Optical technology method shows promise for early detection of pancreatic cancer

Evanston 01 August 2007Optical technology developed by a Northwestern University biomedical engineer shown to be effective in the early detection of colon cancer now appears promising for detecting pancreatic cancer, the fourth most common cause of cancer deaths in the United States. Known as a silent killer, with no method of early detection, pancreatic cancer spreads rapidly and seldom is detected in its early stages. The new technique could lead to the first screening method for pancreatic cancer in asymptomatic patients, according to Vadim Backman, developer of the technology and professor of biomedical engineering at Northwestern's Robert R. McCormick School of Engineering and Applied Science.

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Vadim Backman and Yang Liu, a former graduate student of Vadim Backman's, teamed up with physicians at Evanston Northwestern Healthcare (ENH) to test the technique in a pilot study of 51 patients. The researchers found they could detect both early- and advanced-stage pancreatic cancer without touching or imaging the pancreas.

The new detection techniques produce an optic fingerprint from the altered tissue and then enhance the data for a clearer diagnosis. The researchers scanned tissue samples from 19 people already diagnosed with pancreatic cancer and 32 without the disease. They properly distinguished patients with cancer at an accuracy approaching 100 percent. The clearest results came from patients in the earliest stages of the disease.

The extraordinarily sensitive technique, which is minimally invasive and takes advantage of certain light-scattering effects, can detect abnormal changes in cells lining the duodenum even though the cells appear normal when examined with a conventional microscope. The results, which are being published in the August 1 issue of the journal Clinical Cancer Research, show that the changes accurately predict the presence of cancer.

More than 30.000 people in the United States die each year from pancreatic cancer. Count Basie, René Magritte, Billy Carter and Joseph Cardinal Bernardin all died from it; Luciano Pavarotti is fighting the disease. The overall five-year survival rate is less than 5 percent; most patients die within the first two years. If detected early, when the tumour can be successfully removed, however, the survival rate is 100 percent if a precancerous lesion is found and 50 percent for a stage 1 cancer.

"Using endoscopy and taking biopsies of the pancreas are extremely risky procedures that are not used on asymptomatic patients", stated Vadim Backman. "When a patient becomes symptomatic, it is too late. This creates a vicious cycle that we want to break. We have found that we can take measurements safely in the duodenum and use a biological phenomenon called the field effect to our advantage", he stated. "If you have a precancerous or cancerous lesion in the pancreas, even tissue that looks normal and is away from the lesion - including in the duodenum, a different organ than the pancreas - will have molecular and other kinds of abnormal changes. No one can detect these changes earlier than we can."

To test the effectiveness of the technology in screening for pancreatic cancer, Vadim Backman and Yang Liu have been collaborating with Randall E. Brand, M.D., a gastro-enterologist with Evanston Northwestern Healthcare who specializes in pancreatic cancer and is an associate professor of medicine at Northwestern's Feinberg School of Medicine. They have shown that they can detect changes in the duodenal tissue and that these optical markers predict the presence of cancer.

The researchers found that the same optical markers that were significant in earlier colon cancer studies at ENH using Vadim Backman's technology proved also to be significant for pancreatic cancer. An optical marker is a signature at the sub-micro level that shows changes in tissue due to the presence of a precancerous lesion or cancer.

"We also found that the diagnostic performance of the technique is not compromised by risk factors in the patients", stated Yang Liu, now a senior scientist at Johnson & Johnson. "The markers don't depend on age - the cells know if they are old or if they are cancerous. The markers do not change if the patient is a smoker. And the markers do not change with the location, stage or size of the tumour in the pancreas."

Most cancers in the pancreas originate from the main pancreatic duct, a 10-centimeter-long duct located in the pancreas that perforates the duodenum, the first and shortest part of the small intestine. The pancreatic duct is difficult to reach and if attempted, it is a risky procedure with a 20 percent chance of significant complications, including acute pancreatitis.

In the study, biopsies of normal-looking tissue were taken from the duodenum near the opening of the pancreatic duct for analysis. For each sample, light is shined on the tissue. The light scatters and some of it bounces back to sensors in the fiber-optic probe. A computer analyses the pattern of light scattering, looking for the "fingerprint" of carcinogenesis in the nano-architecture of the cells.

By studying tissue extracted from an area adjacent to the pancreas, the researchers were able to screen all 51 patients with little risk of inflammation or other complications. While clinical use is perhaps three to five years in the future, and ongoing studies are needed to confirm the results, the researchers hope the tests can eventually be done without the biopsy.

Because the study uses tissue samples taken from each patient's duodenum, the uppermost section of the small intestine which can be accessed during endoscopies, doctors could potentially generate earlier diagnoses by examining low-risk patients as part of routine examinations.

