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Report From the
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The take-home message from the Hawaii meeting: "We are not sufferers, we are survivors. We are not victims, we are veterans. Just as the doctors and researchers have expertise we admire and respect, so we have experience which is deserving of respect. Together, we can learn to manage VHL." -- Joyce Graff, Mass. |
- Sections of this article:
Introduction: Lamiell, Neumann, Graff
Pathology and Genetic Analysis
Who was there?
Janet Brumblay and Dr. Ted Hsia did an outstanding job of organizing the conference. They worked us very hard! There were meetings from 8:30 in the morning to 5 each day, and Tuesday and Thursday there were lectures in the evening from 7 to 9:30. The week was a lot of work, but wonderful to be together with this outstanding gathering of family members, clinicians, and scientists from all over the world.
There were representatives from New Zealand, Australia, and about eight doctors from Japan. There were an amazing number of people from Europe - twelve hours time difference, half-way around the world! Represented were England, Denmark, the Netherlands, eleven from Germany and eight from France. Altogether about 45 family members and 60 medical professionals.
The conference T-shirt and mug** bore a depiction of the VHL gene. This set the theme of the meeting, understanding the genetics of cancer and the advances in our understanding of VHL through the scientific investigations at the level of molecular chemistry as well as through analysis of the relationship between genotype and phenotype. Along with new understanding and exciting opportunities come new challenges for families and clinicians.
Introduction
Col. James M. Lamiell, M.D., from the U.S. Army Medical Department Center and School in Texas [101] presented a history of knowledge about von Hippel-Lindau syndrome, from 1864 to the present, and predicted that within the next 30 years knowledge about VHL will be on an astoundingly different plane. (See pages 1-3 of this issue.)
Dr. Hartmut Neumann, Nephrologist, of Freiburg, Germany, [102] presented an overview of "Progress, Problems, and Prospects" in clinical management of VHL. Now that genetic testing is available, to analyze the DNA and see the particular change in the VHL gene which affects a particular family, geneticists and clinicians are beginning to study the relationship between a particular genotype (a particular genetic flaw, the position and the type of change in the gene) and the phenotypes (or sets of symptoms) that are found in people with that genotype. He encouraged international collaboration on the identification of genetic germline (inherited) mutations among all the families. The collection of statistical information on the nature of the problems associated with a particular genotype will help clinicians focus their attention and testing funding on the most important areas, and may provide clues to the scientists that will lead to greater understanding of how the protein influences the life of a cell. In his practice in Freiburg, they are hoping to use mutation-specific data for risk prediction for individuals.
He called for specific focus at these meetings on several difficulties in clinical management:
- treatment strategies for asymptomatic spinal hemangioblastoma and small renal tumors.
- use of proton radiation for retinal angiomas
- use of laparoscopy for pheochromocytomas
- encouraging patients to comply with their physicians' advice about regular check-ups, and collection of data on the consequences of non-compliance
- the effect of immunosuppressant drugs (e.g. for transplant recipients) on new tumor development
- what causes the "second hit", the second genetic change which causes a VHL tumor to begin to grow
Joyce Wilcox Graff, Chairman of the Alliance, [103] presented the consumers' view: the concerns, needs, and hopes of the VHL families themselves. One of the biggest concerns is getting early diagnosis. Throughout the world, even in very competent medical institutions, it is often very hard to obtain an early diagnosis of VHL. Having the "name of the enemy" provides patients with essential keys to managing their health.
"Once we have found the name of the condition, whole new vistas of opportunity arise for managing our health and gaining some modicum of control over our destinies. Instead of living from one unforeseen crisis to the next, we can begin to anticipate problems, choose the right moment to act, and avoid serious complications." The VHL Family Alliance works in three key ways to improve diagnosis, treatment, and quality of life for people with VHL: family support, sharing information and helping one another through this experience; creating a chain of information for physicians so they can obtain the data and coaching they need to provide optimal care for people with this rare condition; and supporting scientific research by compiling data, participating in studies, and providing blood and tissue samples. It takes a partnership among the families, the clinicians, and the scientists to move this work forward.
Nursing Management
Three nursing professionals presented their perspectives on screening and nursing management for familial cancers. Debra Schmidt of Honolulu [104] spoke about the important role of the nurse in identifying cancer risks with patients - either familial risk factors or environmental risk factors. Susan Seto-Donlon of Honolulu [105] described cancer risk assessment specific to breast cancer, to improve the outlook for women who may have breast cancer. Ginnie Coggins of Honolulu [106] focused on nursing management following a diagnosis of cancer, helping the patient with both the medical process, dealing with the numerous appointments to be scheduled and kept, and also dealing with the absorption of this news.
