Twenty years ago, Kenneth Wang, M.D., was jarred into his research specialty by a very humane reaction--he was horrified by the consequences of the only available treatment for a patient with Barrett's esophagus that was developing into esophageal cancer.

"He was a strapping young man and all we had to offer him was surgery to remove his esophagus," explains Dr. Wang. "The procedure cured him but, unfortunately, he had an adverse event which meant he would never be able to eat again and that really bothered me."

It bothered Dr. Wang enough that he has studied Barrett's esophagus and esophageal cancer ever since. What sets his lab apart from other groups in the field is the slew of scientific and technical advances that they develop and test to find new ways to attack the disease.

"There aren't many places that have as complete a set of tools as Mayo does," says Dr. Wang. "We're one of few places in the world that has a through-the-scope Raman spectroscopy probe and one of the few with laser confocal microscopy. We have looked at everything from gene discovery to macroscopic ways of slicing tissue."

Pioneers in Photodynamic Therapy

In the 1960s, Mayo physicians Richard Lipson and E. J. Baldes were the first to perform photodynamic therapy in humans. Photodynamic therapy for Barrett's esophagus works by injecting a light-sensitive drug into the bloodstream and activating it in the esophagus with a red laser light emitted from the end of a flexible tube. By demonstrating that the compound they used emitted fluorescence in cancer tissue, the pioneers uncovered a promising new diagnostic tool and initiated the modern era of photodynamic therapy. J. Thorac. Cardiovasc. Surg.42, 623-629 (1961).

Dr. Wang is one of the modern-day pioneers in photodynamic therapy. He is a member of the National Science Foundation's Biophotonics Study Panel--an unusual honor for a medical physician--and has been instrumental in developing photodynamic therapy into an effective ablative (removal) therapy. The goal of ablative therapies is to destroy abnormal cells allowing new, healthy cells to grow in their place. The Food and Drug Administration has approved the treatment for Barrett's esophagus with high grade dysplasia (precancerous changes). Dr. Wang is supported by the National Cancer Institute to conduct clinical trials in photodynamic therapy. The next step would be to see if measuring the deterioration of the light sensitive compound, porfimer sodium (Photofrin) produces a more effective treatment. It has proven effective in animals but requires a special spectrometer.

"As light hits it, the drug goes to higher energy level, transfers the energy to the tissue and kills the cell," explains Dr. Wang. "In the process of absorbing energy, the drug molecule is broken down. The physics term for this deterioration is photobleaching, and it would be really nifty, if we could monitor it because then we would know exactly when all of that drug has been used up in the tissue and, therefore, exactly when to stop. We could render a perfect treatment."

In addition, Dr. Wang has been analyzing patients' tissues prior to therapy to determine their most favorable treatment option.

"We have a large number of treatments now available for Barrett's esophagus," he says. "And we now have the ability to help decide which ones will be best for an individual patient."

Dr. Wang, whose lab is located on the Rochester campus, collaborates with clinical investigators located at the other Mayo Clinic campuses in Florida and Arizona on a variety of ablative therapies. In Arizona, gastroenterologists Virender Sharma, M.D., and David Fleischer, M.D., co-authored a study on radiofrequency ablation. The treatment uses precisely controlled heat that is delivered through bipolar electrode coils on the surface of a small balloon catheter. Their results indicate that the treatment is safe and effective for low-grade dysplasia in patients with Barrett's esophagus.

Chemoprevention

Trained in Dr. Wang's lab, Navtej Buttar, M.D., conducts cell culture and animal studies to look for drugs and natural products that prevent esophageal cancer in patients with Barrett's esophagus. He is also studying more basic mechanisms such as the relationship between inflammation and tumor development. The National Cancer Institute and Mayo Clinic are supporting a study to investigate the role of the Krueppel-like family of transcription factors (Klfs) in malignancy. A transcription factor is a protein that binds to specific parts of DNA. It helps control the transfer of genetic information from DNA to RNA.

Optical Spectroscopy and Imaging

Louis Wong Kee Song, M.D., spent part of his time as a research fellow in Dr. Wang's lab and went on to study at a premiere optics laboratory at the University of Toronto, Canada, to develop skills in optics research. Now he leads the lab's efforts in studying near-infrared Raman spectroscopy. The new device collects a form of light originating from the lining of the Barrett's esophagus. The goal of the study, which is supported by the National Institutes of Health, is to show that the novel imaging technology can provide enough information to replace biopsy as the most effective and convenient diagnostic tool. If true, it would be a boon to patients and their physicians who could make an instant diagnosis and begin therapy during the same procedure.

