In conjunction with our outstanding gastroenterology team (Drs. Canto and Dunbar) and expert pathologist (Dr. Montgomery), my laboratory has been investigating molecular events that drive the progression of Barrett’s esophagus to esophageal cancer.

There are two very important issues that need to be addressed by the Barrett esophagus/ esophageal cancer research community:

a.    First, we need better molecularly targeted treatment options for patients who already have established esophageal cancer.  As we know, the vast majority of presents with advanced malignancy that is often amenable to surgery.  For these patients, we need all the resources (”all hands on deck”) approach for cure.

b.    Second, we need better molecular predictors for identifying those individuals with Barrett esophagus who will progress to cancer.  Fortunately, the vast majority of patients with Barrett esophagus will never develop cancer in their lifetime – but a small minority will do so.  If we can identify this subset right at the outset using genetic tools, we can focus most of our resources on this subset of patients.

In the past year, funded almost entirely by philanthropic monies received through this website and the D’Amato Foundation, we have achieved considerable progress in identifying new targets in Barrett esophagus using cutting edge gene chip and other molecular profiling technologies.  One technique, that we call Serial Analysis of Gene Expression or SAGE, was first discovered right here at Hopkins in the laboratory of Dr. Bert Vogelstein, the most cited scientist in all of medicine.  SAGE allows us to identify all of the abnormally expressed genes in a particular tumor type compared to normal tissues from that same organ.  We have performed SAGE on endoscopic biopsies of Barrett esophagus and esophageal cancer, and have identified several new predictive and therapeutic targets (Figure 1).

Figure 1: A new molecular marker for Barrett progression identified by SAGE.  Expression of this marker is progressively increased during the transformation of Barrett esophagus to high grade dysplasia and cancer.  Moreover, cancers that express this molecule in the malignant cells have a worse prognosis than those that do not, suggesting it could have identify those patients who would need most aggressive therapy.

We have also developed a new technique of data integration in the laboratory called “Integrative Epigenomics” that uses a powerful computer algorithm to identify molecular abnormalities during Barrett progression (Figure 2).  This program was built by a very talented scientist, Dr. Hector Alvarez, who has been funded by philanthropic resources to perform esophageal cancer research.  Using this algorithm, we have also identified several promising new biomarkers for Barrett progression, including a particularly promising “blood test” for esophageal cancer.

Figure 2: Integrative epigenomics of Barrett esophagus progression.  An algorithm to integrate gene chip data that looks at DNA and RNA abnormalities in Barrett esophagus and adenocarcinoma, and helps “zoom in” on those most likely to be a major player in cancer formation.  This method can also help identify new biomarkers (for example, a new “blood test” that we are evaluating)

No Occult Cancer At Esophagectomy in Patients with Barrett’s Esophagus with High-Grade Dysplasia Who Have Undergone Surveillance with the Seattle Biopsy Protocol

Jean S. Wang, Hilary Cosby, Lisa Hicks, Elizabeth A. Montgomery, Malcolm Brock, Marcia I. Canto. Gastroenterology 2007; 132(4): A64. Digestive Disease Week, Washington, DC; May 2007.

Introduction: Historical studies in the surgical literature have reported the prevalence of occult cancer in patients undergoing prophylactic esophagectomy for Barrett’s esophagus with high grade dysplasia to be as high as 30-43%. However, it is unclear what type of endoscopic surveillance biopsy protocol was performed in these patients prior to surgery.

Aim: To determine whether use of the Seattle endoscopic biopsy protocol in patients with high grade dysplasia significantly reduces the prevalence of occult cancer at the time of esophagectomy.

Methods: We reviewed medical records of patients who underwent prophylactic esophagectomy for Barrett’s esophagus with high-grade dysplasia at Johns Hopkins Hospital from 1994-2006. Clinical records were examined to determine whether the Seattle endoscopic biopsy protocol was followed during endoscopy performed prior to surgery. Pathology reports were examined to determine whether occult adenocarcinoma was detected during surgery.

