|
|
 |
Teamwork for Health
This report was abridged for publication in the Newsletter. For the full report, presentation abstracts, and available transcripts, please see the Conference Page. Click here to see the photos that accompanied this article, and additional photos posted on the Conference Page.
"It was great to meet all the folks at the conference. As the locals would say here in Alabama, you threw one ‘humdinger of a shindig!’ I’ve remarked to several of my colleagues that it was the first time I had ever been to a conference where researchers, doctors, health care professionals, and patients were all attending the same sessions and contributing — the synergy was remarkable. My compliments to all the organizers for your remarkable skill in keeping such a wide variety of people moving in the same direction." — Michael Brown, O.D., Veterans’ Administration, Huntsville, Alabama
78 health care professionals and 101 family members gathered in Rochester, Minnesota, on July 20-23 to learn from one another about VHL, and to share ideas for improvements in diagnosis and treatment.
Families attended from many parts of the world, including Mikael from Sweden, who made a special commitment to come.
Thursday was devoted to Basic Science, understanding the mechanics of what goes on in the cell: how the normal VHL protein (pVHL) influences normal biology, and how the lack of pVHL causes tumors to form. It’s like solving a large and complicated puzzle. The good news is that many of the puzzle pieces are already known, and others are falling into place.
While 75 people began their attendance on Thursday, most began on Friday. Health care professionals were encouraged to attend the genotype/phenotype alignment presentations on Friday morning, while the families, especially those attending a meeting for the first time, were encouraged to attend "VHL 101", led by Joyce Graff. There were 34 people in the class. The first half of the class was spent introducing ourselves and telling our VHL stories. That was a learning experience in itself, as there was a broad spectrum of experience represented in the room. We passed out copies of the Handbook, reviewed the highlights of what the doctors would be discussing in depth, and went over some of the scientific terms that would be used. At the Annual Meetings previously held in the United States, VHLFA asks the presenters to aim their talks at a well-informed lay audience, and to keep the language appropriate for that group. The purpose of a Symposium, however, is to allow the health care professionals to talk with one another, so at this symposium there were no constraints on the scientific language.
At each Symposium the assembled participants work together to move our collective knowledge about VHL forward. At the Honolulu Symposium in 1996 we asked that in future, the reports from the various countries should try to present their findings to show characteristics associated with particular mutation types. For a specific mutation (genotype), what disease characteristics (phenotype) do they find? While the new people were in the VHL 101 class, the health care professionals and more experienced family members listened to the genotype/phenotype alignment reports from France, Germany, Japan, Italy, Netherlands, and the United States. Dr. Frederik Hes reported more insertion mutations in the Netherlands than in the U.S., and a preponderance of CNS hemangioblastomas.
After eating lunch together, the two groups joined beginning Friday afternoon and were together for the next two days. Dr. Virginia Michels set the tone of the meeting with her keynote address (see page 1). Joyce Graff explained what a Clinical Care Center does, providing backup and second opinions for local doctors less familiar with VHL. Even the CCC’s don’t know everything, so they have the Expert Centers to rely on in dealing with tricky issues: US NIH, Freiburg, Paris, Jerusalem, and Tokyo.
Dr. Karol Krzystolik from Poland and Dr. José da Rocha from Brazil told us about their relatively new studies of VHL in their countries. For 4 and 3 years respectively they have worked to identify and provide appropriate treatment for people with VHL. There are dramatic differences in the health of the people diagnosed with symptomatic lesions, and those diagnosed early through DNA diagnosis. Dr. Krzystolik’s experience has led him to believe that it is important not to wait for people to come with symptomatic lesions, but to identify people early, before there are symptoms, and work with them in a program of prevention.
Tom Rodenberg, an attorney from Kansas, shared with us his experiences as the family negotiator with health insurance carriers in a large family with VHL. Patricia Rasmussen spoke about the importance of making sure your wishes are clear on paper and with your family so that in a case where you may be unable to speak for yourself for a time, you can be sure your wishes will be carried out. The best instrument for most people is a "health care directive or power of attorney" which enables your chosen friend or relative to speak for you whenever you are temporarily unable to do so. Tom and Patricia both advised us to educate ourselves, meditate on it, take the necessary steps, and remember to change it as circumstances change in the future. Forms are available at doctors’ offices and hospitals.
Dr. Catherine Stolle gave an excellent overview of the process of DNA testing, which will be made available in a future newsletter. Getting a DNA test is in part a fairly routine laboratory test, like any other blood test. But the test is not the biggest part of the process of determining your VHL status. After you get the results, then the real questions begin.
