Army clinical investigation of Von Hippel-Lindau disease, 1977-2000
Lamiell, James M
Aloha nui loa to COL James Bass, MG Nancy Adams, investigators, staff, and guests. I am grateful to be here, and I thank COL Donald Person for inviting me to speak to you. Today I am filled with nostalgia for several reasons. Among them is the fact that I won the first and second Tripler Army Medical Center annual house staff scientific paper awards in 1979 and 1980. 1 will describe some aspects of the research that led to those awards so long ago. This follow-up on my research provides an opportunity to describe a few salient features of Army clinical investigation from what is admittedly a very personal perspective.
I completed a rotating internship at Tripler in June 1977 and immediately began training in the Tripler internal medicine residency. In September 1977, I was working on the Neurology Service, and I was asked to see a woman with polycystic kidney disease who was hospitalized on the General Medicine Ward. She had numerous skin nodules and claimed that her family had von Hippel-Lindau disease. Her physicians consulted the Neurology Service because they considered von Hippel-Lindau disease to be a neurological disorder. They wondered if perhaps she had both von Hippel-Lindau disease and polycystic kidney disease. We later realized that she did not have polycystic kidney disease. Instead, she had von Hippel-Lindau disease with biopsy-proven kidney cancer that metastasized to her skin, causing the cutaneous nodules. She remained in the hospital but died because of the renal carcinoma within 3 weeks of our first meeting. von Hippel-Lindau disease had been diagnosed in one of her relatives about 25 years before she died. She had been told she had autosomal dominant adult-onset polycystic kidney disease 16 years before her death. My colleagues and I reported her case in a 1980 Urology report because of the striking similarities between von Hippel-Lindau disease and polycystic kidney disease.I It was the first time I had encountered von Hippel– Lindau disease. I met many of this patient’s relatives during her Tripler hospitalization. Four things were apparent after talking to them: her family was very large, many relatives either had or could have von Hippel-Lindau disease, there had been no systematic family study, and her relatives knew little about von Hippel-Lindau disease.
von Hippel-Lindau disease was first completely described in 1926. It is named for German ophthalmologist Eugen von Hippel and Swedish pathologist Arvid Lindau. It is an autosomal dominant, precancerous disease with diverse manifestations, including retinal angiomas, central nervous system hemangioblastomas, renal carcinoma, pheochromocytoma, and cysts of the kidneys, pancreas, and epididymis. von Hippel-Lindau disease manifestations are variable in affected individuals and generally become apparent between the ages of 20 to 40 years.
I felt obligated to the Tripler patient’s family to screen for von Hippel-Lindau disease and to provide von Hippel-Lindau disease education. However, most relatives were civilians not eligible for Tripler health care. I requested an exception to this eligibility policy from the Chief of Medicine, COL James Hastings. He supported family screening but suggested making the screening process a research study because civilians may be seen and treated at military hospitals in the context of research. He gave me permission to pursue von Hippel-Lindau disease in the family, and he referred me to University of Hawaii professor and geneticist Dr. Ted Hsia.
I met Dr. Hsia in January 1978, and we discussed the von Hippel-Lindau disease family. He suggested that research be directed toward finding a von Hippel-Lindau disease gene linkage marker, that is, a test that could confirm or exclude von Hippel-Lindau disease even before symptoms. He was unaware of any research to identify a von Hippel-Lindau disease gene linkage marker. He also suggested research to determine the optimum von Hippel-Lindau disease screening strategy. We later met with several key family members to solicit their ideas about family screening and a research study. They were enthused and pledged cooperation, so we proposed this research study.
1. I would obtain a medical history from each family member and then examine him or her. During the evaluation, I would provide appropriate von Hippel-Lindau disease information to each family member.
2. Triplet ophthalmology resident CPT Fernando Salazar would perform an eye examination, including indirect ophthalmoscopy, on each family member.
3. Triplet radiology resident CPT William Fill would perform abdominal ultrasonography on each family member.
4. Brain scans would be made on family members with symptoms or findings suggesting cerebellar hemangioblastoma. Computed tomography scans were not easily available to us in 1978.
5. I would obtain blood, saliva, and urine from each family member. Specimens would be tested for about 30 protein polymorphisms in search of one linked to von Hippel-Lindau disease.
6. Juliet Yuen, Margaret Marshall, and Robert Jewell of the University of Hawaii Genetics Service would provide genetic counseling to each family member.