The group is also evaluating other optical imaging techniques, such as autofluorescence, narrow-band imaging and laser confocal microscopy.

"I really like the new novel technologies," says Dr. Wang. "The laser confocal microscope probe allows us to magnify at 400 times. You basically see what a pathologist sees without having to cut, slice, paraffin fix and stain. And you can make real time decisions and use those probes to help target areas of dysplasia and eliminate them."

Dr. Wang is less excited about the fact that they don't have a confocal microscope in the lab.

"We can look at tissue endoscopically and get this beautiful image of the cell pattern," he explains. "But once we get it out we can't get a matching image because confocal microscopy slices vertically and conventional light microscopy images on a different plane."

Endoscopic Mucosal Resection

The introduction of the endoscopic mucosal resection technique is arguably the biggest advance in the entire Barrett's esophagus field in the last decade. Dr. Wang leads the therapeutic program that deals with the use of advanced endoscopy to treat Barrett's esophagus and early cancers. He has achieved survival results using an endoscopic mucosal resection technique that are similar to the standard esophagectomy--a much more debilitating procedure.

The technique removes small nodules in the esophagus. The nodule is first injected with a solution to decrease bleeding, which forms a blister under the nodule and allows the physician to remove it without damaging the rest of the esophagus. Dr. Wang's group was the first to clinically observe that nodules are associated with a much greater risk of high-grade dysplasia progressing to esophageal cancer. "It's done in combination with all of our other techniques and we've done more than 1000 of them at Mayo," says Dr. Wang. "With EMR you have the answer right away. In the past, you had to biopsy and, if it showed a problem, it required a second procedure. In addition, the tissue sample is large and deep enough that the pathologist can make a firm diagnosis and stage the cancer with 100% accuracy."

Ganapathy Prasad, M.D., the newest member of the group, completed a masters degree in clinical research at Mayo and is now the lab's clinical research specialist. He also studies the interaction between the underlying connective tissue and epithelium in Barrett's and reflux disease.

"Our theory is that acid reflux transforms fibroblasts, which then secrete a substance that causes cells to divide wildly," says Dr. Wang. "It's like fertile soil--you need the right nourishment to take root."

Developing a Registry for Genomics Research

In a separate but collaborative effort, Yvonne Romero, M .D., has spearheaded the development of the Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry (EABE) Consortium.

"I am very excited about the registry because of the breadth of our support," says Dr. Romero. "It is a collaborative effort of 104 physicians from all three of Mayo's campuses and across multiple disciplines. Even more exciting, 60 percent of our patients have agreed to participate even though it requires a lifelong commitment of filling out questionnaires and allowing us access to their biopsy samples."

The registry collects and organizes physical, pathological, genetic, and environmental risk factor data from patients with Barrett's esophagus. The masses of comprehensive data collected is a growing and valuable resource for researchers studying the genomic steps involved leading from Barrett's esophagus to adenocarcinoma (cancer arising from glandular tissue).

Dr. Romero is interested in the risk factors and genetic basis for Barrett's esophagus and adenocarcinoma. Her goal is to help develop a genetic blood test as a simpler and more convenient way of screening for Barrett's esophagus than the current surveillance endoscopy. Her studies have shown strong evidence for susceptibility genes in familial Barrett's esophagus and adenocarcinoma.

She is also a member of the Barrett's Esophagus Genomic Study Group, a multi-disciplinary group of 154 physicians and scientists throughout the United States, Canada, South America and Europe, who collaborate to identify families in which two or more members have classic long segment Barrett's esophagus, with or without esophageal adenocarcinoma. The group collects blood specimens for genetic linkage analysis.

The Power of Research in a World-Renowned Medical Center

Mayo Clinic has a well-earned reputation for having a specialist in almost every disease. Mayo physicians become experts in rare diseases because they treat large numbers of people who have them. Good medical research requires access to volumes of patient data and samples. Mayo Clinic physicians see patients who have Barrett's esophagus every day. That means lots of opportunity for clinical observations that raise questions for researchers. They have performed the most radiofrequency ablation procedures to treat Barrett's esophagus, and the most endoscopic mucosal resections of all the academic medical centers in the U.S. And all of this data is being collected.

"We're making good headway," says Dr. Wang who is most proud of a study that shows long term survival data following ablative therapies for high grade dysplasia. The study demonstrates survival outcomes as good as those treated with the standard esophagectomy. (Am J Gastroenterol. 2007 Nov;102(11):2380-6. Epub 2007 Jul 19.) Now when Dr. Wang opens his door to find another strapping young man who has Barrett's esophagus, he can feel good about the treatment options he can offer him.

- Yvonne Hubmayr, March 2008