NIH CLINICAL CENTER GRAND ROUNDS
Episode 2009-007
Time: 58:04
Recorded Feb. 25, 2009

ONCOLOGIC IMAGING:  ENDLESS HORIZONS
Dr. Hedvig Hricak
Chairman, Department of Radiology, Memorial Sloan-Kettering Cancer Center

ANNOUNCER:  Discussing Outstanding Science of the Past, Present and Future – this is NIH Clinical Center Grand Rounds.

(Music establishes, goes under VO)

ANNOUNCER:  Greetings and welcome to NIH Clinical Center Grand Rounds.  On this edition, we bring you the Eighth Annual John Doppman Memorial Lecture for Imaging Sciences, recorded February 25, 2009.  A diagnostic and interventional radiologist at the NIH Clinical Center for 36 years—and chairman of the hospital’s Diagnostic Radiology Department for 28 years, Dr. Doppman developed, refined, and performed numerous semi-surgical radiologic procedures. During his tenure, the department was among the first in the nation to have CT and MRI scanners.

Today's speaker is Dr. Hedvig Hricak, chairman of the Department of Radiology and the Carroll and Milton Petrie Chair at Memorial Sloan-Kettering Cancer Center.  She is also a professor of radiology at the Weill Medical College of Cornell University.  Her topic:  "Oncologic Imaging:  Endless Horizons."  We take you to the Lippsett Ampitheater at the National Institutes of Health Clinical Center in Bethesda, Maryland, where Dr. David Bluemke, Director of Radiology and Imaging Sciences at the NIH Clinical Center, will introduce today's speaker.

(Music fades)

BLEUMKE:  We are extremely pleased to have this memorial lecture for Dr. Doppmann.  Our speaker today I would like to introduce is Dr. Hedvig Hricak who is presenting the 8th annual memorial lecture to help us honor him as a wonderful teacher and mentor, a great physician who made lasting contributions to our understanding of medicine and imaging sciences.  Dr.  Hricak is our honored speaker today.  She is currently chair of the Department of Radiology at Memorial Sloan-Kettering.  She's professor of radiology at Weill Medical College of Cornell in addition.  Dr.  Hricak received M.D. degree from the university of Zagreb and Ph.D. from the Karolinski Institute in Stockholm.  She holds an honorary degree from the Ludwig Maximillian University of Munich in Germany.  She's also served as member of the board of scientific counselors at the NIH Clinical Center.  She's been a pioneer in advanced molecular imaging methods for oncologic disease in the GU tract.  She has pioneered the use of MRI and CT in gynecological cancer, the application of MRI and MR spectroscopy to prostate cancer and use of ultrasound to study medical renal disease.  She has edited or co-edited 17 books and author or co-authored more than 300 peer reviewed research papers in over 127 book chapters.  She's given over 30 named keynote lectures and is a speaker in high demand throughout the world.  She's been a visiting professor at more than 30 institutions worldwide.  Dr.  Hricak is a fellow of the American College of Radiology as well as other societies including International Society of Magnetic Resonance in Medicine and the Society of Uroradiology.  She's currently chair of Board of Directors for the RSNA which holds the largest annual medical meeting in the world in Chicago annually.  She's slated to become that society's president in 2010.  She's a member of the Institute of Medicine of the National Academies and serves on the Nuclear and Radiation Studies Board.  In addition she continues to be engaged in clinical practice through her peers in radiology and other whose know her in many other fields, she's consistently recognized as one of the world's foremost experts in the use of diagnostic imaging in oncology.  In the past 7 years she's been repeatedly included in the New York Magazine lists of that city’s best doctors and in America's Top Doctors as recognition of her expertise.  So we're very excited to have her and she'll be speaking on a topic oncologic imaging.  Dr.  Hricak.  

[Applause]

HRICAK:  Thank you, David, very much, and it's indeed a pleasure and it is an honor to be invited to give a John Dobppman lecture and for John, and David, thank you, very much.  I was told to start with the slides to say I have nothing to disclose.  I don't consult and I don't sit on any boards.  Sometimes I'm not so sure who is more strict, Memorial Sloan-Kettering or the NIH, but having had -- I think there's great similarities.  It is really a pleasure to give this lecture on John Doppman celebrating the life of John Doppman.  He definitely was a pillar of the NIH clinical research community for many, many years.  I also had a pleasure and honor knowing John and Anna Marie very well.  So a few of the comments that I would like to make border on our personal relationship and my memories. 

