Multi-Modality Diagnosis Heading for Lab Medicine

Systems biology shifts thinking toward multi-specialty approach

CEO Summary: At the upcoming Molecular Summit in Philadelphia on February 10-11, 2009, pathologists, molecular imaging experts, and informaticians will share the latest developments on the integration of in vivo (imaging) and in vitro (pathology) diagnostics. A major theme will be discussion about multi-modality diagnostics and how this new discipline—driven by advances in genetics and personalized medicine—will reshape laboratory medicine as it is practiced today.

THERE’S A PHRASE gaining new currency in the clinical community. It is “multi-modality diagnosis” and it is gaining wider use in radiology as a way to describe imaging procedures that might involve several different technologies, such as MRI, CT, PET, and fluorescent imaging, to name a few.

However, researchers and physicians working interactively with specialists in nuclear imaging and radiology are increasingly using this term to describe any diagnostic process that incorporates a specific combination of data inputs from different scientific disciplines to produce the diagnosis.

Here is where multi-modality diagnostics intersects with laboratory medicine. In research settings across this nation, pathologists and laboratory scientists are beginning to engage with other disciplines to develop, for specific diseases and conditions, appropriate diagnostic pathways that integrate multiple relevant sources of clinical information.

Two factors are propelling this development forward. One involves the ongoing and rapid advances in genetic knowledge. The second is the recent development of a new generation of sophisticated health informatics platforms that can pull together and assess traditionally disparate sources of clinical data.

In particular, genetic medicine’s use of multi-modality diagnostics will have an important consequence for pathologists and clinical laboratory professionals. Among other things, it will help tear down the isolationist attributes of laboratory medicine that have marked the specialty for decades.

Instead, during the genetic age, laboratory medicine is fated to become a highly-collaborative specialty. Laboratory professionals will interact regularly and daily as part of the patient’s essential care team. This outcome will be a natural consequence of personalized medicine. It also opens the door for laboratory professionals to contribute tremendous value to patients, referring physicians, and the healthcare system.

First-mover pathologists and radiologists in this drive toward multi-modality diagnostics will be speaking at the upcoming Molecular Summit on the Integration of In Vivo and In Vitro Diagnostics. The conference will take place in Philadelphia on February 10-11, 2009 and is produced by THE DARK REPORT. (

Here is an example of how molecular imaging pioneers are bringing other disciplines, including pathology, into their clinical studies. Ralph Weissleder, M.D., Ph.D., is Professor of Radiology at Harvard Medical School, and Director of the Center for Molecular Imaging Research at Massachusetts General Hospital in Boston, Massachusetts.

Weissleder has stated that “In cancer detection, subcentimeter cancer metastases that are missed by conventional, anatomically-based imaging methods may be detected in patients by molecular imaging methods. Together with other biomarkers and emerging molecular tools (e.g., DNA screening, tissue proteomic and metabolomic analysis, serum markers), this information soon may be used for screening, diagnosis, detection of recurrence, and treatment assessment.”

Weissleder’s team is actively integrating in vivo and in vitro techniques to achieve these goals. At the upcoming Molecular Summit, Weissleder’s colleague, Mukesh G. Harisinghani, M.D., Assistant Radiologist, Department of Abdominal Imaging & Intervention at Massachusetts General Hospital, will discuss the team’s efforts to integrate multiple modalities to realize the clinical capabilities described above.

Molecular Intersection

THE DARK REPORT’S interest in this intersection of molecular pathology and molecular imaging began during its analysis of why Siemens AG—one of the world’s leaders in imaging and radiology—had spent $14.1 billion in 2005 and 2006 to acquire Diagnostics Products Corporation, Bayer Diagnostics, and Dade Behring Corporation and become the world’s second largest in vitro diagnostics (IVD) manufacturer.

Even as these events were unfolding, imaging giant GE Healthcare was making its own inroads into IVD, first with an aborted $8.3 billion agreement to buy Abbott Diagnostics, then earlier this year with the creation of a joint venture with University of Pittsburgh Medical Center (UPMC) to create and market a digital pathology system.

In Vivo / In Vitro Integration

As clients and regular readers of THE DARK REPORT recall, at the time of these corporate transactions, Siemens and GE each articulated a vision of more sophisticated diagnosis and patient care that would require the integration of molecular imaging and molecular diagnostics. Siemens further stressed the importance of adding informatics to its integration strategy and described its vision of pre-symptomatic diagnosis.

There is no better way to learn about a trend like the integration of in vivo and in vitro diagnostics than to seek out the pioneers and innovators and invite them all to come together at the same time and conduct sessions on their work. That was the genesis of the Molecular Summit. It took place in Philadelphia last February and was an immediate success, with 225 attendees. Fifteen different health publications sent editors and reporters to cover the event!

Trend Is Just Beginning

As pathologists and radiologists listened to the innovators in molecular imaging and molecular diagnostics last February, it was clear to both groups of specialists that integration of in vivo and in vitro was already under way—even if only at a limited number of sites across the country.

