Melanie Cole, MS (Host): Welcome to the podcast series from the Specialists at Penn Medicine. I'm Melanie Cole. And we have a thought leader round table panel for you today with three Penn Medicine experts to highlight the Center for Precision Surgery's 10-year anniversary. Joining me in this panel is Dr. Sunil Singhal, he's the Executive Director of the Center for Precision Surgery and the Chief of Thoracic Surgery at Penn Medicine; Dr. Jim Delikatny, he's a Research Professor in the Department of Radiology and the Director of Translational Research for the Center for Precision Surgery; and Dr. Janos Tanyi; he's a gynecologic oncologist and Associate Professor of Obstetrics and Gynecology in the Department of Obstetrics and Gynecology and Division of Gynecologic Oncology.

Doctors, thank you so much for joining us today. And Dr. Singhal, I'd like to start with you. Can you give us a little background on the Center for Precision Surgery, its mission. How would you summarize the center's accomplishments in the decades since its founding?

Dr. Sunil Singhal: Great. Thank you, Melanie, on behalf of all of the physicians on the line. We want to thank you for this opportunity to talk to you a little bit about our Center for Precision Surgery. I'll trace back a little bit about the history. So over a decade ago, Dr. Delikatny, Dr. Tanyi, and, our other comrade in action who couldn't make it today, Dr. John Lee, in neurosurgery, started talking about the problems that exist in cancer surgery.

Specifically, when people undergo cancer surgery, there are some major problems that can occur in the operating room. The first is the surgeon can accidentally cut through the cancer and have what we call a positive margin or leave cancer behind after they've left the operating room.

The other problem is that frequently when doctors are trying to remove cancer throughout the abdomen, there's many different locations it can be, and a surgeon can miss some of these locations, and these locations will then come back. So, the four of us were talking about ways to do this operation better, and we identified a possibility to inject patients with contrast agents that basically fluoresce or glow. So, we give the contrast agent before surgery, they go to the tumors and they make the tumors fluoresce or glow so that when the surgeon is doing the operation, they can be sure that they get the entire cancer out and they find anything that might be missing.

Now, this idea that started as a simple conversation amongst a group of us turned into a small little group of four and five, and then eventually now 110 members into the Center for Precision Surgery. And we do exactly that. We've done 16 clinical trials over 10 years. We've developed a cadre of fluorescent contrast agents that can be injected into patients. When we started, Dr. Tanyi led the charge for ovarian, but we've gone to lung cancer, Dr. Delikatny has done work in sarcomas. We also now have Dr. John Lee in neurosurgery who's doing work on brain tumors. And this simple idea has now gone all the way through clinical trials that is FDA-approved and is being used around the country.

Our group led the charge on this. We're now the largest group in the country that performs this type of surgery and have been able to really make an impact on patients' lives. We have numerous patients who have left the operating room with margins that would've been missed by traditional surgery. We've also developed ways to identify additional metastases that would've been missed.

And in collaboration with the Abramson Cancer Center here at the University of Pennsylvania, we feel we've really moved the dial on the way we deliver cancer surgery in the United States. So with that, it'd be good to hear the opinion of Dr. Delikatny and Dr. Tanyi as well on some of the new advances that have really come up in the last 10 years.

Dr. Jim Delikatny: That was a great introduction, Sunil. And one thing I'd really like to add is the truly collaborative nature of what Sunil and the others have established in this Center. And it really is a multifactorial, multidisciplinary Center where we have participation from departments of surgery, departments of chemistry, radiology, bioengineering, bringing in scientists from multiple disciplines to tackle this really multifaceted problem that includes camera design, that includes contrast agent design, that includes modifying surgical methods. So, it really has been a great intellectual coming together of, as Sunil said, 110 different people. And I just wanted to emphasize the collaborative nature of what we do.

Dr. Janos Tanyi: So, I remember back in 2013, 2014 when we started to work with Sunil. We operated next to each other in neighboring ORs, and I visualized directly how he does these surgeries, these lung surgeries when he tried to reach clean edges and one or two extra lesions. We were able to use this because my cytoreductive surgeries want to remove as much disease as possible because in ovarian cancer we had hundreds of lesions inside of the abdomen. And there are certain points of the abdomen, which is not easy to visualize, not easy to palpate.

