Chapter 29: Work on Ulcerative Colitis and A Growing Interest in High-Risk Patients
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Dr. Levin begins this Chapter by recalling that his interest in high-risk patients began with his work with his mentor at the University of Chicago, Dr. Kirsner, who was interested in the relationship between ulcerative colitis and colon cancer. Dr. Levin set up a very fruitful study (between 1977 and 1983), taking random biopsies in four Chapters of the colon to find dysplasia. (It turned out that the patient pool included mostly moderate risk individuals.) He explains that the methods of study available were not sophisticated in comparison to today’s technologies. He explains the weaknesses of the study, its findings, what could have been learned with more sophisticated approaches, and the lessons learned from this experience. Dr. Levin also notes that even though this study did not provide “robust conclusions,” it laid the groundwork for later work on the relationship between dysplasia and cancer. He also defines dysplasia as an abnormality in cellular and tissue architecture that can lead to pre-cancerous conditions.
Dr. Levin emphasizes that this work strengthened his interest in high-risk patients, and he believed that this kind of study to lead to greater understanding of colorectal cancer, work he continued when he came to MD Anderson, when he began to study Lynch Syndrome (hereditary nonpolyposis colorectal cancer). He explains that this work was enhanced when he was able to recruit Patrick Lynch and Bruce Boman, both experts in high-risk individuals. Dr. Boman started to DIFI cell line with a high expression of epithelial growth factor (used eventually by Dr.John Mendelsohn in studies leading to discovery of monoclonal antibody 225). Dr. Levin describes the support he provided both researchers in his capacity as Department Chair.
Identifier
LevinB_05_20130827_C29
Publication Date
8-27-2013
City
Houston, Texas
Interview Session
Topics Covered
The Interview Subject's Story - The Researcher The Researcher Overview Definitions, Explanations, Translations Professional Practice Understanding Cancer, the History of Science, Cancer Research The History of Health Care, Patient Care Discovery and Success
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Disciplines
History of Science, Technology, and Medicine | Oncology | Oral History
Transcript
Well, the importance of having a good design, having a very good idea of the underlying numbers that it would take to have an outcome that would be meaningful, and probably not enough statistical consultation ahead of time and not enough ability to make changes during the course of the study that were scientifically valid. Now, having said all that, this did lay the groundwork for others to follow, and others did take some of the data that I had helped to generate and managed to follow it up and put together a publication reporting some of this work.
Tacey Ann Rosolowski, PhD:
And what were the findings of some of these later projects?
Bernard Levin, MD:
Tacey Ann Rosolowski, PhD:
So we are recording, and let me just put the identifier on. It is the twenty-seventh of August, 2013. This is Tacey Ann Rosolowski, and I am on the phone today with Dr. Bernard Levin. This is our fifth session together. Thank you very much, Dr. Levin for your patience with our audio challenges and for joining us again.
Bernard Levin, MD:
You’re always welcome.
Tacey Ann Rosolowski, PhD:
We were going to start talking today about some work with ulcerative colitis that you did when you were at the University of Chicago.
Bernard Levin, MD:
Right. It had been one of the interests of my mentor there, Dr. Joseph B. Kirsner, K-i-r-s-n-e-r, who recently died at the age of 103, that he had observed, as had others, that people with longstanding ulcerative colitis had increased risk of colon cancer, and that cancer usually occurred in an earlier age than the usual and was often more virulent. And the challenge which I had undertaken was to try and see if it was possible to identify individuals by doing colonoscopies and doing biopsies, random and multiple biopsies of the lining of the colon, and then to have these biopsies examined by a specialist pathologist who was experienced in looking at these kinds of biopsies to determine if there was any signs of precancer. We recruited a pathologist from St. Mark’s Hospital in London, which was known for its research on colon cancer and ulcerative colitis, and his name was Dr. Robert Riddell, R-i-d-d-e-l-l, and he came to the University of Chicago and we set up a very fruitful study to determine if there was a way of finding these high-risk individuals.
Tacey Ann Rosolowski, PhD:
About what year was this?
