The gold standard

A novel technique is changing lymph node biopsy, reducing radiation exposure in breast cancer patients

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ST. LOUIS—A new technique by researchers at Washington University in St. Louis utilizing information obtained from a new application of photoacoustic tomography (PAT) is offering new hope to breast cancer patients.

Dr. Lihong Wang, Gene K. Beare Distinguished Professor in the Department of Biomedical Engineering, with a joint appointment in radiology, and Dr. Younan Xia, James M. McKelvey Professor in Biomedical Engineering, with a joint appointment in chemistry in arts & sciences, both at Washington University in St. Louis, recently used gold nanocages to map sentinel lymph nodes (SLN) in a rat noninvasively using PAT.

Wang's lab is the largest PAT lab in the world, credited with the invention of super-depth photoacoustic microscopy, and Xia's lab invented the gold nanocages.

According to Wang, PAT can potentially provide image-guided cancer treatment and early prediction of response to chemotherapy.

"Owing to its highly sensitivity to hemoglobin, PAT enables us to localize cancers by mapping tumor angiogenesis and tumor hypoxia, and to monitor treatment response chronically without injecting any contrast agent," he says. "Such measurements can be used to personalized treatment plans and accelerate development of new drugs.  The personalized medicine is expected to reduce side effects and improve survival rates of cancer patients. Further, when combined with exogenous contrast agents—such as gold nanoparticles and organic dyes—that molecularly target cancer-specific biomarkers, the sensitivity and specificity of PAT can be enhanced."

Their work, supported by the National Institutes of Health, can minimize invasive surgical lymph node biopsy procedures to determine if breast cancer has metastasized and reduce the patient's exposure to radioactivity. The nanocages also have the potential to serve as an alternative to chemotherapy, to kill targeted cancers by heating them up.

"Currently, our group explores noninvasive photoacoustic mapping of sentinel lymph nodes in breast cancer patients using a modified clinical ultrasound system," Wang adds. "Our initial goal is to replace the current standard procedure of invasive and ionizing sentinel lymph node biopsy with minimally invasive photoacoustic and ultrasonic image-guided fine needle aspiration biopsy."

Wang adds that the team's next goal is to provide noninvasive mapping of cancer metastases labeled with targeted contrast agents.

"PAT can potentially be applied to many forms of cancer and other diseases such as breast cancer, brain cancer, prostate cancer, skin cancer, port wine stains, Barrett's esophagus, and hemangeoma," he says.

PAT blends optical and ultrasonic imaging to give high-resolution images of the body that contain information about physiology or tissue function. Wang points out that the molecules already present in the body (endogenous molecules), such as melanin, hemoglobin, or lipids, can be used as endogenous contrast agents for imaging. When light is shone on the tissue, the contrast agent absorbs the light, converts it to heat, and expands. This expansion is detected as sound and decoded into an image.

"Using pure optical imaging, it is hard to look deep into tissues at high resolution because light scatters. The useful photons run out of juice within one millimeter," Wang explains. "PAT improves tissue transparency by two to three orders of magnitude because sound scatters less than light. This allows us to see through the tissue by listening to the sound."

Exogenous contrast agents (found outside the body), like the gold nanocages developed by Xia's group, can be used to image parts of the body that even contain endogenous contrast agents. These nanocages are especially attractive because their properties can be tuned to give optimal contrast and gold is non-toxic.

Xai points out that by controlling the synthesis, "we can move the absorption peak for the nanocages to a region that allows them to be imaged deep in tissue. We can also attach biomolecules to the surface of the nanocages so they are targeted to cancer cells."

The SLN, the first draining node, is often biopsied in breast cancer patients to determine if the cancer has metastasized.

Wang points out that to find the SLN, doctors inject radioactive particles and a blue dye into the breast.

"The lymphatic system gobbles up the injected material, treating it as foreign matter and accumulating it in the SLN," he says. "The radioactive particles can be detected using a Geiger counter held to the breast to locate the lymph nodes. Then, the doctors surgically open the breast, follow the blue dye, and dissect the SLN."

Wang and Xia's technique allows the SLN to be imaged safely without radioactivity or surgery. A piece of tissue can then be removed using a minimally invasive needle biopsy and tested for cancer.

Because of its use of nonionizing radiation, low cost, portability, and high sensitivity, Wang notes that purely optical imaging has great promise as an imaging modality.

"However, owing to strong light scattering, conventional optical imaging techniques suffer from either shallow penetration, such as optical microscopy, or poor spatial resolution, such as diffuse optical tomography," he notes. "PAT is a hybrid biomedical imaging technique that overcomes the drawbacks of conventional optical imaging modalities. PAT can provide strong optical contrast with high ultrasonic resolution, based on internally generated ultrasound due to short pulsed laser irradiation."

Wang also points out that the spatial resolution and imaging depth are scalable with the ultrasonic frequency. Therefore, this imaging modality breaks through the fundamental limitation of purely optical imaging in penetration depth while maintaining strong optical sensitivity and high spatial resolution.

"From a clinical practice view, a clinical ultrasonic scanner can be easily adapted to PAT so as to combine the high contrast of optical imaging and the high resolution of ultrasound imaging," he says. "Consequently, PAT systems are portable and relatively inexpensive. This field has grown explosively since 2003 and boasted the largest conference in the annual Photonics West meeting in 2010."

Moving forward, Wang notes that the next step for this technology involves both fundamental and translational research.

"More tissue components such as lipids and water, in addition to hemoglobin and melanin, have been recently imaged," he says. "Such new contrast mechanisms should enable new applications of PAT. Academic institutions and the industry are working with clinicians to translate this new technology to clinical applications."

Wang concludes that in addition to the continued growth of this research field, an important indicator of success is the use of PAT by biomedical researchers and clinical practitioners.

"According to the history of the field on PAT, the growth is expected to continue in years to come," he says. "Quite a few companies are commercializing PAT, which will make the technology available to the ultimate users."

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