He was very well known to always say the spoken word perishes, the written word will endure.  Publish, publish and publish.  So true to very this day.  He was a great teacher and researcher.  Clinician.  He was a father and a wonderful family man.  And he was such a good, loyal friend and mentor to so many of us.  He was very visionary. 

This is a private picture of him as a friend, as a family man.  But also as a visionary man.  Picture was taken in Germany where he together with Joseph Listener and Alex Margoles co-founded the Garmand Symposia, done in 1982, way before we said global reach, global extension, international education, he was right there.  Sorry for this.  It was supposed to be taken out.  So he also was known for his efforts. 

Case report is a first in a series.  I'm sure when many of you heard that.  I would like to put that in a context on his vision and leadership.  It’s observational science.  Now as we celebrate 200 years of Darwin, we're finally recognizing again the value of observational science.  Take the clinical observation to the animal laboratory.  Always have the curiosity to find out.  Today we call that translational research.  Many of our studies are emphasizing translational research.  Report all complications.  Stand up and be brave.  You're going to learn.  Today we call that quality improvement.  So many of the things that he was doing 10, 15 years ago now we just rename them but they are very much a part of our life.  Collaboration and congeniality make progress.  How true.  I would like to put a parallel to that right now as we celebrate Darwin’s Origin of the Species.  We all know very well that it's not the strongest, not most intelligent are those that are able to adapt.  But I'm not so sure that I studied that everybody that is well-known, that one of the famous Darwin quotations was that in the long history of human kind, those who learn to collaborate and improvise most effectively have prevailed.  And that collaboration as I look around the great leaders in the world -- philosophers, each and every emphasize yet in a practice it's not always easy to implement. 

Another full aphorism of Darwinism to survive and breed, you're all familiar with adaptation, competition of excellence will make you strive.  Collaboration, and always remembering that evolution is not an alternate path of relationship.  And disruptive technologies in our life should be welcome.  They're our greatest opportunities. 

So how about cancer imaging?  Evolution and adaptation?  Well, in imaging we certainly came a long way in the last 50 years, from regular x-rays to targeted imaging, anatomy, function, and biology.  This is why I hope you don't mind, if this lecture is called, oncologic imaging, and endless horizons.  Advances that we have seen in the last ten years are nothing short of spectacular.  MRI of the pelvis, patient with uterine cancer, it's no longer looking at a simple anatomy but truly contributing to our colleagues in radiation oncology and surgery in looking at the -- not only presence and location but exactly the extent of this uterine cancer from the fundus to the external cervical to the vagina.  So as new modalities are being done, they can really approach minimal invasive surgery in a different way.  In PET-CT as we do a total staging in spite of the fact that patient has lung metastasis, liver metastases, ability to correctly stage, and therefore design the first treatment aggressively to have the best chance of survival is what imaging has brought to the table.  Lung cancer and PET-CT bronchoscopy.  Again, anatomy is excellent.  Metabolic information of the lung superb.  But ability of spatial localization, so prior bronchoscopy is done, exactly to know what to expect, how to prepare for the biopsy, or perhaps which new element of the minimally invasive surgery can we apply are really the parts that imaging is bringing to the table. 

It's not surprising, therefore, then in 2001 when there was an article in Health Affairs ask healthcare providers, testimony medical advances in the last 30 years.  MRI and CT were number one.  Balloon angioplasty, also in the field of imaging and intervention, number 3.  And mammography number 5.  It's not only as we do survey.  As we look at the National Academy of Science, the lobby, science and evolution, but if you look at the wall of science, there's imaging.  There's MRI, there are CTs, imaging touches every part of our life from healthcare to science to advances in technology.  And it continues to touch and expand and be extremely important.  Those are the five technologies set to change the decade published in Forbes in January this year.  As you can see molecular imaging is number 3.  Expecting to really change the way we diagnose, treat, and do treatment follow-up in patients.  In our area it's in cancer patients. 