Coping
Tuesday began with a discussion of ways of coping with cancer. Rev. David Torres of Kauai [201] spoke on the role of spirituality in providing strength and helping us to move forward "without losing our minds trying to figure out why." Dr. Ted Hsia of Honolulu [202] talked about the search for alternative medicine, which he categorized as unproven remedies, outside the approved set of "rational" or proven medical treatments, which may or may not be helpful. He urged caution in relying on unproven remedies, and recommended using them in addition to, not instead of, the standard treatments. Jeanne Hoffman of Honolulu [203] reminded us that the focus should be on life and living as a way of allowing the patient and family to focus on normal and positive processes, even while coping with the very difficult process of treating the cancer. Jeanne encouraged all family members to grieve the loss of the former self-image of the person who is ill, and to redefine the self in a way that makes sense in the new situation and celebrating that new self. She recommended a helpful book about dying, Closer to the Light by Melvin Morse. Joan McCarthy of Honolulu [204] discussed the phenomenon of burn-out among patients with chronic illness and their partners and families - how to spot the signs, hopefully prevent burn-out, and rekindle the flame of hope and energy required.
Jane Hill, a humorist from California [205] who is a breast cancer survivor, delighted us with irreverent humor about breast cancer and a presentation on love, laughter, and healing. She has a funny and honest approach to everyday life, whether you've been touched by cancer or not. Jane's daughter, Kelly Hill, [206] shared how she and her friend Jon Wagner-Holtz set up a friendship network called Komen Kids for children who have a parent with cancer, based on a free telephone line into Jon's bedroom where he matched kids up with telephone pals in similar situations. There are now Komen Kids chapters all across the United States, with support meetings facilitated by professionals but from which all parents are banned. Kids talk openly with each other, and give other kids support and advice on what they did when they went through a similar situation. Komen Kids services are available to children of families dealing with VHL. We were all moved by these two outstanding presentations.
Jeanne Hoffman of Honolulu [207] and Janet Brumblay of Honolulu [208] talked about how families internalize and cope with the news that one of their members has cancer. Janet's session provided an opportunity for those present - families and health care professionals alike - to discuss communication between the doctor and the family members. The participants in the two discussion groups found their experiences were very similar, and their recommendations to doctors were much the same: take your time with patients, be honest, admit when you don't know the answers, and be willing to go to the library.
Pregnancy and VHL
On Wednesday the sessions began to get more medical in flavor. In the morning, we heard three presentations concerning pregnancy and VHL. We heard from every speaker that evaluation for pheochromocytoma is a priority. If diagnosed too late, a pheo can be fatal to mother and/or baby. VHL women have a special caution during pregnancy in that the normal symptoms of pregnancy can mask symptoms of VHL tumors. Special precautions need to be taken to ensure that both the mother and the child come successfully through the pregnancy.
Dr. Dominique Chauveau from Paris [301] presented the results of a survey of 49 VHL women selected at random from the French registry of VHL patients. Data were obtained from 56 pregnancies in 30 women, resulting in 54 surviving infants. Only three (5%) of the mothers developed VHL symptoms during pregnancy, and both the mothers and infants survived following treatment for VHL. This study indicates that pregnancy should not be discouraged in VHL women, but does not address the question whether pregnancy accelerates development of VHL lesions.
Dr. Greigh Hirata from Japan [302] presented a case history of a pregnant woman with an acute VHL spinal lesion, and how his team managed this high-risk pregnancy to a successful conclusion. Dr. Hirata [303] also shared a review of management of other cancers during pregnancy. His findings are that there seems to be no influence of pregnancy on the progression of the disease.
Registry Studies
Ruth Merz of the Hawaii Health Registries [304] discussed issues in the establishment of a registry. In addition to the mechanics of collecting and housing information, there are a number of policy and startup issues which must be addressed. Debra Collins, [305] genetic counselor from the University of Kansas Medical Center, who works with a large number of VHL families, presented a review of the complexities and costs involved in screening, including a review of policies toward privacy and confidentiality in government and the insurance industry.
Dr. Gladys Glenn, coordinator of the VHL clinic at the National Cancer Institute in Maryland [305] presented a review of what NCI has learned about screening, diagnosis, and monitoring in VHL. Under their research program they use a very thorough screening protocol which she readily admits is not practical in most clinical settings. She challenged the group to work together to devise a screening protocol which is in fact practical for clinicians, insurers, and national health care systems, and supports patients in optimizing their health. The VHL Family Alliance accepted the role of facilitating this work, as part of revising the Handbook, now under way.
