gentleman for example, you just have evolution. It was treated, it was not a responder. And now you can see a number of lesions and a CT counterpart. But, of course, it does not make sense at all to wait. You may pretend, okay, this gentleman has three lesion, so the likelihood that they are true positive is very high. But what do you do if you have a patient with one hotspot only and you cannot put a needle there, which is the confirmation that you could claim for in such situation.

So, it comes to the philosophical point. Why do we want to confirm something? By the philosophical point of view, confirmation is very simple. It means, if you conclude something, let's say A, on the basis of good evidence, you cannot use B, obtained with less good evidence, to confirm. A very simple example. Nobody during COVID time would consider to use an antigenic test to confirm a molecular test. It's all about rank of evidence. And everybody agreed here that PSMA PET as the higher accuracy and detection rate. That's, for example, in BCR with low PSA values. But that's the same in many other settings. So if you have a rank of evidence, stay with the most accurate method.

Now, is everybody convinced in this room? Honestly, I don't think so. I have to admit, and the problem is, there's an elephant in this room, we have to admit it, and it's called false positive. I clearly avoided to mention so far, everybody knows, PSMA PET, like any other imaging method, suffers from false positive findings and it's independent of the tracer. And that's the case. Staging high-risk patients. You see faint uptake in one rib. How do you consider that patient? Is that suitable for radical treatment or is that already metastasized? Now, in some cases with biomarker, what you do is move the threshold so you can reduce the false positive and you pay a price increasing the false negative. But you cannot do that with PSMA PET. It's not a biomarker, it's not a number, but you can do something. And it's our dues as nuclear medicine physician to do that. Choose the best tracer and learn how to report. So increase your expertise.

PSMA tracer is a basket concept. We have several tracers, different tracers with different characteristics and we should know that. Some papers have taken into account that. So for example, what is known is that fluorinated PSMA-1007 has none specific uptake in the bone marrow. This is very important, because, as clearly stated here, if you're searching for distant metastasis, it could be dangerous to have physiological uptake in the bone. It could lead to a very high number of false positives. The comparison directly between 1007 and PSMA-11 led to those findings. The number of lesions that could be attributed to recurrent prostate cancer is almost the same, but the number of lesions attributed to benign origin, thus potential cause of false positive, are five times higher with 1007. That's very important to take into account.

And then expertise. Learning curves. We have to be humble as nuclear medicine physicians, we have to learn, we have to study, we have to review our criteria. It's important, for example, this is a case from our activity. You see BCR and you see, clearly, two hotspots. Lymph nodes, clearly positive, but you see faint uptake in the rib. Would you call that as positive? No. With expertise, you would not call that as positive. You would call that as physiological uptake. No CT counterpart, no need for any further study. And that's independent of the tracer. You can see that with gallium 11, you can see that with any fluorinated tracer.

Another example, staging hierarchies. You see the primary, you see several lymph nodes, and again, you see some faint uptake in a rib. And again, you have expertise. Don't call that as positive. There is no CT counterpart. There is no need to confirmation, it's just about learning A curve. if you follow up the patient, you see it's completely disappearing over time. So it was not a false positive. It was good to not report that as positive.

Does it mean that every hotspot in the rib has to be regarded as negative? Not at all. Not at all. This is an example of a clearly positive rib lesion, no counterpart in the CT, and the patient was treated accordingly to that. And over time, it has a good response. Unfortunately, it relapsed, and now you can see that there is this sclerotic lesion in the CT and there are different sites of recurrence because it has been treated for that.

Now, let's come to some conclusion after this rush. There's no doubt PSMA PET has been a game changer. I was here 5 years ago and it was the panda of the situation. We were barely talking about PSMA PET, and now a lot of discussion is going. It's one of the very hot topics. Everybody is stating the train has left the station, and I guess it's quite clear, but I guess there are further comments to be done. It's been due to the hard work of many people, and they have to acknowledge, for example, the Germans and the Australians that did a lot to beat the literature on that. At the same time, we still have some guys which are apparently not happy. Well, you still have time to join us. Don't wave the train. The most important point is, the driver, it's not me. For example, the choline train never left the station because the ultimate decider is the clinician, so it's you. So don't be scared. Join us, Pete.

Final conclusion. With great power comes great responsibility, and that's a message for the nuclear medicine community. So what we should do is searching for a confirmation, if possible. Don't pretend to see something in any PSMA finding, otherwise it wouldn't be the most accurate. Don't pretend to put a needle, it's not feasible. Discuss at MDT. That's incredibly important, because the contribution of the clinicians will clarify most doubt that you have. And never forget to use the best tracer and to increase your expertise as much as possible. With that, I thank you for your attention and for the philosophical discussion.