So, I definitely, as a surgeon, needed a new tool to augment this visual inspection and manual palpation to identify further disease so I can really do a debulking cytoreductive surgery, and started to organize the first phase II trial between 2014 and '17.

So as the work went ahead, we just get more and more collaborative partner. And although we are in different fields, we discuss different steps of these imaging technologies and how can we make it better because Dr. Singhal's aim is different than mine, but we can use the same agent and the same technology very beneficially.

Dr. Sunil Singhal: Yeah. Just to echo, Melanie, many people don't realize this, but Dr. Tanyi's being modest. He had the first FDA-approved molecule in the United States. He led that, he was a principal investigator for the phase II and phase III. That is now being used around the country for women who have ovarian cancer to identify additional lesions. And this was truly a groundbreaking accomplishment.

Dr. Janos Tanyi: It's good news that I can announce that we are starting a pilot study using this FDA-approved ovarian cancer imaging agent in endometrial carcinoma. And this study starts in January of 2026. So, we will start to enroll the first patient  this month and the next month. And this will be very exciting if we found similar efficacy in endometrial cancer than what we have found in ovarian cancer.

Host: Dr Tanyi, as long as we’re talking about Cytalux, the product you developed, why don’t you tell us about its journey to that FDA approval and its principal advantages in surgery, because this is a game changer.

Dr. Janos Tanyi: Yes, it is indeed a game-changer. It was very interesting that when I saw the application of code OTF-38 or Cytalux the first-time, I was amazed at how clear edges, how beautiful, tumor background ratio with intraoperative molecular imaging we see. And I started to apply this agent first in the phase II trial in 2014. And I was surprised that when I believed that the surgery is completed and absolutely done and I'm imaging the patient again, I was able to identify more and more lesions. And as I developed using this technology, I got better to find other diseases in hidden locations  or retroperitoneal arm. And at the end of the phase II trial, we were very, very excited. Five centers enrolled, multiple patients, and the results was excellent. In 2017, we presented these results under SGO National Conference. And very quickly after, we tried to work on the phase III trial. Because although we found in the phase II trial, 49% of the patients had additional disease, but that was sometimes on tissue, which was originally planned for removal. So, we wanted to make it more sensitive, more specific. And in the phase III trial, we designed that we want to find the efficacy, want to find disease on tissue originally not planned for removal. And when the phase III trial started in 11 different tertiary care centers, 10 in the United States and one in Europe, so that was international, not just national as a phase II trial, as the trial proceeded, we were able to enroll 178 patients. And from this 178 patients, 150 patients received the agent, so built up the safety analysis set; and 109 patients had ovarian cancer, which was the efficacy analysis set.

And when we evaluated the data, surprisingly, we were able to identify that 33% of the patients had additional disease on tissue originally not planned for removal. That was very exciting. And also, we found that the tissue, which was identified but was not suitable for removal, was significantly lower when the cancerous tissue was identified with the imaging than was identified with manual palpation and visual inspection because the imaging had to delineate clearly the lesion's edges and this helped the surgeon to perform the excision of the particular lesions.

So, the phase III trial ended around 2020-2021, and we presented the results at ASCO, and it was very, very exciting. And later, we presented further evaluation and data at SGO in 2014. So, we are planning to go to other gynecological oncologic diseases. As I mentioned to you, we started a pilot study in endometrial cancer, but this particular agent has lots of future target applications.

Host: So, further indications as you would see in the future, what are you hoping to happen, Dr. Tanyi?

Dr. Janos Tanyi: Number one is endometrial cancer. Also, I believe that folate receptors are often overexpressed in many metabolically active diseases, colorectal cancers, which is out of my field. But for example, uterine sarcomas or cervical cancer also can be a good target of this particular agent.

Host: Wow, that's very exciting. And Dr. Singhal, in 2010, around the time you started publishing on intraoperative molecular Imaging, or IMI, PubMed recorded around 140 articles on the topic. Last year, there were 867. Do you have thoughts on this dramatic increase and the interest in this field?

Dr. Sunil Singhal: Yes. I mean, I think that there's two sides to this. You actually heard a very impressive journey from conception to FDA approval with Dr. Tanyi for ovarian. But it's also gone on to other cancer types such as lung cancer, brain cancer, et cetera. But I think that the other part is that there have been many other tracers developed more than just Cytalux.