So how much have we already done and where are we going? Well, medicine as a whole has markedly changed since the 19th century.  Today medicine especially in oncology, it's really molecular medicine.  In imaging, we have better methodology, we have better spatial resolution.  But we do have a long way to go to really make that molecular imaging a reality of every day clinical practice. 

So number one what we do need to realize in imaging, and that is that matrix for success is multi-disciplinary and interdisciplinary team.  Medicine and science is a team science.  Days of heroes that were 19th centuries are more-or-less gone.  We really do need to collaborate and improvise.  By doing so, we need to understand new frontiers, challenges and opportunities.  Vertical silos will not make progress.  Understanding each other’s values in clinical and basic science arena is the only way to move forward. 

Second, we are not alone in this.  And we need to look at the trends.  For example, trend in oncology for the next ten years.  And per a line, our strategy with those that are societal.  The next ten years the medicine will be predictive, preemptive, personalized and participatory.  If we don't design ourselves, we will be asked to design rational evidence-based treatment decisions.  To do that we need to do it together with laboratory medicine, oncology, surgery, as well imaging being essential part of our P-4 medicine progress and the reality. 

Let's start with a predictive and preemptive medicine for earlier cancer detection.  In large part screening will be high through-put serum screening such as microfluidics or any other of the new nanotechnologies that we are developing.  Imaging plays a reserve role.  It has to be affordable and widely available and so far the only screening that we have is really breast cancer screening.  Screening is only mammography.  Breast cancer mortality through mammography has shown to decline at least 27%.  Detection is where we introduce other modalities such as MRI.  I do believe that for many years to come, screening in breast cancer will stay in the field of mammography only.  But that doesn't mean that we don't continuously improve.  We know the strength of MRI, we know the weaknesses, we're trying to work towards the highest specificity and one of the things that is being developed is really use of spectroscopy in deciding if the lesion that's enhancing on MRI is a malignant or benign adenoma.  We're also looking at MRI and other emerging technology.  One of them is a dedicated breast pet.  Bilateral lesion on contrast enhanced MRI.  It can be either in its own room or together with a pet scanning.  The device is very similar to mammography which allows us to mobilize the breast and also have highest spatial resolution.  Just using a simple FTG it appears that we are improving specificity in the decision if the breast lesion is malignant or non-malignant in this patient malignant lesion was only on the right side.  And by using what we already have, we are making a difference in personalized medicine. 

Use of MRI in treatment selection.  In this patient who was referred to Memorial only based on mammography, they were thinking of doing lumpectomy.  Prior to -- lumpectomy.  Prior to that patients received bilateral MRI.  In this patient there was a lesion in the right breast which was seen on mammography.  There was a second lesion on the right side, different quadrant, not seen on mammography but there was lesion on the left as well.  Doing lumpectomy on the original lesion would not make patient survive or do well.  Treatment decision after MRI was bilateral mastectomy. 

What happens when we don't use imaging? Both patients, two different patients were referral from the outside.  Patient had a lumpectomy, patient one had a lumpectomy and positive margins.  Positive margins after lumpectomy without imaging are over 50%.  There is a positive margin, there's a defect surgical defect.  Look at the amount of the tumor that was left behind.  So the judgment unfortunately from the mammography was underestimation of tumor volume.  Back in this patient, it's not just cutting another centimeter of margin, the tumor is rather large.  This patient had a lumpectomy, came to Memorial, and unfortunately there's a second tumor and there's even invasion of the intercostal muscle so therefore we all know lumpectomy was not the right procedure.  She needs a much more aggressive approach. 

When we come to chemotherapy in breast cancer imaging is all that we have.  The tumor size does not correlate to tumor response.  A large breast cancer, excellent response, relatively small cancer, almost no response.  As we combine the morphologic data with kinetics we're now able even to predict tumor aggressiveness and try to predict tumor response as well.  This is how you use imaging in the algorithm of patient's management.  In treatment selection, imaging is a roadmap to evidence-based treatment selection.  Is it going to be stage, location, volume, total tumor burden which now we try to calculate for estimation of some drug of tumor biology. 