The next stages of the pancreatic cancer research trials incorporate some examinations that are biopsy-free and use a shoebox-sized fiber-optic version of the new system, a device now being tested during colonoscopies. The portable system however was not yet used in the pancreatic cancer studies because the probe needs to be modified for the different scope used in endoscopy, but the underlying technology behind all of the examinations is the same.

"Besides improving on the technology, we need to determine whether other medical conditions including other cancer types or diseases of the pancreas such as chronic pancreatitis or acute pancreatitis can be distinguished with our technology from pancreatic cancer. It is also important for us to validate our prediction rule on a larger number of pancreatic cancer cases as well as different control groups", stated co-author Randall Brand.

The researchers found the technique identified with 100 percent accuracy each person who had a resectable cancerous tumour in the pancreas. Resectable means the tumour can be removed surgically, which in this study is defined as stage 1 or 2 tumours. Some people were identified who did not have a tumour; it is uncertain whether this is a false finding or if it means those people could be at risk for developing pancreatic cancer and need to be watched closely.

The method combines two complementary technologies developed with the support of seven NSF grants, including a CAREER award, by Vadim Backman and colleagues in his lab: four-dimensional elastic light-scattering fingerprinting (4D-ELF) and low-coherence enhanced backscattering spectroscopy (LEBS). The researchers found that the two combined work better than one alone in pancreatic cancer screening.

The success of the pancreatic cancer screening study follows on the heels of extremely positive results in studies using the two optical technologies for the early detection of colon cancer. In the colon cancer work, Vadim Backman has been collaborating with ENH gastro-enterologist Hemant Roy, M.D., associate professor of medicine at the Feinberg School, who is overseeing clinical trials at Evanston Hospital. Dr. Roy also is a collaborator on the pancreatic cancer work.

"The results in our colon cancer work, in which measurements are taken from the rectum, led us to wonder if we could use tissue taken from the duodenum to screen for pancreatic cancer", stated Vadim Backman. "Our study published in Clinical Cancer Research (CCR) has shown that not only can we detect large tumours but early tumours as well."

"This new work extends the concept of the field effect, or field carcinogenesis, to the pancreas", stated Dr. Roy. "While the pancreatic cancer research is preliminary, this extraordinarily exciting work offers the prospect of providing an accurate and practical means for screening this lethal malignancy."

In the trials that began before the pancreas research, the researchers saw encouraging results with colon cancer detection in a study of 500 patients. The new approach also predicted, with 100 percent accuracy, polyps in patients diagnosed with a simultaneous colonoscopy. Because the experimental procedure only scans the outer few centimeters of the colon and does not require the uncomfortable cleansing process required for a colonoscopy, the researchers believe the approach will encourage more people to get screened before they develop symptoms of disease.

Whether in a laboratory or in the portable, fiber-optic system, a xenon lamp shines intense, white light through a series of lenses and filters onto the specimen. The light refracts through the outermost layer of tissues and scatters into a spectrograph, a device that separates a beam of white light into its component wavelengths and measures them. An image sensor captures the result for analysis by a computer. The technological breakthrough is the ability to cause light to penetrate the cells most affected by cancer without hitting deeper unaffected cells and to scan cell structures on the scale of nanometers, smaller than a doctor can see with a microscope.

"Contemporary diagnostic medicine frequently relies on invasive procedures, such as endoscopy, to detect disease. In the fictional world of Star Trek, a doctor is able to make a diagnosis without ever interrogating an organ. Biophotonics shows that this approach may be closer to reality that one might expect", added Vadim Backman.

The pancreatic cancer screening test currently is in a larger clinical trial at Evanston Hospital to validate the effectiveness of the technique. Funded by the National Science Foundation (NSF) and the National Institutes of Health (NIH), the study has approximately 200 participants. The pilot study also was supported by NSF and NIH.

"We were so encouraged by the successes with colon cancer that we decided to drive the research in a new direction. With colon cancer, you have time, even years, to treat it successfully. Unfortunately, for pancreatic cancer it's not only critical to detect it early, or even before it becomes cacnerous, but in many cases it is really the only hope", stated Leon Esterowitz, the NSF programme officer who has been supporting this research.

Eventually, the researchers hope to expand their study to breast cancer, lung cancer and other variations of the disease. While the new techniques must undergo further study before their effectiveness can be confirmed, the researchers have partnered with American BioOptics to fully develop the technology. In July, American BioOptics received an NSF Small Business Innovation Research grant to further develop the technology for colon cancer screening and ready the system for commercialization.

In addition to Vadim Backman, Yang Liu (lead author), Randall Brand and Hemant Roy, other authors on the CCR paper, titled "Optical markers in duodenal mucosa predict the presence of pancreatic cancer", are Vladimir Turzhitsky and Young L. Kim, from Northwestern University's department of biomedical engineering, and Nahla Hasabou, Charles Sturgis, Dhiren Shah and Curtis Hall, from Evanston Northwestern Healthcare's department of internal medicine.


Leslie Versweyveld

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