The appropriate Tripler authorities, including a fledgling institutional review board, approved my von Hippel-Lindau disease research study. We began seeing family members in February 1978 intending to evaluate as many relatives as possible. I traveled to Kauai in April 1978 to see 15 family members in their homes. In October 1978, we traveled to Letterman Army Medical Center in San Francisco to screen 40 relatives living in the San Francisco Bay area. In keeping with our concept of providing von Hippel-Lindau disease education for health care professionals as well as family members, the San Francisco trip was in conjunction with the presentation of our work at a medical genetics meeting in Vancouver, British Columbia.”
The Hawaiian von Hippel-Lindau disease family consisted of more than 220 people in six generations, 15 of whom had previously been diagnosed as having von Hippel-Lindau disease. After about 1 year, I had obtained detailed medical histories on 180 relatives and examined 160 relatives. We made new diagnoses of von Hippel-Lindau disease in 28 family members, 11 of whom had no idea that they had von Hippel-Lindau disease. We discovered serious medical problems that required urgent treatment. There were many newly diagnosed retinal angiomas and one impending retinal detachment. There were several central nervous system hemangioblastomas that required neurosurgical intervention. There was one case of metastatic renal carcinoma. There were 4 asymptomatic family members with bilateral renal carcinoma, and all were younger than 30 years old. We advocated bilateral nephrectomy for these people, and 2 of them were managed at Tripler. Many family members were admitted to Tripler as Secretary of the Army designees for diagnostic evaluations such as renal and cerebral angiography and myelography.
We described our findings and experiences in several reports rather than one, allowing us to explain von Hippel-Lindau disease in greater detail. Radiographic screening results were reported first in Radiology.4 We reported a notable von Hippel– Lindau disease patient in the Journal of Urology.5 These were followed by reports of the ophthalmologic screening in the American Journal of Ophthalmology,6 the psychological impact of von Hippel-Lindau disease in Birth Defects,’ and the von Hippel– Lindau disease gene linkage analysis in the American Journal of Human Genetics.8 Our gene linkage analysis only allowed us to conclude that the markers we tested were not linked to von Hippel-Lindau disease.
In December 1980, I traveled to Puerto Rico to present our von Hippel-Lindau disease research results at a medical meeting in Mayaguez and to search for the roots of the Hawaiian von Hippel-Lindau disease family. I tracked the family forefather, who emigrated from Puerto Rico to Hawaii around 1900, to Yauco, a small town in southwestern Puerto Rico. I talked to several Hawaiian von Hippel-Lindau disease family relatives in Yauco, but I was unable to find any Puerto Rican von Hippel-Lindau disease patients.
Significant advances in molecular genetics began to occur at a rapid pace. In late 1983, Dr. Hsia contacted Dr. James Gusella, a Massachusetts General Hospital molecular geneticist who was lionized as the first person to localize a gene from scratch (Huntington disease). He was studying the genetics of another hereditary neurological disorder, neurofibromatosis. In late 1984, we planned another study of the von Hippel-Lindau disease family in collaboration with Dr. Gusella. He assigned responsibility for von Hippel-Lindau disease molecular genetics research to his associate, Dr. Bernd Seizinger. In 1985, we again collected blood and tumor specimens from as many family members in Hawaii and San Francisco as possible, and we forwarded the specimens to Dr. Seizinger in Boston for DNA polymorphic marker analysis. After about 1 year, Dr. Seizinger pooled the specimen information from nine families and 71 von Hippel– Lindau disease patients to localize the von Hippel-Lindau disease gene to chromosome 3, as reported in Nature in 1988.9 About one-third of Dr. Seizinger’s specimens were from our subjects. This was the first significant step in identifying the von Hippel-Lindau disease gene. In 1989, we summarized our clinical research on the Hawaiian von Hippel-Lindau disease family in Medicine.” Dr. Seizinger collected blood from additional von Hippel-Lindau disease families, but precise von Hippel-Lindau disease gene localization eluded us, as reported in the Proceeding of the National Academy of Science in 1991.11 Finally, a different research group at the National Cancer Institute headed by Dr. Berton Zbar reported the identification of the von Hippel– Lindau disease gene in Mav 1993 in Science.12
The von Hippel-Lindau disease tumor-suppressor gene has been precisely located on the short arm of chromosome 3. It consists of about 850 bp. At least 200 different von Hippel– Lindau disease gene mutations have been observed in von Hippel-Lindau disease patients. There is ongoing research to study the genetic and biochemical mechanisms of von Hippel-Lindau disease. Because the von Hippel-Lindau disease gene participates in angiogenesis, it is possible that a detailed understanding of the gene could lead to an understanding of basic mechanisms of many neoplasms.
