Although the encounter with a patient that changed my professional life forever occurred more than twenty years ago, the poignancy of it feels as if it happened yesterday. I had just finished my Fellowship in Medical Oncology at Roswell Park Cancer Institute in Buffalo, New York. A beautiful, young 32 years old woman was admitted with a diagnosis of acute myeloid leukemia (AML). The story she gave was rather peculiar. She had become pregnant almost two years before this admission with twins. During the pregnancy, she developed a fetish to smell gasoline. So, most days of those nine months, she would go to the corner gas station, buy a dime's worth of gasoline and smell it all day. At the end of nine months, she delivered a healthy set of twin daughters, but six months later, she was found to have low blood counts and eventually, a diagnosis of myelodysplastic syndrome (MDS) was made. This was probably, in some part at least, related to the toxic exposure she had experienced as a result of smelling gasoline. In any case, there was no treatment for MDS at the time, and she only received supportive care with blood transfusions. Six months later, the disease progressed to AML and that is when she came to see us at Roswell Park.

We gave her high dose induction chemotherapy, to which she responded well and after a rather stormy course, entered a complete remission six weeks later. How sweet it was to see her going home with her lovely daughters at the end of this therapy! We then gave her three courses of standard consolidation therapy and she did very well. During these repeated hospitalizations, and interim outpatient clinic visits, we became very close to each other. During each encounter, we talked to our hearts' content, and JC shared many of her personal anxieties with me, and I learned to appreciate the challenges of a schizophrenic life torn between fighting a potentially lethal illness at the ripe age of 32 while pretending to be a normal mother to 3 year old girls. At times it was heart-breaking and at other times, the sheer force of her courage and sublimity of the human spirit was brought home with incredibly graphic detail.

Courage takes many forms. There is physical courage, there is moral courage. Then there is still a higher type of courage; the courage to brave pain, to live with it, to never let others know of it and to still find joy in life; to wake up in the morning with an enthusiasm for the day ahead.

After the final round of chemotherapy was stopped, JC actually returned to her normal life and was caught up once again with the daily routine of raising 3 year old twin daughters. Unfortunately, after a year and a half of remission, her leukemia relapsed, and this time around, none of our therapeutic approaches seemed to make much of a difference to her resistant leukemia. Eventually, she developed a fungal infection of the lungs as well, and we were not able to give her any chemotherapy for fear of making the fungus spread faster. At this time, she made a wish to be admitted to the Hospital for her terminal illness as she did not want her daughters to be frightened unnecessarily. With a heavy heart, I took her in. It was instructive and astonishing to watch her face almost certain death with such unparalleled grace and equanimity. I noticed on my daily rounds that she would be writing furiously. Finally, I mustered enough courage to ask her one day, "JC, what are you writing?" And the answer she gave me changed my life forever. She said, "I am writing letters that I want my twin daughters to open on their birthdays. I have reached their twelfth. Keep me alive till I reach their twenty-first".

Alas, we could not keep her alive for the few days she had asked for. I went home that day and told my husband that I should also be studying myelodysplastic syndromes since this is a stage that precedes the development of acute leukemia in a number of patients. Maybe I could have saved JC if I had treated her at the MDS stage of her disease. My idea was that the molecular and genetic lesions in a frankly leukemic cell are too complicated. Perhaps, it would be better to start studying the biology of these cells at an earlier stage of the disease, say as in JC's case when it was still MDS. If we follow the course of the disease and study serial samples, it may become possible to identify the sequence of events that convert a normal cell into a leukemic one. Another advantage of studying MDS would be that if we could effectively treat the patient at this earlier stage of the disease, then the patient would never evolve into the potentially lethal acute leukemic phase. Finally, I felt that at the MDS stage, the drugs required for treatment may not be as toxic as those needed for the acute leukemia stage. For all these reasons, back in 1984, I decided to dedicate myself to the study and treatment of MDS along with my continuing research in acute leukemias.