In treatment planning, exploratory laparotomy is a procedure of the past.  Today we perform virtual laparotomy by imaging.  There is today absolutely no excuse in a patient such as this one with ovarian cancer, right node, right super node.  You could do exploratory and say cannot dissect because they're super diaprhomatic nodes.  Chemotherapy is a better way and the right treatment planning for this patient.  It's not only in surgery.  Radiation therapy and definition of biologically targeted lesion, the only way we are going to make advances in IMRT or the new IGT is really by a precise use of imaging where biological target is extremely important. 

And then there's image-guided intervention.  In the memory of our great leader John Doppman, we really think today what he thought when he said 20 years ago that image guided intervention is the main stay of modern cancer care.  There are new approaches and better way to do things daily.  This is simply a use technique that we use in breast cancer localization.  Why localization? Now we use that for non-palpable lung noduals so that surgeon when he or she goes in palpate where the lesion is, it's not always easy and does minimally invasive resection.  Image guided intervention is and will facilitate advances in minimally invasive surgery simply by better localization.  It is advancing tumor ablation for either cure of paliation.  You know, you have an outstanding interventional department here and many of those have started high focus ultrasound, microwave laser.  I always tease them, every time I turn around they have an another tool.  But they're improving outcome by combining therapies as well, chemo full ablation, focus ultrasound RT, RT and so on.  In each guided intervention will enable stem cell and save gene therapy.  There won't be just a save gene therapy unless we further perfect our image-guided intervention.  And the knowledge that by combining molecular imaging such as this bone marrow stem cell looking at where exactly that localize, so if you want to biopsy to see if the graft did or didn't take, now in the near future we do hope we'll be able to localize by imaging and with precision of imaging your biopsy exactly the area that will give you the biological answer we're looking for. 

Hybrid equipment in image guided such as angioCT.  Visualization 3-D that we never had.  And then smart catheter and navigation softwares are opening windows in image guided intervention that I always say no way, takes out the art that they used to have.  Even somebody perhaps like me would probably dare to put a catheter in this patient and by navigation software really see in which position is that tumor going to be totally embolized. 

Those are things of today that before we were only dreaming about.  CT robotics, where you're at the forefront gives us precision and much more wide use of the precision and biopsy so not only Brad Wood but many other people in IR and community world can do precision in biopsy.  MRI and intervention is here, but ability to have software such as this one in planning for skin cut.  So the small nodule in retro therapy peritoneum can be biopsied on single track precision that this gives.  It's really actually in a way a Star Wars game and fantasy. 

Image fusion for biopsy guidance.  Biopsying on the MRI takes a long time.  It's very costly, and not always pleasant for patients.  But fusing such as in prostate cancer, MRI and ultrasound in doing biopsies on the ultrasound.  So we develop the technology and then we simplify it.  So it can be used in everyday practice. 

Then there's a treatment follow-up.  Monitoring treatment response, prediction, imaging as a biomarker and detection of recurrence.  We spend endless hours deciding is the single measurement of volumetric measurement better for tumor response? You know logically it's the volume measurement and I'll show you -- I can show you many examples, I'll only show you one.  Technology is not widespread and this is why oncology is resisting but I would like to take a slightly different approach for the expansive of the new expanse chemotherapy.  For the toxicity of the new chemotherapy and the patient that is behind, would you rather continue the toxic therapy based on resist criteria where there's almost no change?  Or would you continue based on the volumemetric display, there has been actually tremendous volumetric response to this drug.  The drug works.  When you show patients this and the patient sees that tumor is getting smaller, he or she will have a totally different approach to continuing under that particular therapy than this you say well maybe does or maybe doesn't work.  So in patient reference, this is very, very important.  We do need to develop tubes such as automated segmentation because volumetric measurement are very time consuming and have interobserver variability between different interpreters. 

No matter in the liver lesion whether where the cursor was placed.  The volumetric display was always the same.  So that further computer technology is extremely important.  And then it isn't just morphology, it isn't just the tumor volume, it is tumor heterogeneity.  And this is why we do have tools to combine.  So we cannot say that we can only do tumor response based on a single measurement.  We are not getting the information that we can get today.  Biology, metabolism and imaging, of course FDG and metabolism changes before doctor's eyes.  We have the tools and we should working to on utilizing it in better and on a larger scale. 