On Saturday morning Dr. McClellan Walther of the U.S. National Cancer Institute (NCI) delivered the keynote address, describing the work of his group on kidney cancer. Kidney cancer is rising sharply, up 30,000 cases per year in the U.S.. It accounts for 12,000 deaths each year, and there are 200,000 people alive with a history of kidney cancer. NCI has been studying the changes in chromosome 3 associated with kidney cancers, establishing genetic diagnoses for kidney cancer, and identifying targets for therapy.
A link has now been established between smoking and kidney cancer. Smoking also increases the risk of other cancers, but VHL patients who smoke were found to have faster-growing kidney tumors compared to nonsmokers. They studied 53 VHL patients with 117 kidney tumors over 3 years, and the smokers had significantly shorter tumor doubling times than the nonsmokers. People with VHL are therefore advised not to smoke, and to reduce their exposure to second-hand smoke.
NCI has worked out a strategy of "resetting the clock, not curing" kidney cancer. They wait until one of the tumors reaches a size of 3 cm., and then they remove all the tumors they can see, "shelling out" the tumors, with a thin (1-2 mm) margin. They have generally been able to do this with minimal loss of kidney function. So far, following 52 patients over 1-17 years, there have been no metastases. The number and position of the tumors is unimportant, the strategy is working. See also RFA, a less invasive experimental approach.
Six physicians reported on clinical research programs in their countries, calling out some interesting differences from one country to another.
Dr. Gladys Glenn of NCI described their clinical program, studying families with various kinds of familial kidney and pancreatic cancer. Pancreatic islet cell tumors tend to spread to the liver, and they have had some good results from infusing liver cells with chemotherapy. Dr. Taro Shuin found that Japanese patients have more of the rarer tumors (e.g. liver, pituitary, skin), and cases where age of onset is not typical. Dr. Giuseppe Opocher reported that in Italy they now check all people diagnosed with renal or pancreatic cancer for the VHL mutation. His clear conclusion is that an integrated clinical approach improves the quality of health care, helping people identify the various clinical specialists needed to treat the problem.
The series on Clinical Issues began with two physicians reporting improvements in diagnosis and treatment for adrenal tumors. Dr. Jacques Lenders of the Netherlands described a new test for pheochromocytoma (reported in VHLFF 7:4, December 1999), Plasma Free Metanephrines (PFM). This test is not yet widely available, but it is not expensive to implement. The laboratory procedures to be followed in doing the test are now available on the internet at www.catecholamine.org and any laboratory that wants to do the test is invited to obtain them. In tests conducted so far this test has been found to be more specific (100%) to pheochromocytoma than any other test, and more sensitive (99.3%) than any other. In a test among 131 patients the test missed only one very small tumor in a person with VHL. The test is currently offered for about $230 by Mayo Clinic, with additional labs coming online rapidly.
Dr, Geoffrey Thompson noted that the first surgical resection of a pheo was done at the Mayo Clinic in 1927, and the patient lived to the age of 93. Untreated pheos are often first discovered at autopsy: 75% of those recorded at Mayo died suddenly, one-third during or shortly after childbirth. He is looking at PFM testing, and finds CT the best imaging modality for finding pheos. He prefers laparoscopic surgery unless the situation is tricky. If the pheo is too close to the vena cava or main artery, or if it is malignant, he prefers open surgery. Posterior adrenalectomy often leads to chronic pain, bothersome numbness, and weakness in the oblique muscles of the back. He finds that while laparoscopic surgery takes a bit longer operation, there is less pain and more patient satisfaction.
Dr. Walter Hall of the University of Minnesota described his work with intraoperative MRI. He has a special operating room and an Interventional MRI system designed for intraoperative use. He finds that it allows him to do surgery more safely, since the MR can calculate within 14 seconds a comparison to previous images, determining for example whether something seen on the image is the same tumor seen before surgery, or something caused by surgical trauma. He has had particular success with glioma. He can do "functional imaging" to map motor, voice, or memory areas of the brain just before putting the patient to sleep. This marks areas to avoid in dissecting the tumor. They have limited but positive experience with hemangioblastoma. He invites inquiries. 612 624-5108 or hallx003@tc.umn.edu.
Dr. Hartmut Neumann, whose work in "preventive medicine" with VHL was recognized by the insurance providers of Germany in 1999, has turned his focus to finding undiagnosed cases of VHL throughout Germany. He did a nationwide study of 270 patients with symptomatic pheos. 100 had inherited conditions, including 76 with VHL, 17 with MEN2, and 6 with NF1. Of those under age 10, all had VHL mutations. Between ages 11-19, 60% had inherited pheos, and all but one had VHL mutations. He is hoping to do a nationwide study of other aspects of VHL to find what the penetration of VHL is in each of these issues.