After speaking at the event, Jared Schwartz, M.D., Ph.D., wrote in his CAP Today President’s Letter column “Returning from the Molecular Summit in Philadelphia on Feb. 6, I had to tip my hat to whoever named the meeting. They captured it perfectly. Publishers of THE DARK REPORT presented the Molecular Summit as an opportunity for professionals in pathology and radiology to learn firsthand from physicians, scientists, and industry leaders about the integration of imaging and diagnostics and the advanced uses of molecular technologies …an intensive meeting that brings together so many of those working on the cutting edge…”

Schwartz accurately described the remarkable clinical insights tumbling out of these innovative efforts to integrate in vivo and in vitro diagnostics at the first Molecular Summit. But there is more to the story that is particularly relevant to pathologists. It is based on concepts that can be described as “static diagnostics” and “dynamic diagnostics.”

Conceptually, anatomic pathology is a process of “static” analysis. Patient specimens used in pathology represent a specific moment in time for that patient.

Different State-Of-Practice

That makes the current state-of-practice in pathology different from the new capabilities available in imaging and radiology. New imaging technologies permit radiologists to watch the patient in a “dynamic” fashion. For example, an imaging expert can see how a tumor changes from one moment to the next.

The metaphors of “static” and “dynamic” help in understanding an emerging trend which has the potential to radically reshape surgical pathology, as well as all of laboratory medicine as it has been traditionally defined. In the conceptual sense used above, in vitro testing has always provided information about the patient’s condition at the moment the specimen was collected.

From this traditional use of “static” in vitro diagnostics, most new molecular assays and genetic testing function within that tradition. That is true because the molecular specimen is harvested at a specific point in time and the diagnostic information gleaned from that specimen is understood to be based on that moment in time.

Here is where the evolution in pathology and the evolution in radiology and imaging begin to diverge. Traditionally, images collected by the radiologist also showed the patient’s status as of the moment in time when the image was captured. In this aspect, in vivo and in vitro were alike and were “static.”

But new imaging technologies are ready to fundamentally change the specialty of radiology. Latest-generation imaging instruments now permit the radiologist to view tissue in vivo and watch metabolic processes actively change the tissue of interest. This supports the concept of “dynamic” analysis. These molecular imaging technologies will alter radiology in fundamentally different ways than how molecular diagnostics are expected to change anatomic pathology.

Assume, for the moment, that this description about the static nature of IVD in pathology and the dynamic nature of in vivo molecular imaging in radiology is correct. There is a second transformational force under way in molecular imaging which will reinforce and strengthen radiology’s evolution toward a dynamic diagnostic service. This second force is the use of latest-generation imaging systems which are bi-modal.

In the past few years, imaging manufacturers have created hybrid imaging instruments which can scan the patient during a single procedure with two different imaging technologies, such as PET/CT, SPECT/CT, and MR/PET. During presentations last February, radiologists demonstrated how these instrument systems created a new capability.

Use of the term “multi-modality diagnosis,” was expanded within radiology because of how these various imaging techniques were used in combination to evaluate a patient.

These hybrid imaging instruments scan the patient with two technologies during the same procedure. The resulting images correlate precisely. This permits the radiologist to toggle back and forth and see different aspects of the same tis- sue. This capability created new information and new diagnostic possibilities for molecular imaging experts.

As molecular imaging experts shared the insights resulting from these technologies, this created two major “aha moments!” for pathologists at the first Molecular Summit. One “aha” was the recognition of the dynamic view of metabolic processes that molecular imaging technologies produce. The second “aha” was recognition that multi-modal imaging was a major breakthrough for radiologists. Use of the term “multi-modality diagnosis,” has become more common within radiology because of how these various imaging techniques are used in combination to evaluate a patient. But that’s not the end of this story.

Concept Of Systems Biology

The third element contributing to the evo- lution of molecular imaging and multi-modality diagnostics (and not yet present in anatomic pathology to the same degree), is the concept of systems biology. Once radiologists could view tissue in vivo and see changes to a tumor, for example, they needed to understand the metabolic processes creating these changes. Read the comment in the sidebar on page 13 by PET inventor Michael Phelps, Ph.D. of UCLA, as to why systems biology is a main driver to his research efforts.

It is this need to understand the systems biology of the processes visible in a molecular imaging procedure that motivates radiologists to reach out to other medical specialties and collaborate with them. Of course, a natural partner in these collaborations is the molecular pathologist. Tissues of interest revealed by the molecular image must be biopsied and referred to pathologist for molecular and histopathologic analysis. This is the logical reason why in vivo and in vitro integration is already occurring.

Mustn’t Forget Informatics!

These collaborations must include infomatics to enable the integration of in vivo and in vitro diagnostics. Multi-modality diagnostics requires physicians to assemble and evaluate clinical data from a growing number of disciplines. Also, informaticians are independently researching ways to gather disparate clinical data sets, evaluate these data with sophisticated software, then produce an answer that the clinician can use to diagnose the patient, identify the most promising therapies, and monitor the patient’s progress.