Radiological news
Dr. Michael Foerster and Dr. Michael Kreusel of Berlin [308] described the results of their early use of brachytherapy with large solitary peripheral hemangiomas, and the use of proton beam or photon beam therapy with advanced complicated tumors with no therapeutic alternative. This treatment provides a last-ditch effort, but is not a basic therapy.
Dr. Glenn, filling in for Dr. Peter Choyke of the National Cancer Institute [309] presented Dr. Choyke's latest recommendations for diagnostic imaging in VHL.
Genotype/Phenotype Analyses
Thursday began the series of scientific advances, combining clinical information with genotype information to begin to understand the VHL code. If we understand the VHL gene to be a recipe for a protein, having the mutation in a different place along the gene essentially disables, or leaves out, a different key active ingredient, and can therefore be understood to have a slightly different effect. I kept thinking of my Grandmother Wilcox who always left out one ingredient when she gave you a copy of her recipe, so that your attempt would never be as good as hers. But if one time you leave out the vanilla, and another time you leave out the salt, each time you get a slightly different outcome.
Dr. Taro Shuin from Yokohama, Japan, [401] presented his study of VHL in Japan, analyzing the particular locations and types of mutations found in 45 people with VHL. His results suggest that mutations in Japanese VHL patients contain some unique features compared with Western VHL.
Dr. Frederik Hes, from Utrecht, The Netherlands [402] presented his work on three large Dutch families, studied both for their genetic mutations in the VHL gene and for their clinical manifestations. They are beginning to include DNA diagnosis and genetic counseling as normal components of clinical management of VHL.
Dr. Eigil Kjeldsen, from Copenhagen, Denmark, [403] presented a review of the fifty known families in Denmark with VHL. He is establishing a Danish center for molecular genetic diagnosis and a database of information on each patient's symptoms, treatment, time of diagnosis, follow-up, and family history.
Dr. Sophie Giraud from Lyon, France [404] presented her work on genetic analysis of a series of 92 unrelated VHL patients referred to her from different regions of France, including 52 variants of the VHL gene.
Dr. Berton Zbar from the National Cancer Institute said that next year when we see such reports he would like to see the genotypes separately examined for variations in the phenotype as well, so that we can begin to see how true to form the phenotypes in fact are.
Kidney and Endocrine Organs
After lunch, we heard a series of speakers on involvement of the kidney and endocrine organs.
Dr. Andrew Novick from Cleveland, Ohio [405] shared his findings in management of kidney cancer and kidney failure in VHL. He has had very good results from nephron-sparing surgery in patients with VHL. While tumors do recur, there was a gap of 6-10 years for most patients before surgery was again required, giving the patient a number of healthy, trouble-free years before the next round of surgery. If removal of the second kidney is eventually required, renal transplantation tends to go well.
Dr. Hartmut Neumann from Freiburg, Germany [406] reviewed lesions of the endocrine organs: adrenal glands, paraganglia, pancreas, testis, ovaries, thyroid, parathyroid, and pituitary glands. The most frequent of these are pheochromocytoma, paraganglioma, and pancreatic islet cell tumors, but infrequently carcinoid, medullary thyroid cancer, pituitary adenoma, and parathyroid adenoma do occur. The risk for such tumors differs in different VHL families. In his practice, he analyzed the particular genetic mutation and studied the relationship between the genotype (the kind of mutation in the gene), and the phenotype (the set of clinical problems), and came up with risk factors for these various tumors for the various mutations in his study.
Dr. Cornelius Lips of the Netherlands [407], Dr. Dominique Chauveau of France, [408] and Dr. Nobuo Shinohara of Japan [409] presented reviews of their patients with VHL renal involvement. They represented a total of 63 patients (14, 43, and 6 respectively). Their conclusions were in agreement that nephron-sparing surgery with careful follow-up is the preferred method of management. Chauveau and Shinohara in particular noted that ex vivo surgery was not desirable because of a high probability of subsequent vascular thrombosis and loss of the kidney, and Dr. Novick concurred.
Dr. Laura Schmidt of the National Cancer Institute [410] reported identification of another hereditary renal cancer, referred to as hereditary papillary renal carcinoma. She presented findings from a large affected Canadian family.
Dr. Glenn, [412] reported in detail on NCI's work on familial and sporadic types of renal cancer in her talk in the evening.