The Hawaiian von Hippel-Lindau disease family members are among the bravest people I have known. Twelve of the 28 living family members that we identified in 1978 as having von Hippel– Lindau disease have died. Furthermore, 15 new family members have been diagnosed as having von Hippel-Lindau disease, and many new disease manifestations have been discovered in family members known to have von Hippel-Lindau disease. After observing this family for 22 years, I have learned that although von Hippel-Lindau disease cannot be cured, it can be effectively managed provided that all involved have sufficient knowledge, honesty to confront problems, and courage to prevail against those problems.
Now my primary involvement with von Hippel-Lindau disease is educational. A surprising number of people ask me questions about this disease. von Hippel-Lindau disease education must be ongoing because the disease is dynamic, that is, the situation is sure to change in any individual with von Hippel-Lindau disease, and there will be new cases among relatives at risk. Education must involve von Hippel-Lindau disease patients, their families, and their health care providers. Few health care providers have experience with this disease. von Hippel– Lindau disease patients and their families cannot sensibly deal with the disease unless they know what to expect. People affected by the disease formed the von Hippel-Lindau Family Alliance in 1992. The Alliance includes patients, relatives, physicians, and other health care providers. This group has become a powerful resource for dealing with and studying von Hippel-Lindau disease. It is a model of how patients can be proactive in dealing with medical problems.
The experience of seeing, evaluating, and knowing so many people from such a large family over such a long time has profoundly affected me. I have been present for major surgery on many family members and managed hemodialysis in two of them. I have seen them in the operating room, the intensive care unit, the hospital wards, and their homes. I have given many of them bad news. I became a good friend of many family members. Several of these friends have died, and I grieved, and still grieve, over their deaths. I attended a christening, two weddings, three funerals, and three family reunions involving family members. My involvement with the family has been sustained. In 1978, I wrote a letter to an asymptomatic family member living in Germany. I informed her that she could have von Hippel-Lindau disease and that she should be evaluated. An ophthalmologist discovered retinal angiomas that confirmed von Hippel-Lindau disease. Subsequent evaluation revealed renal carcinoma, and a nephrectomy was performed at Fitzsimons Army Medical Center in 1979. In 1985, another nephrectomy was performed in Augusta, Georgia, to remove renal carcinoma, and she began hemodialysis. She received a cadaveric renal transplant in 1987. I finally met her for the first time in San Antonio in 1999. She recently had a craniotomy for excision of a cerebellar hemangioblastoma.
I described my experience with this research study to illustrate several things. In my opinion, the best clinical research studies address questions that arise at the bedside. Good clinical research should be designed to produce generalizable knowledge by answering these bedside questions, thereby improving the situation of specific patients or classes of patients by application of the new knowledge. Clinical research should not be intended to benefit investigators. Investigator profit or fame may be a side effect of clinical research, but such goals should not motivate the clinical research. This general concept is often summarized in clinical and research ethics as the principle of beneficence, that is, the principle that there should always be efforts to secure the well-being of research subjects. The three general prescriptive judgments of autonomy, beneficence, and justice were first clearly articulated for us in the Belmont Report. 13
Where do these bedside questions come from? Who asks these questions? Do you think patients will ask these questions? Will relatives, or administrators, or ancillary personnel ask these questions? It should be obvious that health care providers are the only appropriate people to ask these questions. They must maintain and nurture inquiring minds. They must be reflective. They must spend time with their patients to truly understand their patients’ situations. They must continually question everything. They must be prepared to test the status quo, and if warranted reject the status quo for that which is better. Health care providers must resist pressures to become mindless but efficient production line workers delivering costeffective health care according to rigid practice guidelines. I am not advocating that health care providers be inefficient and cost ineffective. I do advocate that health care providers be thoughtful and that they continually question that which should be questioned.
It follows from the principle of beneficence that clinical research studies should be well designed. The bedside questions should be meaningful for patients. These questions should be addressed by well-designed studies that are likely to answer the questions. What is the point of clinical research that generates no useful knowledge? There should be sufficient subjects to answer the questions, but there should not be an unnecessarily large number of subjects.
Every clinical decision is associated with risks. It follows from beneficence that the risks of participation in research be appropriate in relation to the benefits. The assessment of risks and benefits is usually approached differently by subjects, investigators, and institutional review boards. However, the assessment must be considered by all.