And actually, that's where Dr. Delikatny comes in. I mean, he has spent most of his career developing new tracers for new indications. And that's where the real exciting future of the Center for Precision Surgery lies, in the translational research that's going on. Maybe he can fill us in a little bit on the most exciting achievements in the research world.

Dr. Jim Delikatny: Thanks, Sunil. And, yes, that's what I do. I mean, I was originally a chemist by training. And so, I still think in terms of molecules and I think of how molecules interact with targets and how these targets can be overexpressed in cancer and how we can make those molecules fluorescent so that we can look at them.

Starting in cells, starting even with the basic proteins, and then moving up into mice and then into large animal models, we conduct veterinary clinical trials in conjunction with Dr. David Holt in the veterinary school. And then, finally, translation into the clinic. Dr. Tanyi elegantly expressed the various cancers that we think overexpress folate receptor. But as we know, there are hundreds of other targets in cancers that we can go after, and some are going to be more expressed in certain cancers than others. And as I think we'll touch on later, it's also the concept that we could use multiple dyes to target multiple targets within one single cancer.

So, we've been looking for, when I first met Dr. Singhal, I guess getting close to 15 years ago, I was introduced to him as, "This is somebody you really should meet." And I was at that point a dye developer looking for various targets. All I wanted to do at that point in my life was make a mouse light up. And as soon as I started talking to Sunil, I realized that there was a potential here for real clinical medicine that we had not previously realized. So, the targets that we've been interested, my basic research for a number of years has been in lipid metabolism. So, a lot of my targets are based on aberrations in lipid metabolism. One of them is choline kinase. Choline kinase is an enzyme that cells used to make membranes. And so, every cancer cell needs to make membranes in order to divide. So, it's a multi-cancer target.

Another one is in signaling phospholipases. Phospholipases make signaling molecules that regulate growth. And we've developed probes to investigate that as well. And so, we work on a model that we've developed over the last decade where we start with our basic targets and then move into mice. Our choline kinase target molecule has been in veterinary clinical trials for the last three or four years. We've currently run I think 35 dogs and these are not experimental dogs. These are real people's pets. They're real patients that come to the veterinary school. And so, it gives us the opportunity to test out the technology, test out the dyes, work out camera issues and things like that with the very expert help of David Holt and others in the veterinary school. This has led to a number of grants. Sunil and I have written a number of grants together. And we just got one funded last August to take this choline kinase targeted dye into a phase 1 human clinical trial.

So, this is really exciting for us because this is now a homegrown Penn dye that we can move into a clinical trial. We hope that we'll have Penn cancer usefulness. We've tested it in biopsies of lung cancer, of brain cancer, of ovarian cancer, and it lights all of those up quite nicely. And so, we're quite excited about that.

Our second set of dyes are the phospholipase dyes and they're scheduled to go into a veterinary clinical trial. We just did a major mouse experiment this week showing how formulation can affect targeting. And so, we're preparing to get that one ready for veterinary clinical trials.

The other really exciting thing we've been developing is to move our dyes from the near-infrared into what they call the near infrared II or shortwave infrared, which is farther red-shifted. And in that wavelength range, very exciting things happen. All of the scattering that we normally see in tissues, all the things that make our images blurry disappear. So in those longer wavelengths, we can image tissue deeper. We can image tissue with higher resolution. And we can image tissue with less background. And so, we have a program now, developing these long wavelength, short-wave infrared dyes. And again, Sunil and I are putting together a grant application to further study these. And I think that's going to be one of the next big changes in the field, as the dyes develop and as the camera technology develops and we're going for deeper, brighter, and sharper images.

Dr. Sunil Singhal: Yeah. I'll just follow up on one more point that Dr. Delikatny said that I think just needs to be emphasized. You were talking about the future. Dr. Tanyi, for example, has been down in the weeds, trying to cure women with ovarian cancer. And he is really focused on that, and that moved on to endometrial cancer. I think what makes Dr. Delikatny's research different is that he's looking for the holy grail tracer.

The tracers that exist right now tend to be only good for one cancer type at a time, maybe two or three. Dr. Delikatny's trying to develop a universal tracer, something that can be used for every person in the world who has cancer. And so, I want to just make sure the audience understands the critical nature of what he's doing.

Host: Thank you all for that, and I'd love to give you each a chance for some final thoughts here. And Dr. Delikatny, as long as we were on this topic of your dyes and IMI as complex and evolving, I’d like you to speak a little bit about the complexity that it presents to users and the ongoing work to improve that efficacy and usefulness and what the future holds. What would you like to see the future hold as a research scientist?