Image guided intervention.  Is it a tumor? Is it so easy to guide such as in this case in the lesion in the region of FDG activity and therefore, knowing that you are biopsying the active part of the tumor.  The use of PET scanners in image guided intervention is a rapidly expanding and gives us unique, unique opportunities.  Prior to RF ablation, following RF ablation, superb response.  We are using FDG-PET both to find the active lesion as well as to monitor our treatment. 

But this is just FDG.  We have a menu of the tracers today that we can really say that we are moving in the field of therapy, we started imaging and targeted therapy.  Our tracers going to be target to proliferation such as FLT, we even like it more specific androgen receptor, estrogen receptor, different type of antibodies or just simply looking at the bone scanning and bone mineral metabolism. 

Let's start with bone scanning.  The same patient, done the same week, prostate cancer, bony metastasis.  As we perfect imaging and become more and more precise, it is so often frightening how little we knew yesterday.  This is the regular bone scan.  Of course there are few lesions.  This is now more advanced.  There are lesions -- look at the multi-focal SPECT, all the lesions that we actually don't see on the regular bone scanning and look at the same time the number of lesions under sodium FAT bone scanning.  If you design a new drug and you're going to base your treatment or decision to treat not to treat or continue on bone scan, or if you're looking at the number of lesions in sodium, how many lesions we really don't see. 

Not only that we have new bone scanning.  Whole body MRI, our ability to look at soft tissue and bone lesions, this is not screening by MRI, this is a metastatic work-up looking at everything in one single time.  So the question very often that people say, well, we can only use FDG-PET or we can go and use MRI, we need both.  We need anatomy and we need metabolism.  We need tumor burden, biology, and our data have to be quantitative which gives us size and PET-SUV values.  We need new tools.  One now being done is MRI-PET. 

Why MRI-PET? This is a clinician's point of view.  Number one is radiation exposure.  We are dealing in oncology.  No question.  But our patients are surviving.  We are making cancer a chronic disease.  They keep coming back for the follow-ups, it is not unusual that for cancer surveillance we do 27 CT scans in first five years.  When you are 20 years old, that's a lot of radiation.  Next we do need multi-parametric simultaneous measurements of imaging biomarkers.  We need that quantification of target concentration in MRI still difficult and PET can greatly help.  Cancer and tumor is a living tissue.  Doing sequential scans few days apart is not a biology marker that we are looking for.  It's not a molecular imaging that we are hoping for.  And this is why we believe that MRI-PET has a great future. 

And we want targeted imaging.  Here is a bone scan, FDG-PET and the targeted imaging, FDHD which is androgen receptor imaging.  And again, the same awareness, how much are we missing? All done within actually those are our clinical trials, bone scan, FDG-PET and FDHD are done within three days.  The metastasis that we don't see, the number of soft tissue lesions that we don't appreciate unless we do targeted imaging.  At times becomes frightening.  There are many things we are learning and we don't know.  Obviously recurrence on CT, but look at FDG.  Absolutely no metabolic uptake.  Look at FDHD, tremendous activity. -- tremendous activity.  By seeing the metabolic activities of the region, seeing where the androgen receptors or maybe where glycolysis is high.  We are going to be able to design a personal treatment for those patients. 

Follow-up and the use of CT scan.  Use of CT scan for bony metastasis in prostate cancer, there's obviously a scelerotic lesion on CT here.  Nothing changed.  FDC shows you bony metastasis and shows you excellent response.  For targeted for the new targeted therapy we need targeted imaging to really see the receptors that the drug is aimed at.  The same in breast cancer.  Use of androgen receptors in scanning in this patient.  There are activity in the breasts as well as the axilla.  Why do we need an estrogen receptor image something because we are giving hormones we believe if the pry player tumor is ER positive -- primary tumor is ER positive metastasis are going to be ER positive.  Not true at all.  Tumor dedifferentiates and we cannot biopsy each and every metastatic site.  Two patients, patient 1 and 2 in both patients the primary tumor was ER positive.  They developed bony metastasis and both treated with a hormonal estrogen suppresssant.  In patient number 1 and 2, they have bony metastasis.  Following treatment on FDG pet, patient number 1 had excellent response.  Patient number 2 had no response.  So what you say, or just not allow unlucky patient.  Not at all.  Maybe an ignorant doctor.  Because in patient number 1 under FSC-PET scanning, there are androgen receptors within the metastasis and of course the response.  On patient number 2, there are no estrogen receptors in the metastatic lesions.  There was nothing to respond to.  This is an intelligent therapy design which is facilitating through targeted imaging. 