Dr. Jane Green described her work over the last 20 years with families with VHL in Newfoundland. In this remote part of Canada there are large families (12-15 children). In the first family they studied in 1982 there were 24 affected members, 10 of whom were already deceased, 10 with blindness in one or both eyes, many with neurological disabilities or anxiety. Through a systematic screening program, 84 tumors were identified in the first few years. As their understanding of VHL increased, more VHL families were referred to them and entered the screening program. While these families had severe disease in 1982, in the last 20 years there have been only four more deaths, and four more blind eyes. 150 tumors were treated successfully, 3 renal sparing surgeries, two people on dialysis, and one renal transplant.
She finds that a clinical screening program allows earlier diagnosis and treatment. Genetic testing allows more efficient screening, since you can target the right people for conscientious follow-up. She therefore feels that genetic testing for VHL in early childhood is justified, both because of the early age of onset on pheo and eye problems, and because there is now effective treatment to prevent the worst consequences of these occurrences.
She has done extensive cost comparisons for the Canadian government. Just from the perspective of the health care system, the cost of management of VHL with screening is lower than the cost of management of symptomatic disease. More than that, the societal cost of managing a family with early deaths and disabilities is great than the cost of health maintenance.
Three talks focused on preserving organ function in the kidneys and pancreas. Dr. Walther presented the work NCI is doing on pheochromocytoma, which occurs in VHL, MEN2, NF1, and other familial conditions, as well as sporadically and outside the adrenal (extra-adrenal carotid body tumor). They have 12 patients with adrenal tumors which were not functioning for several years, which they have chosen to watch until they begin producing hormones or until the patient is planning a pregnancy.
Dr. Pascal Hammel of the Francophone VHL Study Group shared his work on the pancreas. Now that there are better strategies for CNS and kidney tumors, neuroendocrine tumors of the pancreas are becoming relatively more important. 75% of VHL patients in France have pancreatic lesions. In 7% of the cases, pancreas is the only affected organ. There are usually no symptoms. Of 153 tumors, 10% were islet cell tumors, and 10% were neuroendocrine tumors (NET), and the rest were benign tumors or cysts. NETs sometimes cause pain (compression or acute pancreatitis). CT or MRI can identify them, and scintigraphy can be used to confirm the diagnosis.
Dr. David Goldfarb reported experience with partial nephrectomy at the Cleveland Clinic. They have found that conservative surgery leads to longer survival and better quality of life. They use 3-dimensional volume rendered CT to ensure identification of all existing tumors of resectable size, and a detailed assessment of the vasculature, the kidney tissue, and the collecting system. It is a non-contrast integrating information provided by arteriogram, venogram, IVU, and 2-D CT that produces a 3-5 minute video showing the location of kidney relative to ribs, spine. It helps to predict what will be encountered in the operating room, and removes the need for preparatory films. Just as NIH is using heat (Radio Frequency Ablation), Cleveland is using a freezing probe to destroy kidney tumor tissue, which can be done successfully laparoscopically. They have now treated 34 tumors less than 4 cm. in 32 patients, most of which are RCC in older patients (mean = 65.4 years) who required an average stay of 1.8 days, 15 minute procedure, and 2 weeks to normal activity. At six months there was no evidence of cancer. This may be a possible treatment for some VHL patients.
Five physicians presented their findings on hemangioblastomas of the CNS and Retina. Dr. Atom Sarkar of the Mayo Clinic talked about the 31 VHL neurosurgical patients treated at Mayo. Two-thirds of them had some lesion in the kidney, pancreas, or adrenals. They found that incidence of spontaneous hemorrhage of spinal tumors was very low (0%). Not all spinal tumors require removal.
One-fourth of all their VHL patients have some lesion in the spine. He noted that before operating on the spine it is critical to understand what involvement there is in the cerebellum. If there is a mass effect in the cerebellum, and you release the pressure in the spine, the brain could herniate into the spine and cause a fatal accident.