Those who conduct clinical research incur an obligation to their research subjects. It follows from beneficence that if a primary purpose of clinical research is to improve the well-being of subjects, then investigators should always endeavor to realize these improvements for their subjects if possible. At the very least, any knowledge generated by the research study should be provided in a meaningful way to the research subjects. This is a nonnegotiable commitment. If practical knowledge is generated by clinical research, then the investigators are obligated to disseminate this knowledge to health care providers, either through publication or by presentation at appropriate meetings such as this one.
None of you will receive much money from the Army to conduct your clinical research studies. Even though our results were significant, the Army spent very little cash on our von Hippel-Lindau disease research study. The Army provided funds for five trips and funds for shipping specimens to Dr. Seizinger. Total costs were much more if one includes the hospitalization of subjects for tests such as angiography. None of our collaborators charged us for their services, and I always made it clear that the cost of collaboration was that there be no fee for services. If I needed something from someone, I made him or her a collaborator and an important part of the study. I endeavored to make it impossible for them to say no. If you are cleaver and resourceful, you can conduct good clinical research at minimal cost.
It is important to find a mentor for your research. Your mentor should be experienced and well versed in the research area. Your mentor should have contacts that will help to ensure your success. My mentor was Dr. Hsia. He knew little about von Hippel-Lindau disease, but he knew a lot about genetics and mentoring. He knew most of the major genetics researchers, and he was well respected. Dr. Hsia was always willing to talk to me, and he always had good ideas that I rarely considered.
You should have freedom to do your research. BG Hastings gave me freedom. I am grateful for his support and encouragement.
You will usually only succeed if you work in teams. von Hippel-lAndau disease is inherently multidisciplinary. Our research study involved geneticists, general internists, ophthalmologists, radiologists, neurosurgeons, urologists, general surgeons, nephrologists, pathologists, psychiatrists, hematologists, oncologists, pediatricians, genetic counselors, and others. I learned a great deal by working with these colleagues. We always strived to work together for the good of the patients and the research study.
In closing, let me caution you not to forget your patients when conducting clinical research in this environment of rapid technical and scientific change. Patients are the raison d’etre of clinical research, so please conduct good and ethical research for their sake.
Allow me to convey to the clinical investigators here today and to all those who supported them the thanks and congratulations of the Surgeon General, LTC Ronald Blanck, my supervisor, MG James Peake, and myself. Aloha.
1. Lamiell JM, Stor RA, Hsia YE: Von Hippel-Lindau disease simulating polycystic kidney disease. Urology 1980; 15: 287-90.
2. Lamiell JM, Salazar FG, Polk NO, Hsia YE: Pre-symptomatic surveillance for von Hippel Lindau disease in a large kindred. Am J Hum Genet 1978; 30: 57A.
3. Marshall M, Hsia YE, Lamiell JM, Jewell RW, Yuen J: Gene expression of 33 von Hippel Lindau (vHL) patients in a single kindred. Am J Hum Genet 1978; 30: 60A.
4. Fill WL. Lamiell JM. Polk NO: The radiographic manifestations of von Hippel– Lindau disease. Radiology 1979; 133: 289-95.
5. Blight EM, Biggers RD, Soderdahl DW, Brosman SA. Lamiell JM, Raleigh EN: Bilateral renal masses. J Urol 1980; 124: 695-700.
6. Salazar FG, Lamiell JM: Early identification of retinal angiomas in a large kindred with von Hippel-Lindau disease. Am J Ophthalmol 1980; 89: 540-5.
7. Yuen J, Jewell R Lamiell JM, Hsia YE: Impact of a late-onset autosomal dominant precancerous disease on the knowledge and attitudes of a large kindred, Birth Defects 1984: 20(6): 135-46.
8. Go RCP, Lamiell JM, Hsia YE, Yuen JM, Paik Y: Segregation and linkage analysis of von Hippel-Lindau disease among 220 descendants from one kindred. Am J Hum Genet 1984; 36: 131-42.
9. Seizinger BR Rouleau GA, Ozelius LW, et at: Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature 1988: 332: 268-9.
10. Lamiell JM, Salazar FG. Hsia YE: Von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine 1989; 68: 1-29.
11. Seizinger BR, Smith DI, Filling-Katz MR, et al: Genetic flanking markers refine diagnostic criteria and provide new insights into the genetics of von Hippel– Lindau disease. Proc Natl Acad Sci USA 1991; 88: 2864.
12. Latif F, Tory K, Gnarra J, et al: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993; 260: 1317.
13. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research: The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. DHEW Publication (OS)78-0012. Washington, DC, US Government Printing Office, 1979.
Guarantor: COL James M. Lamiell, MC USA
Contributor: COL James M. Lamiell, MC USA
Copyright Association of Military Surgeons of the United States Oct 2001
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