Dr. Jim Delikatny: So, we're at a point of time where this is a field of great growing interest. But it's a very complex field. Every cancer, as our surgeons will tell us, is completely different, and many of them need different methodologies. They need different camera technologies, possibly. They can be surface cameras or laparoscopic cameras as it may be. And then, you have this multiple dye problem where you've got multiple different targets that are overexpressed in different cancers.

So, ideally we would like to develop a system where we can uniformly calibrate cameras to be used with different tumor types and, as Dr. Singhal said, come up with some form of universal markers that we can use to target multiple cancers at once. And I think that's where the holy grail is going.

And one of the opportunities that I've had as a scientist is to work with people like Dr. Tanyi and see how these exciting things get applied in real life. But then, I've also had the opportunity to work with industry, with camera manufacturers, with other dye developers and really see the field grow. At one point, I know we had up to six different cameras in the operating theater that we could use for various indications, and we're trying to one day bring that down to one or two that will do it all for us.

Dr. Janos Tanyi: In GYN Oncology, the surgical technology and the arsenal of chemotherapy and biologic agents are very drastically changing. And we are right now doing far more minimally invasive surgeries than like 10 or 15 years ago. And we are hunting much smaller cancers with more hidden location, retroperitoneal location. So, we definitely need new dyes with deeper penetration, easier identification. And also, we will possibly introduce this technology for very early lesions, like a screening technology in very early cancer, which is very minimal and possibly will not be seen with a PET CT, but possibly can be seen with some minimally invasive approach, hysteroscopy or a laparoscopy, using special cameras and the special dye. So, that will be the future. And this is what we want to reach in GYN oncology.

Host: The work you're all doing is so exciting. And this has really been such an enlightening discussion. Dr. Singhal, I'm going to give you the last word here. The Precision Surgery Center has been the source of several FDA approvals for intraoperative molecular imaging. Tell us about some of those, how they came about, And what you envision as your vision, your goals for the Center in the next 10 years.

Dr. Sunil Singhal: Sure. Thank you. I think the group has pretty well summarized where we're at. We have developed a library of contrast agents that can be injected into a patient that go to their tumors to make them fluoresce. We have developed cameras that are seeing deeper and deeper into organs and allowing us to find smaller quantities of disease that are being missed by CAT scans and PET scans and all the conventional technologies that exist. And I think, as Dr. Tanyi kind of alluded to, we're developing new indications, new directions to do clinical trials. So, that's where we are at this moment. As you peer forward to the next 10 years, which is very hard to do. It's hard to see even two years out.

We do need to work on universal tracers so we don't have to develop a different tracer for every different cancer type. Second, this concept of seeing deeper and deeper in organs, it's going to become more and more important. Because right now, the current generation of tracers can only see one or two centimeters deep into an organ. And the new generation should be able to double or triple that distance. Third, the cameras are going to get better and better. We're going to get more precise readings. And a number of us are now starting to develop artificial intelligence methods that can inform the surgeon if the surgeon's about to miss something, almost like a little warning signal that the surgeon's about to close the patient up and there's something left behind.

And I think, fourth, what still needs to be appreciated is we take it for granted here at Penn that we're at the cutting-edge technology. And we provide the best care we can for our cancer patients. But this is going to take a long time to penetrate into the rest of the United States And the world, because of education, because of lack of knowledge, because surgeons are just busy and they don't have a chance to stay caught up. So, I think the road is just beginning. We're at the tip of the iceberg and the Center of Precision Surgery will continue to grow and tackle some of these problems.

Dr. Janos Tanyi: And ultimately, the Center and our work, we work at the end of the day to provide, with these intraoperative molecular imaging technologies a survival benefit for our patients.

Host: It certainly is multidisciplinary and comprehensive and very exciting. I want to thank you all so much for joining us today and really highlighting the Center for Precision Surgery's 10th anniversary. Thank you all, well done, and thank you for joining us. And to refer your patient to Dr. Singhal, Dr. Delikatny, or Dr. Tanyi at Penn Medicine, please call our 24/7 provider-only line at 877-937-PENN or you can submit your referral via our secure online referral form by visiting our website at pennmedicine.org/refer. That concludes this episode from the Specialists at Penn Medicine. I'm Melanie Cole.