Results: A total of 39 patients underwent prophylactic esophagectomy for Barrett’s esophagus with high grade dysplasia during the study period. Among patients who had undergone endoscopic surveillance with the Seattle biopsy protocol, there were no (0/15) invasive adenocarcinomas detected within their resected surgical specimens. In contrast, among patients who had not undergone endoscopic surveillance with the Seattle biopsy protocol, 33% (8/24) had invasive adenocarcinoma detected in their resected surgical specimens.

Conclusions: The prevalence of occult adenocarcinoma in patients with Barrett’s esophagus and high-grade dysplasia is very low if the Seattle biopsy protocol is followed during endoscopic surveillance. Therefore, the standard care of esophagectomy for Barrett’s esophagus with high-grade dysplasia should be reconsidered.

E. Montgomery, MD

Here are some recommendations for reducing GERD and decreasing the amount of acid and food exposure in the esophagus

Stay upright for 3 hours after eating – this will allow your food to digest more completely and reduce the amount of reflux you have when you lay down

• Elevating the head of the bed – this can also decrease the amount of reflux that occurs when you lay down as gravity will help keep food in your stomach. Propping on pillows may not be as effective as putting blocks, books, or bricks under the upper posts of your bed. A big pile of pillows can cause you to hunch over, which may increase reflux
• Eat a low-fat diet – lower fat meals will digest more quickly, so you’ll have less reflux
• Don’t smoke – while smoking is more strongly associated with squamous cell cancer of the esophagus, it can also contribute to esophageal adenocarcinoma, which is the kind of esophageal cancer related to BE
• Reduce caffeine intake – caffeine relaxes the lower esophageal sphincter, which is the muscle at the bottom of the esophagus. When this muscle is relaxed, you’re more likely to have reflux of stomach contents into the esophagus. A little caffeine is probably okay, but multiple cups of coffee a day is too much. Remember that a standard size cup of coffee is actually pretty small, so one giant cup of coffee is actually equal to 2 or 3 cups of coffee! Many carbonated sodas also contain caffeine and tea (hot and iced) also contain some caffeine. To find out the caffeine content of beverages, a quick internet search for ‘caffeine content’ will pull up several sources, such as this one: http://www.cspinet.org/new/cafchart.htm
• Alcohol – drink in moderation. Alcohol relaxes the lower esophageal sphincter and can increase reflux. However, there are some studies that suggest moderate wine or alcohol intake can lower the risk of Barrett’s and esophageal adenocarcinoma (this will be addressed in a separate post)
• Weight loss – weight loss will also help improve reflux symptoms. Obesity increases the risk of both Barrett’s esophagus and esophageal cancer

- posted by Kerry Dunbar, MD

The study Dr. Montgomery mentioned followed the patients in the big photodynamic therapy study (mentioned in the blog post on PDT) for 5 years.  This new paper includes 5-year results for 138 patients who were treated with photodynamic therapy plus omeprazole and 70 patients treated with only omeprazole for 5 years.  Patients in the study were followed with upper endoscopy after treatment to look for residual BE, subsquamous BE, and dysplasia. 

Here are some details of what the study showed:

• The researchers looked at 33,658 biopsies from patients in both study groups (PDT vs omeprazole)
• About 5% of patients had subsquamous BE prior to treatment
• About 1/3 of patients in each group had some subsquamous BE after treatment
• The number of biopsies for each patient that showed subsquamous BE was very low, with only about ½ of one biopsy showing subsquamous BE for each patient (the exact numbers are 0.48 biopsies with subsquamous BE in patients treated with BE and 0.66 biopsies per patient in patients treated with omeprazole)
• The risk of buried BE was very low for patients in the study
• For study patients who later went on to develop dysplasia or cancer, the dysplasia/cancer was found in multiple biopsies on the surface. No dysplasia or cancer was only found in the subsquamous BE.