Bernard Levin, MD:
This would have been between 1977 and 1983. The methodology available at that time wasn’t all that sophisticated in terms of being able to really look at the lining of the colon with anything other than the magnification of the scope itself. There weren’t any now currently available special types of filters and imaging devices, so we relied on random biopsies, multiple biopsies in four segments of the colon. And this was a study that was quite painstaking and time-consuming, but actually probably wasn’t well enough designed to really yield a definitive outcome.
Tacey Ann Rosolowski, PhD:
What do you mean that it was not well enough designed?
Bernard Levin, MD:
Well, we didn’t actually have the numbers of patients that we required to really find the number of cancers that we could then identify, so the study was inconclusive. We probably helped a few people because we found some very early cancers in a couple of people, but in terms of actually coming up with a scientifically valid and robust conclusion, we just didn’t have enough numbers. But also it turned out that the patients who were entered into the study were probably also those who had, for whatever reason, a largely inactive colitis and were not in a high-risk group. So within the high-risk group there were probably various stratifications, and this was a particularly low-risk group, so the number of cancers we found was very low.I conducted this work under the auspices of the University of Chicago Cancer Research Center then under the direction of Dr John Ultmannn a formidable figure in oncology in the USA.
Tacey Ann Rosolowski, PhD:
Just so I’m clear, so did you know going in that these patients were not high risk, or was that discovery an outcome of the actual study itself?
Bernard Levin, MD:
It was one of the incidental findings, yes.
Tacey Ann Rosolowski, PhD:
I see. And what were the indications of this high risk, or lack of high risk?
Bernard Levin, MD:
Lack of high risk. Well, just the low incidence of cancer, and, in fact, the low incidence of the change in the lining of epithelium which we were looking for, called dysplasia. So we, in a sense, stumbled on people, or we were drawn to study, or I was drawn to study, particularly low-risk group, as far as people with colitis was concerned, that didn’t develop much cancer. And it was interesting and, in retrospect, perhaps we would have been able to learn more if we had some of the technologies that are available today to examine the lining of the colon with the more sophisticated types of approaches, as well as more sophisticated ways to analyze the epithelium itself.
Tacey Ann Rosolowski, PhD:
I see. I see. So what were the kind of big lessons that you took away from this study, in terms of your own work?
Bernard Levin, MD:
Well, that the classification of the dysplasia that was used was usable in practice and that there was some evidence of reversibility. Even if you had developed evidence of dysplasia at an early stage, it was reversible. So it wasn’t inevitable that those people who showed signs of this change all went on to cancer, and that there were some people where it just remained at a very low ebb for a long time.
Tacey Ann Rosolowski, PhD:
Hmm. Interesting.
Bernard Levin, MD:
Yeah.
Tacey Ann Rosolowski, PhD:
Yeah. And I suppose—has there been any work on what makes individuals manifest those different outcomes?
Bernard Levin, MD:
Yes. Now there’s much better understanding of ulcerative colitis, not only its pathogenesis as an inflammatory condition, but also its management and quite a lot about the biology of inflammation.
Tacey Ann Rosolowski, PhD:
I never really asked you what dysplasia is. Is it primarily an inflammatory effect?
Bernard Levin, MD:
No, it’s not. I should have defined it. It’s an abnormality both in the cellular architecture and in the architecture of the tissue that could lead to precancer. It’s on the pathway, but it’s not a one-way road. In other words, the fact that you show these changes doesn’t mean that it’s inevitably going to lead to a more dire outcome.
Tacey Ann Rosolowski, PhD:
And what exactly are the changes in the architecture of this—
Bernard Levin, MD:
Well, they’re changes associated with cells that look as if they’re dividing abnormally. And the tissue itself begins to assume an appearance that looks more like it could be premalignant.
Tacey Ann Rosolowski, PhD:
I see. So I can understand why there’s a pressing need to have pathologists who are very skilled actively involved.
Bernard Levin, MD:
Correct.
Tacey Ann Rosolowski, PhD:
Yeah. Now, you mentioned, before we turned on the recorder, that this work actually led you to become interested in high-risk patients, as opposed to the low-risk patients that happen to be involved in this study.
Bernard Levin, MD:
Right.