One example of this multi-modal, integrated informatics approach is occurring at Rutgers University. At the upcoming Molecular Summit, Anant Madabhushi, Ph.D., Assistant Professor and Director at the Rutgers Laboratory for Computational Imaging and Bioinformatics (LCIB), will discuss this topic. He describes his team’s work as “with the advent of multi-modal, multi-parametric high resolution radiological imaging providing anatomical, bio-chemical, and physiological information, it has become increasingly important to identify the potential value of this information in the pre-operative or pre-therapeutic cancer population.”

Machine-Learning Methods

At his laboratory, Madabhushi is focused on “developing image, spectral analysis and machine-learning methods for efficient analysis and correlation of disease signatures across multiple scales and modalities—from gene expression to histopathology to radiology, with an emphasis on prostate cancer and more recently breast cancer. Our systems approach for quantitatively analyzing multi-functional, multi-scale, multi-modal data in an integrated fashion will be extremely important in diagnostic, theranostic (predicting response to therapy), and prognostic settings.”

All of these examples demonstrate that real and powerful forces in support of multi-modality diagnostics are at work in the healthcare system today. For the reasons described above, molecular imaging and radiology seem to be the most active specialty in this developing field. But a number of innovative pathologists are equally involved in expanding the boundaries and capabilities of multi-modality diagnostics.

Collaborating On A Case

For example, many pathologists are watching how neuropathologists and neuroradiologists increasingly want to see each other’s images before each signs out their report on the same patient. This is also happening with bone pathologists and orthopedic oncologists. At Molecular Summit, there will be a case study from the University of Kansas where a radiologist and a pathologist are jointly looking at microcalcifications in breast cancers. These physicians report that the collaboration has not much changed the diagnosis of these patients, but, in surprisingly effective new ways, it is changing how the patients are managed.

One reason that multi-modality diagnostics has not received more attention and discussion among pathologists and the laboratory industry is that much of the current impetus behind this developing discipline is coming from outside laboratory medicine. In fact, THE DARK REPORT may be the first laboratory publication to describe multi-modality diagnostics in this fashion.

Watch The First-Mover Labs

It is too soon to predict the specific ways in which genetic medicine, multi-modality diagnostics, and the integration of in vivo and in vitro diagnostics will alter and reshape anatomic pathology as we know it today. That will take more study and observation of those clinical sites where radiologists, pathologists, and informaticians are working together to create an integrated diagnostic pathway for specific cancers and other diseases.

In the meantime, observations and comments on this subject are welcome. THE DARK REPORT is also interested in news and information about laboratories and pathology group practices which are actively involved in efforts to integrate molecular diagnostics with molecular imaging.

At UCLA, PET Inventor Michael Phelps, Ph.D. and Pathology Dept. have In Vivo-In Vitro Collaboration

AT UCLA, THE RADIOLOGY AND PATHOLOGY DEPARTMENTS are collaborating on integrated clinical services which combine in vivo and in vitro molecular technologies.

Michael E. Phelps, Ph.D., Chair of UCLA’s Department of Molecular and Medical Pharmacology at UCLA and inventor of PET, is incorporating systems biology into this effort. Phelp was profiled in Medical Solutions, which wrote that:

Phelps views biology and the human body from a systems perspective, looking at molecular pathways in normal tissues as electronic integrated circuits, and the process of diseases as a malfunction in those circuits that can be fixed.

“If you think about a systems biology view of disease, you have to begin thinking about how the body is organized into an integrated function in the cell and the networks of cells,” explains Phelps. “You have to think about how disease can reprogram those circuits to gain and lose functions and do harm to us in a different configuration in the circuit.

“People in the field of systems biology don’t believe in the old concept of what breast cancer is, or prostate cancer, or Alzheimer’s disease,” he continued. “They believe that cells are being progressively reprogrammed into different configurations of cell circuits and intercellular networks throughout the developmental course of dis- ease to gain and lose functions that do harm to the organ systems of the body and we must understand this so that we can deal with it effectively and therapeutically.

All of that begins with molecular diagnostics, whether it’s in vitro in cells and blood, or in vivo with molecular imaging, to identify the critical proteins that consolidate specific biological processes of disease that occur in the reprogramming process. Those are the therapeutic targets; we need to either push them or to drive them back to normal or to terminate them,” concluded Phelps. [Underline by TDR.)

At UCLA, the Department of Pathology and Laboratory Medicine is in active collaboration with Dr. Phelps and his colleagues in molecular imaging and pharmacology. They are developing clinical approaches which integrate molecular imaging and molecular diagnostics. At the upcoming Molecular Summit, Jonathan Braun, M.D., Ph.D., Chair of Pathology and Laboratory Medicine at UCLA, will describe the work unfolding in prostate cancer and glioblastomas where PET-based biological probes, used in concert with molecular diagnostics, are helping physicians stratify patients with these diseases. It is an early example of integrating in vivo and in vitro molecular methods to advance patient care.

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