At that time, there was very little interest in the disease, and only a handful of investigators were devoting any research effort towards understanding the basic biology of MDS. JC's tragic death spurred us on to try and change this. We began a serious effort to explore the underlying pathology of the disease in an attempt to identify new therapeutic targets. What struck us immediately was a clinical paradox in MDS since patients present with low blood counts, yet their marrows contain more than normal number of cells. This appeared to indicate that blood cells are being made in the marrow, but are not able to reach the blood for some reason. Thanks to the studies of our group, we were able to develop novel techniques to study cell cycle kinetics of the bone marrow in MDS patients and found that the marrow cells were indeed actively proliferating. In other words, the bone marrow is definitely not failing in MDS patients.

So the question is if so many cells are being produced in the marrow, why are they not making it to the blood? Our group was the first to demonstrate that this paradox is the result of excessive and premature death of the blood cells while they are still in the marrow. The bone marrow cells appear to be dying by a peculiar mode of suicidal cell death known as "apoptosis". Certain proteins that are typically produced in abnormally high amounts during inflammation such as Tumor Necrosis Factor or TNF appear to mediate this suicidal program in cells so that instead of being released into the blood, they die prematurely in the marrow. This appreciation immediately led to the idea of suppressing TNF. Thalidomide is a potent anti-TNF agent, and our group published the first trial of this agent reporting a 20% response rate in MDS patients. Subsequently, an analog of thalidomide called Revlimid was synthesized which has produced complete transfusion independence in almost 70% of patients with chromosome 5 abnormality, as well as in 26% without it. Future combination trials of Revlimid with other effective and innocuous therapies are likely to yield even better results for more patients. In addition, we finally have several approved drugs for MDS now (Vidaza, Dacogen, Revlimid, Exjade). What a success story!

And now a few words about why I feel that the SVCCC MDS Program is unique in the country. It is because of our commitment towards development of non-toxic therapies for earlier stages of MDS. We try to diagnose every cancer as early as possible so we can institute therapy early when our chances of completely eliminating the disease are higher. Unfortunately, when we diagnose MDS in its earliest stages, we tell the patients to go home and come back when they are really sick with either transfusion dependency or transformation of the disease towards leukemia, and then we open "the big guns" of therapy on the patients. This strategy is starkly counterintuitive but cannot be helped because the "big guns" or FDA approved agents are only meant for patients with advanced disease. Over the last decade, we have dedicated our efforts towards developing non-toxic therapies for early stages of MDS based on the idea that the "Time to fix the roof is when the sun is shining!" We have been committed to combining the best of what the East and West offer. We offer treatment with harmless herbs/spices such as Ginger, Curcumin, Turmuric (substances that form part of the Eastern diet and are presumably one of the reasons for their lower cancer incidence) to treat earlier stages of MDS and use the latest Western technologies to understand their precise mechanism of action. Thus we are unique in offering non-toxic therapies in earlier stages of MDS with the hope that we will nip the disease in the bud by arresting and reversing the pathology.

When I turn back and look at all that has happened since JC so inspired us to start studying MDS seriously, even I am shocked at the rapidity of advances which have finally led to the development of such effective therapies for subsets of MDS patients. It is a direct testament to the dedication and hard work of countless clinicians and scientists who have worked non-stop for years to provide the necessary biologic insights that could be translated into better and improved therapies. Now that day has come, when for several subsets of MDS patients, we do have specific therapies to offer, therapies which are not as toxic as chemotherapies. For me, the determination to find a cure for MDS was inspired by JC, but since has been sustained through the motivation derived from all my MDS patients. It is they who provide invaluable lessons on a daily basis in dignity, courage, and perseverance. I am grateful not only to JC, but to all my patients whose astounding valor and decorum continues to humble, invigorate and enthuse me. I thank them all for this inspiration.

So, I end this personal statement with renewed expectations. Great achievements are built on great expectations. Let us challenge each other to attempt the extraordinary, the undoable. Together, we can do it.

"If I had a choice between a walk on the moon and saving one life from cancer, I would never look at the moon again."