fact that it "forces you to step outside of your traditional thinking."

Wells, who is associated with Norris Cotton Cancer Center's Comprehensive Breast Program, agrees whole-heartedly. Her role in the research has been to try to correlate the pictures generated by each of the modalities with characteristics in actual tissue extracted through biopsies or surgery. "Instead of just saying, 'Yes, we saw cancer,' and 'Yes, Wendy says it's cancer,' we [try] to think of things that were happening in the tissue . . . that could be measured," says Wells. That is, the characteristics that created the image.

Mammograms, she explains, look at architectural distortions and masses in breast tissue. So clinical pathologists are trained to look for their correlates—accompanying changes in the structure of cells in those tissues. But the new modalities look at totally different things. They look at oxygenation, hemoglobin concentration, elasticity, conductivity, permittivity (a measure of a tissue's ability to store electrical energy)—"all these things that, to be quite honest, I didn't have a clue as to what the underlying tissue correlatesmight be," admitsWells. "So we had to all sit down and figure out what the correlates were supposed to be. . . . That requiredme to do some really abstract lateral thinking."

Now, instead of focusing on cytology and epithelial architecture, Wells looks at blood vessels, fat content, water content, and various characteristics of the stroma (the supporting tissue) when she's working with tissue samples from the breast imaging projects. It fascinates her, she says, that in her clinical, non-research work, "I make all these diagnoses on one category of cells, and it turns out that tons of information is happening around it that I don't even register."

Finding the tissue correlates for the modalities is "a huge amount of tedious work," she admits. But "if those modalities can be validated in a way that can either prevent multiple [mammography] follow- ups or screening biopsies, that's a big deal." That's

Mammograms look at architectural distortions in breast tissue. But the new modalities look at totally different things. They look at oxygenation, hemoglobin concentration, elasticity, conductivity, permittivity . . . "all these things that, to be quite honest, I didn't have a clue as to what the underlying tissue correlates might be," admits pathologist Wells.

because many women would know sooner whether they have breast cancer or not and thus could avoid the stress and expense of those additional procedures.

However, all the clever engineering and innovative pathological techniques won't matter much if the modalities don't help real, live patients. And figuring out whether they are able to do that is resting on the generosity of hundreds of women who have agreed to participate in trials of the research.

As the project's clinical research coordinator, DHMC nurse Christine Kogel recruits women to participate in the breast imaging studies. In the main branch of the study, women who have been called back for a biopsy have their breasts imaged by some or all of the new modalities. "Recruiting these women is extremely difficult," says Kogel, because they have just been told that they may have breast cancer. Many women feel too overwhelmed to even consider participating in research that they are probably not going to benefit from themselves. Yet some women agree to participate because they have had mothers, sisters, other relatives, or

"Recruiting these women is extremely difficult," says Kogel, because they have just been told that they may have breast cancer. Many women feel too overwhelmed to even consider participating in research that they are probably not going to benefit from themselves. Yet some women agree to participate because they have had relatives or friends who have had breast cancer. And some are just altruistic.

friends who have had breast cancer. Others are drawn to the possibility of creating any way other than mammography to detect breast cancer because of the discomfort involved in compressing breast tissue. And some are just altruistic, explains Kogel.

The other branches of the clinical studies depend on women who have already been diagnosed with breast cancer. In what the researchers call the neoadjuvant branch, women who are receiving chemotherapy to shrink their tumor before surgery agree to have their breasts imaged at set intervals: before chemotherapy, 48 hours after the first dose of chemo, one week after the first dose, every subsequent time they come in for chemo, and one last time before surgery. In this study, the researchers are interested in seeing whether the modalities can help monitor the effectiveness of chemotherapy.

In the third branch, measurements of a tumor are taken with a probe: first in the operating room, while the tumor is still in the woman's breast, and then later in the pathology lab. The hope here is to better correlate the images with the actual tissue.

Paulsen and Poplack hope that the data gleaned from the latest round of clinical trials will help determine which modalities to take to the next level—a large, national, multicenter trial. The current clinical trials will also help clarify where these modalities might fit into the clinical setting. But it will be several years before the teams reach either of those goals.

The comprehensive results from the first round of clinical trials were just published, in May 2007, in the journal Radiology. The results were "reasonable, probably better than I might have expected when we first started," says Paulsen, but "not eyepopping." None of the electromagnetic modalities (EIS, MIS, and NIR) were fantastic at detecting malignant breast tumors by themselves. (MRE was not included in the study because it is not as developed, and so the researchers did not have as much data.) Each electromagnetic modality showed strengths, however. EIS showed good sensitivity (meaning that it was good at