Her-2, we like herceptin.  We all know 40% of patients do not respond but we can image her-2 receptors in the metastatic lesion such as shown here.  Clear cell carcinoma.  Now we have drugs that only goes to clear cell.  Isn't it nice to instead of just saying there are lesions, there is a cyst and there's a small clear cell there as we biopsy, as we do intervention of treatment we really know even the histologic type of the lesion through new family of molecular imaging.  It doesn't have to be only in the radiology suite.  Now we have hand held probes.  It's taken in the OR.  This is the antibody imaging, iodine 124, A-33 which is specific for colon cancer.  So we can look and help the surgeon not only remove the primary lesion but find satellite nodules that are very difficult to palpate. 

So as we look at the anatomy lecture and we look today we're saying really today anatomy lecture is molecular imaging is molecular, as is treatment.  There are unprecedented opportunities looking at biology, genetics, targeted therapy, always IGI and then prediction and assessment of tumor response.  We do believe that success in molecular medicine depends on a strong researching imaging.  Even more so, molecular imaging is the research engine for a new application in molecular medicine.  So when we practice today we always have integrated diagnostic approach to management of cancer.  There has to be knowledge of serum screenings, protenomics and in the case of prostate cancer, molecular pathways that are identifying targeted radiology cannot be practiced in isolation.  We are one team, we are a team, disease management team looking at different problems.  This one is prostate cancer.  As radiologists we have to know anatomy, have to be precise, what is the peripheral zone, what's a transition zone.  Those are not the details of the academia.  This is the reality that needs to be known, a reality that was actually published in the late 1970s, 1977 but somehow have very slow way of migrating into mainstream radiology.  When there is a peripheral zone, when there is cancer, has to be seen in two planes of section, extra capsular extension and then there's a lesion under normal central zone on the left and the lesion on the right side as well.  Prostate cancer, as you know is multi-focal in almost 80% of cases. 

We are developing technology continuously.  This is the regular T-2 weighed image.  This is diffusion image with a parent diffusion.  For those that like reverse contrast, we can software and computer science -- we can display every which way that makes you more comfortable looking at the lesion.  The tools are here.  And we need to apply them. 

Dynamic scanning looking at the curvature being able to judge tumor aggressiveness.  This is not debatable.  Of course it works.  We know from our friends in pathology that microvessel density in prostate cancer is a significant independent biomarker of prostate cancer recurrence.  We're not reinventing the wheel.  We're just applying the tools that we have.  Then that everything has to be multi-parametric like with serum screening.  There's more than one variable.  And specific to prostate cancer there's a definite element of how applying spectroscopy.  As we look at imaging is very often non-specific.  They have abnormalities in right and left side of the gland.  On the right side the spectra are absolutely normal with the high seat rate.  However on the left side the spectra are very abnormal and they have high choline.  You look at the ratio between choline and C trait and when it's greater than .5, this was done in the late '90s.  We know they're suspicious of cancer. 

But today we know much more.  It is no longer just C trait in the colon as we look for, we also today look at the polar image.  And every basic scientist that works in prostate cancer is also interested in -- we now see those.  We see those elements and look at different variables.  We know our limitations on spectroscopy, sensitivity for detection is only 57%.  But what we miss are low-grade lesions where the proliferations and therefore choline is not elevated to the same degree.  We do very well with high grade lesions. 

So we always say in Chinese word crisis has two letters only.  One means danger, the other is opportunity.  So it is dangerous to say that spectroscopy is the answer to everything we have.  But it is an opportunity that using spectroscopy we don't miss high-grade lesions at all. 

Polyamines.  Now we enter another element.  We look at polyamine, it's a wonderful triage for us to look if the lesion is benign or malignant.  When the polyamine is greater than choline, they are normal.  When they're equal it's probably cancer and when we no longer see polyamines we know this is definitely cancer.  We are now using three tests in looking at choline, polyamine and C trait is becoming much more clear.  And we are a team so we understand diagnostics and cell signaling.  We're looking at our friends in pathology and seeing how they're doing their new immunohistochemistry, here AR-67 or AR that they are doing and compare with the tools that we have.  Soon to be published actually realize that those both markers that really predict aggressiveness and predict tumor response are associated with cancer as they're seen on MRI and MRSI. 