Tacey Ann Rosolowski, PhD:
And why did you develop that particular interest?
Bernard Levin, MD:
Well, I thought that it would be a clue to understanding colon cancer in general and would be a way of making a difference for a particularly at-risk group. I also, at the same time as I’d mentioned previously, was able to conduct some studies on the chromosomes of people with—or not on the people, but on the lesions themselves, on the adenomas and the cancers that arose in people with cancer of the colon, and I thought that being able to study these abnormalities would give some insight into what went on in the regular risk, not low-risk, but the regular-risk cancers. So they were tied in my mind as a way of trying to understand how colon cancer developed. As I may have mentioned, my close collaborator in this work was Dr Amelia Reichmann, a cytogeneticist from Argentina.
Tacey Ann Rosolowski, PhD:
I see.
Bernard Levin, MD:
But as I think I may have mentioned previously, all of this work was relatively primitive compared to what followed at Johns Hopkins and other places, where the real understanding of the genetics of colon cancer came about from the phenomenal efforts of Bert Vogelstein and others who were able to put together a theory of colon cancer developed based on very sophisticated gene discoveries, and any work that I had done was minor in comparison.
Tacey Ann Rosolowski, PhD:
Is there more that you would like to say about that period of your work?
Bernard Levin, MD:
Only that when I came to MD Anderson, I was very interested in continuing at a departmental level the work on high-risk individuals, those with Lynch syndrome, which is an inherited predisposition not only to colon cancer, but also cancers of female genital cancer and kidney cancer and pancreas cancer and others. And that work was enhanced by the ability to recruit Patrick Lynch, the son of Henry Lynch, who’s the discoverer after whom the syndrome is named. Patrick was then ending his training at Baylor, and he joined the faculty at MD Anderson, and I was delighted to recruit him. I also recruited somebody who stayed for a while at MD Anderson, Bruce Boman. He came from the National Cancer Institutesand he, too, was interested in high-risk individuals, particularly those with familial polyposis and the related syndrome called Gardner syndrome, which are one in the same except that those with Gardner syndrome show evidence of growths under the skin as well, fibromas. And Bruce Boman, amongst his other achievements, was able to develop a cell line called DiFi, D-i-F-i, which happened to have a very high expression of epithelial growth factor—this is kind of a small-world story—and subsequently used quite extensively by Dr John Mendelsohn in his early studies on epithelial growth-factor antibodies.
Tacey Ann Rosolowski, PhD:
Interesting.
Bernard Levin, MD:
None of this was intentional, of course.
Tacey Ann Rosolowski, PhD:
Mm-hmm. Mm-hmm. Did you end up collaborating with Dr. Lynch and Dr. Boman in studies?
Bernard Levin, MD:
Yes, yes, of course.
Tacey Ann Rosolowski, PhD:
And would you like to talk about that a bit?
Bernard Levin, MD:
Well, Dr. Boman’s work related to a number of issues. I was involved with him in the DiFi work as was Dr Marsha Frazier, and then subsequently he left. Then Patrick Lynch and I and others were very much involved in studies of familial polyposis, and the first celecoxib (Celebrex) chemoprevention study was done by Patrick Lynch and Gideon Steinbach, who’s now in Seattle, and investigators at St. Mark’s Hospital in London. They studied the patients and the families whom Patrick Lynch had been accumulating because of his expertise and great reputation in the field of high-risk families. So he is knowledgeable not only about Lynch Syndrome, but also about this other condition where the colon and, in fact, other parts of the GI tract are just carpeted with hundreds or thousands of adenomas.
Tacey Ann Rosolowski, PhD:
And what were your contributions to those studies and the finding?
Bernard Levin, MD:
Well, I was an active participant, supporter, involved in, I suppose, helping to make sure that the right academic environment existed, as the department chair and also as an interface with the company that provided the study drug.
Recommended Citation
Levin, Bernard MD and Rosolowski, Tacey A. PhD, "Chapter 29: Work on Ulcerative Colitis and A Growing Interest in High-Risk Patients" (2013). Interview Chapters. 1365.
https://openworks.mdanderson.org/mchv_interviewchapters/1365
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