Dr. Tung Nguyen of the U.S. National Institute for Neurological Disorders and Stroke (NINDS) described the research he has been doing to learn more about the natural history of CNS lesions, in hopes of being able in future to predict which of the various small tumors we can see on medical images is likely to grow and when. Because of the potential complications from treatments, they do not want to operate until it is truly necessary, until there is some kind of neurological compromise. If we could predict which tumors were thinking about growing, we could possibly use less risky therapies such as stereotactic radiosurgery or gene therapy to inactivate these tumors before they got to a symptomatic size. In his analysis of 88 patients, symptomatic lesions grew faster than asymptomatic lesions. 26% of the tumors studied grew in two "phases," with intervening periods of quiescence. Of tumors treated with stereotactic radiosurgery, 90% of the lesions stabilized, shrank, or disappeared, leading to the conclusion that this is a useful therapy for tumors that meet its criteria for success. But even if a tumor shows no growth over a 3-year period, is it really inactivated, or is it a growth plateau? We need to refine the criteria for evaluating these tumors.
Dr. Nguyen is looking for more indicators of the readiness of a tumor to grow, including possibly checking the levels of VEGF in the blood. He is also examining other factors that might cause tumors to grow. One area of inquiry is hormones. They have found a progesterone receptor in hemangioblastomas. There is some suggestion that pregnancy or puberty can accelerate tumor growth.
Dr. Mika Niemelä of Finland reported his study using interferon alpha to treat hemangioblastomas (hBs) of the CNS. He found no decrease in size of existing hBs, but no new hBs during the treatment. One patient had a new lesion 9 months after the therapy ended.
Dr. Hélène Dollfus of the Francophone VHL Study Group studied the natural history of VHL tumors of the retina over time among 240 patients ages 6-71 years. She found that most activity occurred during ages 10-19, with the number of new hB per year decreasing with the age of the patient. She finds that the period of greatest sensitivity to eye damage is 15-30 years. The larger the number of hBs, the greater the risk to the vision. Her study also identified that patients with more pancreatic manifestations tended to have less retinal involvement.
Dr. Hiroshi Kanno of Japan described 43 cases of hB 1975-2000, 13 of whom have VHL. He found that the monoclonal antibody against vhl protein (VHL40) reacts to both mutated and wild type proteins of vhl gene. Sporadic hBs have the same protein expression as VHL-related ones.
Sunday morning Jay Platt of Georgia (see article) shared with us some inspiring stories from his 2160 mile hike of the tough mountainous terrain of the Appalachian Trail. More than a physical effort, it was an exercise in commitment which taught him many life lessons, which he shares in his new book.
Dr. Peter Choyke of the diagnostic radiology department of the NIH shared his experiences with uses of imaging in VHL diagnostics. He said that ultrasound is particularly well suited to children because it doesn’t matter if they wiggle or squirm, it’s like a movie.
Ultrasound can be used intra-operatively, even on a laparoscopy probe, to avoid the possibility of removing healthy tissue. Intraoperative MRI is also an important tool. Radio frequency ablation can be used to cook tumors of the kidney, but is less likely to be useful in the pancreas, and is not useful in the adrenals as it would make the pheo angry.
Telling the difference between a cystadenoma and a neuroendocrine tumor is not easy — it’s a judgment call. It is easy for radiologists in the field to overreact to these tumors. Location is important, especially in the pancreas. Positron emission tomography (PET) is a radioactive technique that measures the sugar uptake. It is still expensive and not yet widely available, but it shows you what is metabolically active in the body, so it is very useful in differentiating the neuroendocrine tumors from cysts. The contrast dye is excreted into the kidney, so structures in the kidney are hard to see. In general he feels it is best to choose the method that is best for you and stick with it. If you move from one modality to another, you don’t know whether it’s you that changed, or the difference in technique. He stressed the importance of regular screening, and doing good analysis at the first sign of symptoms. He advised patients to advocate for themselves, and to go to centers with the best equipment, and maintain consistency in your medical imaging records. Imaging provides early detection, and early detection means better outcomes. He also stressed the importance of communication — all the doctors involved need to understand and communicate with one another.
If you have a reaction to contrast, it is usually to ionic contrast. Non-ionic is more expensive, but causes less reaction. Another technique to lower reaction is to slow down the rate of injection. Talk with the doctor about an anti-emetic agent. Dr. Choyke has found gadolinium to be the safest contrast agent he has dealt with — it’s more expensive, but it adds a great deal to the scan and enables him to look for areas that are active. Contrast uptake is not specific for tumors, but it is very helpful in VHL.
There was a question whether open MRI’s are as good as the closed ones. He said that three years ago he would have said no, but today, especially if you require sedation to go through a closed MRI, the open ones are probably okay. It takes longer, but the result can be as good especially if it helps you avoid sedation.