Dr. Rudolf Scheremet of Freiburg [411] gave an excellent talk on hemangioblastoma of the central nervous system, showing his techniques for excision which have proven to be very effective among the patients treated at Freiburg. He found that the surgical outcome correlated more with the preoperative neurological condition than with the size of the tumor. Patients who waited until their symptoms were already severe, and neurological deficits had already taken hold, were less likely to have a complete recovery of these functions. For this reason he recommends surgery at a relatively early stage. There were no other neurosurgeons in attendance, but family members in attendance agreed that that was their experience.
Understanding the VHL Protein
Dr. William Kaelin of Dana Farber Cancer Research Institute in Boston [413] gave two very exciting talks, one Thursday evening, followed by the first session Friday. Dr. Kaelin gave us an excellent tutorial on the basic molecular biology work required to understand the function of the VHL gene and the protein which it encodes, and the progress of this work. In particular, he told us that in his work with retinoblastoma, another tumor suppressor gene, it takes alterations in four genes and the presence of an accelerating factor in order for the manifestations of retinoblastoma to occur. There may well be other partner genes or accelerating factors needed to accompany the alternation in the VHL gene. His team is working to find drugs which will mimic one or more of the activities of the normal VHL protein. His Friday talk [501] was a functional analysis of what we know to date about the VHL protein.
Pathology and Genetic Analysis
Dr. Hiltrud Brauch of Munich [503] presented mutational analysis of sporadic renal cell carcinoma, and the differences between these tumors and the hereditary types found in VHL. Her analysis of 146 kidney tumors was very interesting, as she is working toward understanding what kinds of changes may indicate a more or less aggressive tumor.
Dr. Christophe Béroud of Paris [504] and Dr. Joachim Decker of Germany [505] discussed their findings of changes in the VHL gene in sporadic renal cell carcinoma, using different methods to pursue a similar line of inquiry. Dr. Zbar requested that in the future such studies should break out the different kinds and positions of alteration in the VHL gene to assist in understanding the correlation between the kinds of changes in the gene and the kinds of affects.
Dr. Stéphane Richard of Necker Hospital in Paris [502] presented a pathologist's view of hemangioblastomas and endolymphatic sac tumors. Dr. Hiroshi Kanno of Japan [506] discussed his work on sporadic hemangioblastoma. As found in kidney cancer, sporadic hemangioblastoma of the central nervous system also show alternations in the VHL gene. In 50% of the 20 cases he studied, he was able to clearly show changes in the VHL gene. Four of the ten cases where there were changes in the VHL gene there was recurrence of the tumor; in all 10 of the unchanged cases, there was no recurrence.
Molecular Biology
Dr. Michael Chamberlin of the University of California, Berkeley, [507] described the basic mechanisms of transcript elongation by RNA Polymerases. This was a difficult concept even for most of the doctors, but Dr. Chamberlin used a bicycle analogy that kept the audience with him most of the time.
Dr. Thomas Stackhouse of the National Cancer Institute [508] added the findings of the NIH with regard to transcription elongation.
Dr. Nikolai Kley of Bristol-Meyers Squibb [508] described the work that Bristol-Meyers has been doing with a mouse that has VHL (one normal copy of the VHL gene, and one altered copy). Having a mouse with VHL gives them a "biological model" where they are able to study the effects of various proposed treatments on an organism with VHL. So far, at nine months, none of the mice with VHL had shown any manifestations of VHL. They noted that where they bred a mouse with no VHL gene at all (what is known as a "knock-out mouse"), the baby mouse was not viable at all. Knock-out mice are useful in many conditions as they do not have to wait for the animal to develop the manifestations. However, the fact that such a mouse was not viable confirms the findings that the VHL protein is so essential to the life of a cell that without any VHL protein the animal cannot live.
Dr. Eamonn Maher of England [509] did not attend, but did submit a poster and abstract of his work on genotype/phenotype correlation. He found a strong correlation between pheochromocytoma and missense mutations or large deletions in the gene, resulting in a truncated protein. He found no association between the type of mutation and age-related risks for retinal and cerebellar hemangioblastomas, but statistical analysis of variations within the families showed clear evidence of modifier effects, probably the effect of accompanying changes in other genes.
Dr. Hsia and associates presented a poster describing the results of DNA screening among the Hawaii family. They found nine people with the altered VHL gene who were the children of people with no symptoms, but who carry the altered gene. These were particularly important finds, since they provide early warning information both for the children and for these previously unaffected parents.
[as published in the September 1996 issue of VHL Family Forum, vol. 4, no. 3]
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