Contributions to Cancer Research

• Research on Immunoproliferative Small Intestinal Disease (IPSID).
• Research on lymphomas other than IPSID.
• Research on new agents and new treatments.

 

• The first and most important concept is that a chronic repetitive infectious insult to the gastrointestinal mucosa would eventually lead to inflammatory changes that left untreated would progress to malignancy. Our early studies on IPSID in the seventies were the first to show that repeated chronic infection in a childhood lead to the development of lymphoma in the small intestine 10 to 15 years later. Although we could not determine the precise nature of the infectious microorganism, but the fact that patients who were treated with tetracycline at an early stage, rarely developed the lymphoma was a strong argument that the process that lead to the lymphoma was infection related.  Other investigators followed this concept with later research in the late 80’s and early 90’s that showed association between H. Pylori, an infectious agent in the stomach and stomach cancer. In the 90’s it became clear that H. Pylori had a causative relationship to peptic ulcer and to stomach cancer. Accordingly, in the year 2005, the Nobel Prize in Medicine and Physiology went to two Australian physicians who worked extensively on H.Pylori’s relationship to stomach cancer. The citation made by the Nobel Prize committee, the committee emphasized the importance of the different avenues of research including research on IPSID which lead to the development of the research on the causative association between H. pylori and stomach cancer.

• The second concept is that the process of inflammation resulting from a chronic repetitive infectious insult to the gastrointestinal mucosa, is reversible.  My team and I identified the benign phase of IPSID and we treated those patients with antibiotics and most patients achieved a complete remission and avoided the inflammation from progressing to cancer.  It was one of the very first evidences that cancer in men is chemo preventable. Chemoprevention is the reversal of the neoplastic process after it start and we have proven beyond doubt that treating the infectious or the inflammatory phase of the neoplastic process of IPSID with antibiotics like tetracycline could reverse the process. It would prevent the deterioration of the inflammation to malignancy. Concept which was generated in IPSID research is the corner stone of chemoprevention of cancer now. This was corner stone of the two national trials done in the Unites States on chemoprevention of breast cancer and also chemoprevention of other solid tumors. I was personally the principal investigator of two clinical trials under the sponsorship of the National Surgical Adjuvant Breast and Bowel Project ( NSABP) at St. Luke’s Episcopal Hospital in Houston, Texas. These clinical trials have shown that breast cancer in women at high risk for the disease may be prevented in the majority of women by taking Tamoxifen or Raloxifene over a period of 5 years.  The first study was part of National Surgical Adjuvant Breast and Bowel Project, breast cancer prevention trial that compared Tamoxifen to placebo for breast cancer prevention. first trial proved that Tamoxifen reduces the risk of breast cancer in high risk women by 50%. The second NSABP study, compared the efficacy of two drugs, Tamoxifen and Raloxifene for prevention of breast cancer in women at high risk, and the study revealed that Raloxifene was as effective as Tamoxifen in prevention of breast cancer but had fewer side effects and perhaps some more benefits.

• The third concept, is the observation that the neoplastic process goes through a histopathologically benign appearing phase before progress into frank malignancy.  My team and I were among the first to describe the so called benign phase of IPSID. At this phase, at least hitopathologically , there are no changes which are diagnostic of cancer. However, the disease may indeed be already malignant at the molecular level. Very few studies have been done in IPSID in the benign phase, to determine the molecular nature of the lesion, when it is still in the benign phase. However irrespective as to whether the benign phase is malignant at the molecular level or benign at the histopathological level, this phase remains reversible by the use of antibiotics like tetracycline. This so called benign phase has also been shown in breast cancer, colon cancer and mouth cancer. When we described this benign phase in the early 70’s it was indeed a very novel idea and concept that cancer could indeed go through a benign phase before it becomes frankly malignant.I believe that the above three concepts made a major impact on how we treat cancer now and how we try to prevent it. Also they made a major impact on the evolution of cancer research and its funding. In my own mind I cannot think of a more important preventable cause for cancer than infection. And modern cancer research should focus on the relationship of infection to cancer. The model of Gardasil vaccine and the prevention of cervical cancer is only the iceberg in the story of the impact of infection on cancer.  I would not be surprised should in 10 to 20 years from today we learn that many of the diseases we treat now, ranging from leukemias, lymphomas and some solid tumors are indeed infectious in nature and could be easily prevented in the early stage. I cannot personally think of a more important and urgent research.In addition to my work on IPSID, my team and I have done a lot of research on lymphomas in the Middle East.  Research in this area is enclosed in section number 2 entitled “Lymphomas other than IPSID”. My research in this area has delineated the special features of lymphomas in the Middle East which distinguished these lymphomas from those seen in the west. In addition to the presence of IPSID in the Middle East, we were the first to show the high incidence of extranodal lymphomas in the Middle East. Almost half of the lymphomas seen at the American University of Beirut Medical Centre were extranodal , and among these extranodal forms, the intestinal lymphomas were most common. We have also delineated the rarity of follicular lymphomas in the Middle East. And that in children the most common lymphoma was Burkitt.

The third section deals with my research on new agents and new treatments. And here basically I made two major contributions:

1. The first relates to my work on Cisplatinum. In the early 70’s when Cisplatinum was discovered as an agent for the treatment of cancer, it was extremely toxic when given in one single dose. While I was serving as visitor professor of cancer medicine and research at M. D. Anderson Cancer Centre in 1976, I worked on the fractionation of the dose of Cisplatinum and instead of giving the whole dose over a period of 1 to 2 hours, I fractionated the dose to be given in 5 days. My research in this area eventually showed that fractionation of the dose of Cisplatinum make Cisplatinum more efficacious drug and certainly significantly less toxic. Cisplatinum is now used all over the world in a fractionated manner as a result of the work I did on this drug in the mid-seventies.
2. The second contribution is related to my work on intra-arterial hepatic infusional study. This was an attempt to explore the value of administering a higher dose to cancer confine to the liver versus giving the drug intravenously with a smaller dose reaching the liver tissues. This approach has shown success in several cancer categories specifically in cancer which are limited to the liver. This approach is currently used for the treatment of primary and / or metastatic disease to the liver.