Dr. James J. Augsburger of the University of Cincinnati and Dr. Klaus-Martin Kreusel from the Free University of Berlin, Germany, shared their experiences with radioactive plaque therapy for large eye tumors. They choose this modality when dealing with larger tumors, extrapapillary locations, with persistent progress of the tumor or its secondary abnormalities. Ruthenium brachytherapy (Rub), involves suturing a ruthenium plaque to the globe of the eye. The German team has now treated 35 angiomas in 32 eyes. All angiomas were destroyed, and all eyes were preserved, but vision was not always preserved. There are still questions whether the plaque therapy may induce other cells to mutate and form future angiomas. Both stressed that the truly "best therapy" is pre-symptomatic screening and maintenance of small lesions with laser therapy, as the larger the tumor, the higher the risks of any procedure.
Four physicians shared their experiences with management of retinal angiomas. Dr. Helmut Buettner of the Mayo Clinic; Dr. Emily Chew of the U.S. National Eye Institute (NEI), Dr. Michael Gorin of the University of Pittsburgh; and Dr. Kreusel from Berlin.
Dr. Buettner reviewed the monitoring and maintenance of small lesions with laser, and larger tumors with cryotherapy. Earlier treatment is preferred, as cryo causes more scarring and more vision impairment. Dr. Chew’s research shows that VHL eye tumors have been shown to have genetic alterations of the VHL gene. Under the microscope, they are identical to VHL hemangioblastomas of the CNS. She is testing drugs that block VEGF production as a way of limiting the vascularization of VHL tumors, and are using these therapies as well for diabetic retinopathy. Some of the retinopathy drug trials are now in Phase 3, and these may prove useful for VHL as well.
Dr. Gorin reported his work using fluorescein potentiated argon laser (FPAL) to treat 55 angiomas in 25 eyes of 17 individuals, with very good success. He stressed the importance of treating very small lesions because they are trivial to treat at that stage, and much more difficult to control when they are larger.
Following the review of Thursday’s Basic Science presentations, Dr. Adrian Harris from Oxford, England, shared with us the preliminary findings of his clinical trials with the anti-angiogenic drug SU5416 from Sugen. This drug must be administered intravenously, three times a week in the doctor’s office. There will be an oral form next year, and oral drugs from two other drug companies as well.
SU5416 is one of many new drugs that target Vascular Endothelial Growth Factor (VEGF). It has been shown to be in high supply in cancer tissues, growing a blood supply to feed the cancer tumor. It is therefore a very good target for a drug that wants to stop cancer tumors.
SU5416 blocks the receptors on the surface of the blood vessel that respond to VEGF. Instead of actually lowering the levels of VEGF, SU5416 reduces the sensitivity of the blood vessels to the VEGF signals. At this time they are working only with patients whose cases cannot be treated with standard treatments. Results to date have been very mixed, with no dramatically positive results to report. The drug does not seem to be effective in shrinking or stopping the growth of well-established tumors. Ultimately, we will probably need a combination of multiple drugs to work on the same tumor simultaneously with multiple strategies.
Another possible strategy is to target the over-production of growth hormone. Just as families report rapid progression of lesions in adolescence and pregnancy, there are drugs used to treat over-production of growth hormone in pituitary tumors — somatostatic analogs — which are being used successfully in treating diabetic retinopathy, where growth factor synergizes the angiogenesis and makes it worse. He is in fact treating one patient with a somatostatin analog.
He underscored the importance of depositing tissue with the tissue bank. It is critically important to research to have tissue material to test new drugs in the lab to determine which ones are most helpful with particular tissue types.
There is a new test using a positron emission tomology (PET) scan with an antibody that picks up VEGF. You inject the tracer, it is soaked up by VEGF, and then lights up on the scan to indicate the amount of VEGF in difference parts of the body. This test is in the process of FDA approval now. He expects it will be used for every cancer patient, and also for VHL patients.
The VHL protein has now been shown to be an important factor in the regulation of a number of important proteins in the body and play a role in angiogenesis: PDGF beta, Endothelin1, Adrenomedullin, TKF alpha, TGF beta, Nitric oxide synthetase, COX2 prostaglandinsurokinase receptor, and PAK — all of which may be potential targets for therapy. There are drugs in cancer therapy trials for all of these. Drugs blocking VEGF are the highest priority, but we should not ignore other pathways. Because it is difficult to shrink well-established blood vessels, this may be an argument for treating lesions at earlier stages, or to use a combination of multiple drugs. We need more information on dosage and long-term safety. Prospects are very optimistic, and within the next 3-5 years we will have a great deal more information about how to proceed.
As printed in the VHL Family Forum 8:3, September 2000. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org. |
| Contact Us | Copyright 1993-2008 |