So we try to get the best of the tools that we have and moving them forward.  We also do under high magnetic fuel strain because there's so much that we don't see on the lower fields.  We learn on the high and just like John said, take it back, in this case is the reverse.  We have seen the clinic and we take it back in to the laboratory.  And vice versa in the cycle.  To learn more and be better in our diagnostic possibilities. 

So what is our future?  Imaging biology markers and it is terranostics, targeted imaging and targeted therapy.  It's elution of imaging and intervention in the next decade.  We are radiologist bus we do read and understand six hallmarks of cancer.  Because this is how we design our study.  Then we learn and teach you back, that the old dogma that tumor hypoxia was related to tumor size is wrong.  Some tumors are large and hypoxic, some are not.  Some tumors are small and they show hypoxia already.  It is much more than tumor size.  This is how we continuously learn from each other, we offer you in addition to hypoxia perfusion, try to correlate and understand, hay really do not go hand in hand.  Hypoxia is high, profusion may or may not be there.  We are learning about tumor biology in vivo continuously.  Imaging hypoxia and then terranostics targeted imaging, targeted therapy.  In head and neck tumor where the tumor really is escalated dose as you do with the radiation therapy.  We are developing targeted probes such as PSMA imaging.  This is nanoparticles oxide.  This is why the tumor that's PSMA positive is going to be low in signature low in signal intensity than the other side. 

Now planning to go into clinical trials and actually going to do renal cancer because BSMA is greatly expressed in the neovasculature.  But that is progress.  That is what we try to move and do forward.  There's evolution of contrasting agents that you can put on the Darwin tree of life.  The higher we go, the higher we select, the more complicated things are.  But we can do that, most of that today, and have moved far away from the good old gadolinium only. 

We are learning to be brutally honest.  Few people care that bacteria have different shape which is a shame because the bacteria seem to care very much.  We used to do contrast media, the smaller the better.  Only to learn it isn't just the size, it is the shape that makes such tremendous difference.  So show you our print particles on the mouse macrophages.  This one how the shape does make a difference.  It makes a difference if it's solely our print particles are hollow in the middle, how they do enter the cell.  We have ability through different imaging modalities to really see what's happening and as we design our new probes at the same time we verify where and how they are distributed. 

We're now putting drugs on the materials.  And then look at those containing cytotoxic doxorubicin, how they enter the cells and do thelysis and how the second experiment is not only having the drug by having the imaging agent so we can image at the same time.  And we always learn asking ourselves immunotherapy is a big part of our future.  Can ablation stimulate the human system to graft tumor cells in the other side? Jim Ellison is on our faculty so this is why we have CTLA-4.  Indeed when we did experiment in the mouse and only gave the mouse CTLA-4, and then we do ablation and gave CTLA-4, the results are very different. 

Look how well the mouse that had combined ablation and anti-CTLA did in survival as opposed to either treatment only, no treatment, or ablation only.  This is advancing the field through working together and getting ideas from each other. 

At the end success is a journey, not a destination.  But in imaging what a journey it has been and only to say that we're only at the beginning and now that we can image not just the cell but the nucleus with a DNA structure in it, I think the horizons are truly endless.  And all I can say, it's never been a better time in being in oncology, molecular imaging and seeing the fruit of our work making patients better is rewarding more than anything else.  Thank you, thank you very much for your attention.  

[Applause]

BLUEMKE:  Thank you very much, doctor.  We have time for one or two questions I think if there are any.  I was wondering, you presented this concept of MRI-PET which is kind of novel.  How do you think that's going to may a role in oncologic disease, which areas?

HRICAK:  Well, I know that the first MRI-PET was done for head only because they believe there are so many applications in the head.  I think that MRI-PET in oncology is going to be very important because if we are serious about looking at tumor biology then it really has to be to combine imaging integrated imaging at the same time and maybe follow through.  People look at hypoxia and angiogenesis right now.  They think this is only the beginning because that's all we have right now.  I actually believe in cell signaling and I think we will have something in a few years.  When you go to that level of imaging cell signaling or looking at enzymes you have to do it at a single dissecting. 