Another study, presented at Digestive Disease Week 2008, an international GI meeting (but not yet published as a full article), looked at subsquamous BE before treatment with RFA (Barrx) and after treatment with RFA. 

Here are details of what the study showed:

• 127 patients participated in the study and 2,151 biopsies were examined prior to any treatment
• Before treatment, 32 of 127 patients had some buried BE – about 25% of the patients
• Of all 2,151 biopsies, only 67 (3%) showed buried BE, so the number of buried BE biopsies per patient is low
• 35 patients had RFA and had completed all their follow-up biopsies. After treatment with RFA, only 1 biopsy showed subsquamous BE out of 1,223 biopsies
• For 16 patients who received sham treatment (they didn’t get RFA), and have had follow up biopsies: 20 of 290 biopsies showed subsquamous BE (about 4% of the biopsies)
• The final results of this study analyzing all the patients in the study haven’t been published yet, but probably will be soon

To summarize this information about subsquamous BE:

• Subsquamous BE can be found in many patients with Barrett’s esophagus whether they are treated with ablation or not
• The rate of buried BE/subsquamous BE is low after treatment with ablation therapy
• For patients who have been treated with ablation therapy, surveillance endoscopy with 4 quadrant biopsies should still be performed. Biopsies of the normal-looking squamous tissue (where the BE used to be) should be taken. This is the best way to detect subsquamous BE.

References:

Bronner MP, Overhot BF, Taylor SL, et al.  Squamous Overgrowth is not a Safety Concern for Photodynamic Therapy for Barrett’s Esophagus with High-Grade Dysplasia.  Gastroenterology 2009, volume 136, issue , p. 56-64. 

Shaheen NJ, Bronner MP, Fleischer DE,  et al.  Subsquamous Intestinal Metaplasia Is a Common Finding in Ablation-Naive Patients with Dysplastic Barrett’s Esophagus, and Significantly Decreases in Prevalence After Radiofrequency Ablation. Gastrointestinal Endoscopy, Volume 67, Issue 5, April 2008, Page AB176.

- posted by Kerry Dunbar, MD

Bronner MP, Overholt BF, Taylor SL, Haggitt RC, Wang KK, Burdick JS, Lightdale CJ, Kimmey M, Nava HR, Sivak MV, Nishioka N, Barr H, Canto MI, Marcon N, Pedrosa M, Grace M, Depot M; International Photodynamic Therapy Group for High-Grade Dysplasia in Barrett’s Esophagus. Squamous overgrowth is not a safety concern for photodynamic therapy for Barrett’s esophagus with high-grade dysplasia. Gastroenterology. 2009 Jan;136(1):56-64

Elizabeth Montgomery, MD

The HALO 90 and 360 are FDA approved for sale and use.  There are still lots of studies ongoing, which is not uncommon for new technologies in medicine – when any drug, treatment, or device is approved, studies continue to be done after approval. 

There are several types of studies that get done after approval.  Here are a few types of studies that get done after approval:

1.  Studies to confirm the initial results (yes, drug A does work)

2.  Studies too look for long term issues related to treatment – these are longitudinal studies or registry studies (what happens 10 years after drug A is given)

3. Studies of the cost of care and treatment (does drug A save money in the long run if compared to other treatments?)

4. Studies using the drug/device in a new patient population or for a new disease (are the results of treatment with drug A the same in patients over age 80?)

So defining whether a treatment is still experimental isn’t always clear as research continues for many new drugs and devices.   It’s always worth talking with your own physician to get her/his opinion about new medications and treatments.

 - posted by Kerry Dunbar, MD

1. Do you feel that all hospital GI departments are coordinating in an effort to preserve or save all records of patients treated for LGD and HGD, and by all available treatments? I guess that I am trying to ask you if this precious data is being collected by any one particular organization, such as the American College of Gastroenterology, or the National Institutes of Health?