Another big thing about MRI-PET is radiation.  I mean, we have to be cognitive that, thank God, cancer is now a chronic disease.  We got diagnosed at age of 20, we're going to follow you for almost the rest of your life.  Once you have cancer you really are not totally cured and we now see a lot of breast cancer patients coming back 20 years after treatment.  So they always have to be observed.  And I think throughout their life the accumulation, if you can do it, a combine MRI-PET, you do cut the CT radiation exposure, which is almost a half.  We looked at the dosages, then you do, so just the radiation will be something that patients will embrace.  In addition, if you are serious, Forbes article is correct, if it's correct that molecular imaging is one of the five greatest technologies to change the next decade, you will need an integrated approach. 

BLUEMKE:  Perhaps one question.

QUESTION:  Congratulations for the excellent review of the evolution of the molecular imaging and all the other novel technologies.  A short question regarding the imaging of the antibody.  Do you see any myocardial localization? There are some common -- in the myocardial tissue as well as tumor tissue?

HRICAK:  Right.  The clinical trial is ongoing.  And the problem is yes, we do.  The answer is yes, we do.  We don't know what to do, sometimes when you develop something new and you look, it takes you a while to really understand what is significant, what's not significant.  What you should pay attention.  But we do have a data collection and then later on revisit.  But yes, we do but not in everybody.  We don’t know what's going on.

QUESTION:  And a short question.  You are in one of the best -- latest in science and technology.  Considering the high cost of the healthcare issues in the USA, how do you think this could transported in the smaller healthcare places? And implications?

HRICAK:  I actually have a little different approach.  I look at that as a part of patient advocacy group.  If as a patient -- two reasons.  One is we do a lot of chemotherapy that doesn't work.  It's a tremendous waste of money.  If you really have a true marker of tumor response and you don't know -- you know it doesn't work you would save money by stopping.  Second, there's a patient behind.  You give patients any estrogen hormonal therapy and then you wait and say don't worry, come back in three months, we'll see if it works or it doesn't work.  There's a tremendous anxiety.  I am thinking somebody should be able to put patient anxiety, wasted time from -- time, wasted time from work, if it doesn't work as in the patient I have shown the cancer was actually bony metastasis were growing.  And as we do cost effective study, we look at cost, all those elements have to play the game.  Not just oh, we add imaging.  That's not the case.  Imaging is going to change your choice of treatment, duration of treatment.  But also is going to help patients being better.  That's really what we're here all about.  So I think I would love some economies need a small group and they need to look at all the elements, not just the bottom line because there's much more.  You know.  There's good cancer chemotherapy, new therapy to date, all above $100,000 for the cycle.

BLUEMKE:  Thank you very much.   [Applause]  Small token of our appreciation here we have a plaque from the clinical senor regarding the Doppman Memorial Lecture.  Thank you very much.   [Applause] 

(Music fades in, under VO)

ANNOUNCER:  Today we've been pleased to bring you the Eighth Annual John Doppman Memorial Lecture for Imaging Sciences, recorded February 25, 2009.  You've been listening to Dr. Hedvig Hricak, chairman of the Department of Radiology and the Carroll and Milton Petrie Chair at Memorial Sloan-Kettering Cancer Center.  She is also a professor of radiology at the Weill Medical College of Cornell University.  Her topic was "Oncologic Imaging:  Endless Horizons."  You can see a closed-captioned videocast of this lecture by logging onto http://videocast.nih.gov -- click the "Past Events" link, or by clicking the "View Videocast" link for today's podcast at the Grand Rounds podcast page at www.cc.nih.gov/podcast/grandroundpodcasts.html.  The NIH CLINICAL CENTER GRAND ROUNDS podcast is a presentation of the NIH Clinical Center, Office of Communications, Patient Recruitment and Public Liaison.  For more information about clinical research going on every day at the NIH Clinical Center, log on to http://clinicalcenter.nih.gov. From America’s Clinical Research Hospital, this has been NIH CLINICAL CENTER GRAND ROUNDS.  In Bethesda, Maryland, I’m Bill Schmalfeldt at the National Institutes of Health, an agency of the United States Department of Health and Human Services.