Hospital GI departments do keep records of all procedures, but mainly for clinical use.  Keeping records of individual patients by diagnosis and treatment type for research is more challenging.
Depending on the type and amount of data collected, permission may need to be obtained from every patient to store their information in a database.  Databases for research need to be secure (password protected, securely backed up, etc) to protect patient privacy and prevent loss of data.  This kind of data collection and storage is expensive, so not all departments and programs are able to afford this. To my knowledge, the NIH doesn’t have a BE database.  There’s a national database of cancer patients (the SEER network), but it doesn’t include precancerous conditions like BE.  There is a national data collection project, the CORI project, which stands for Clinical Outcomes Research Initiative (www.cori.org),  that collects some data on endoscopy outcomes.  This group has published a few papers on BE, but I haven’t seen anything specifically on types of BE treatment.

2. I was diagnosed with BE without dysplasia, around 3 months ago and have read about a lot of research that has one common theme; “small studies”. This is very discouraging for myself, when cancer from BE has been around so long and is increasing.

Small studies are a problem in many areas of medical research.  As common as Barrett’s seems to be, recruiting research patients isn’t always easy.  Academic referral centers can attract more patients with BE if they have specialized diagnosis and treatment programs, but for small centers and community practices, BE is a less common diagnosis.  For anyone who’s interested in participating in research studies for BE, one place to look for studies is on www.clinicaltrials.gov. This is a searchable website sponsored by the government where clinical trials are registered.  Details are given about research studies that are available and the contact information for the researchers is on the site. 

3. There seems to be a lack of funding from the NIH for BE research. Do you agree? I believe that we need a campaign for awareness of BE and its potential.

I searched the CRISP database, which is a list of all the NIH funded studies.  Using the search term ‘Barrett’s’, there are 25 grants that currently fund (at least in part) research into Barrett’s esophagus.  Certainly there are more NIH funds devoted to other cancers (colon, breast, etc) and for other diseases, such as heart disease, which affect more people.  There’s only so much NIH funding to go around and the budget has been stretched for the last few years for a variety of reasons.  Funding for research studies is also available through several of the gastroenterology societies, such as the American Gastroenterological Association, American Society of Gastrointestinal Endoscopy, and American College of Gastroenterology, although these grants are generally smaller in size than NIH grants. Occasionally funding from private donors is available for research and several of the pharmaceutical and device companies also have research funding programs.

An awareness campaign for Barrett’s would be great!

4. Also, all of the currently available treatments for HGD, excluding removal of the esophagus, must carry a bias by the treatment specialist, as these treatment centers invest in the different equipment, for different treatments. Do you think that any of the treatment results are skewed, or not properly reported due to rival technologies?
There are several treatment options for BE. Not all specialists get trained in every type of therapy.  Buying each type of equipment is also expensive and not feasible for every academic medical center.  These issues make head-to-head comparisons of Barrett’s therapies more difficult.  From attending gastroenterology research conferences, it does seem that there is interest in comparing RFA with cryotherapy, so hopefully some of these studies will be up and running soon. 

There are commonly accepted criteria for reporting studies in the medical literature. For clinical trials, the rules are called the CONSORT criteria and are a list of issues that must be reported in papers about clinical trials.  Most studies also go through the peer-review process, first if they’re being funded by grants, then by the local institutional review board at each hospital, and then also when the manuscript is submitted for publication. The scientific design, results, and reporting are closely inspected, which can help with the reporting process.  Clinical trials of drugs and treatments are also required to be registered with clinicaltrials.gov. These things can help make sure results are reported clearly and honestly. 

Also, most researchers have spent years training (think 8 years of college and medical school plus 3 years of internal medicine and at least 3 years of gastroenterology training), and get specific training in research ethics, so intentional misreporting shouldn’t be common.  For almost all the medical research journals, authors are required to report where all the funding for the study came from.. Authors are also required to report any potential conflict of interest related to the research, such as whether the author is on the board of directors for the company, has been paid to consult for the company, etc. The information about study funding and potential conflicts of interest is usually located at the end of a medical research article.  So, for all the reasons listed above, I don’t think there’s a lot of intentional misreporting or skewing of research results.