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Report from the Boston Meeting
Research - Radiology - Recuperating - Pheos - Genetics and Kidney Cancer - Radio Frequency Ablation (RFA) - Pancreas
Research
The 2007 Annual Meeting was held in Boston, Massachusetts, on June 23-24, 2007. This report contains only the highlights. All presentations have been recorded. A CD or DVD is available for purchase, or you can view selected segments on the website, for a modest fee. We hope that you will benefit from these excellent presentations. See http://vhl.impactlearning.org or mail your order using the coupon in the back of this issue.
Two of the researchers YOU have been supporting for the past year with your research donations were on hand to share their research. Dr. Susanne Schlisio of Dana Farber Cancer Center described her research on the molecular causes of pheochromocytoma. She studies some important clues: first that the risk of pheo varies depending on where in the VHL gene the mutation occurs. Second, VHL is one of five different genetic alterations that can result in a pheo. In all cases, the genetic variations disrupt the normal cycle of creation and elimination of EglN3 and KIF (pronounced eggelin-3) during embryonic development. These left-over cells from before birth hang around in the body and later cause a pheo to form. Her team is working on translating this understanding into treatment.
Dr. Donald Bellgrau of the University of Colorado shared his research on targeting cancer-specific mutations (like VHL) with Immunotherapy. All people develop tumors, but the immune system normally kills the tumor. The immune system looks for foreign material (like a splinter) and launches defenses against this foreign material. It tests to see if cells are “self” or “not self”. A second analysis determines whether this material is dangerous. Cancer has the ability to elude the immune system by fooling the body into believing that this tumor is “self”, or even if it is “not self” it is determined to be “not dangerous.” Bellgrau’s research is working with a yeast preparation that can be used to “wake up” the immune system and sound the alarm that the cancer cells are indeed “not self” and are “dangerous”, spurring the body to mount a defense against the cancer cells. In cooperation with the Cleveland Clinic they have prepared a customized therapy that will work for some of the VHL mutations. This compound has to be customized for each different VHL mutation, or category of mutations. The project continues, with second year funding from VHLFA.
Radiology
Dr. Richard Cohan of the University of Michigan spoke with us about issues in imaging for VHL. Dr. Cohan specializes in imaging of the abdomen and pelvis. For VHL, this means imaging of the kidneys, pancreas, and adrenals. He discussed the differences among conventional X-ray, ultrasound, CT, MRI, and PET. Contrast material is important in a CT: it makes tumors brighter but does not change the appearance of a cyst. There is probably no more increased risk for people allergic to shellfish or topical iodine than for people who have other allergies. He shared ideas for managing people with sensitivities to the contrast materials.
MRI is often preferred, especially in young people, because it does not use radiation. MRI gives excellent images and better contrast than CT, but the image resolution is not quite as good as CT. There is concern about the use of gadolinium contast agent with people who have elevated creatinine levels, an indicator of poor kidney function. This is something that should be discussed with your urologist. Most people with VHL are at extremely low risk for complications with gadolinium.
Recuperating
Amy Lynn Budd, Artist in Residence at the Perishable Theater in Providence, Rhode Island, shared with us her story of having a brain tumor of VHL. After surgery she went back to studying dance, and found that it helped her regain her balance and self-esteem. She now teaches dance to battered women and women who have had breast cancer or other surgery, to help them feel beautiful again. Amy got us up and doing some easy stretches and fun moves to 60’s music.
Pheochromocytoma
The next three presentations focused on diagnosis and treatment of pheochromocytoma. Dr. Arthur Tischler of Tufts New England Medical Center helped us understand what pheos are, and how to diagnose them. Common symptoms and signs include two or more of:
80% of pheos occur in or near the adrenal glands. The other 20% are paragangliomas that occur in other parts of the sympathetic nervous system. These are sometimes called extra-adrenal pheochromocytomas.
Most doctors have been taught in medical school that 10% of pheos are extra-adrenal (outside the adrenal gland), 10% are hereditary, and 10% are malignant. However, this is proving not to be true. Up to 30% of people with pheos have a hereditary risk factor. The risk of malignancy depends on which of the genetic factors may be at work. The good news is that the risk of malignancy is low in people with VHL. Nonetheless, pheos are very damaging tumors that need to be diagnosed and removed as quickly as possible.
Dr. Ronald Lechan, also of New England Medical Center, elaborated on diagnosis of a pheo. To the list of possible symptoms he added:
Attacks can last seconds to hours, and can be as infrequent as once every few months.
Untreated, pheos can lead to devastating consequences: heart attack, stroke, fluid in the lungs, and circulatory collapse (shock). Pheochromocytoma can be associated with metabolic abnormalities: lactic acidosis, hypercalcemia (elevated calcium), glucose intolerance and diabetes, and associated syndromes (ACTH and VIP).
The most reliable test for a pheo is measurement of metanephrines and normetanephrines in blood and/or urine. Drs. Lechan and Tischler like to do both studies to see how they correlate. Each of the hereditary conditions has a particular biochemical phenotype -- a different set of “normal” characteristics. (See Figure 2).
Figure 2: Different profile for pheos in each inherited condition. Pacak et al., J. Int. Med., 257: 60, 2005.
MRI or CT of the abdomen may identify visible masses, but they do not measure the function of the tumor. For function, there are some nuclear medicine tests that can be used: MIBG, Octreoscan, or fluorodopamine PET. The definitive management of a pheochromocytoma is surgery to remove the tumor, preferably by laparoscopy. “Pre-operative pharmacological blockade of adrenergic receptors is mandatory”: that is, before surgery they have to give medications to block the receptors for the chemicals produced by the pheo. These blockers may need to be given for weeks before the surgery, to ensure that there will not be a pheo crisis during the surgery.
Drs. Tischer and Lechan, and Dr. Jonathan Coleman of Memorial Sloan Kettering Cancer Center in New York then listened with all of us to four patients telling their stories of a very long and rocky path to diagnosis of a pheochromocytoma.
Jim B.’s mother had a pheo during her pregnancy (age 20, 1953) when he was born. She survived that one, and had a second pheo at age 42, and a third at age 44. When Jim was 9 in 1962 he had three pheos, one of which was behind his heart. At age 15 he had another pheo near his adrenal gland that caused a collapsed lung. Both Jim and his mother received excellent care for their pheos, but no genetic diagnosis was made. Beginning in 1992, his eldest daughter had pheos at ages 9, 15, and 17. In 2000 a second daughter had another pheo. A total now of 11 pheos over 47 year span, and no genetic diagnosis. It was not until 2005 when Jim experienced blood in the urine that he was finally diagnosed with VHL – now with advanced tumors of the kidney, pancreas, and retina. He and his daughters are now in a proactive program of screening, to find other issues early.
Judy F. of New Hampshire shared the story of her two sons. Her younger son was diagnosed with a pheo at age 12. It was considered sporadic, even though Judy’s aunt and ner daughter had both died of metastatic pheos in the 1960’s. One year later her older son (age 23) began having similar symptoms. The doctor said that pheo was such a rare tumor that the odds that it would happen to the second son were astronomical, and he refused to do the pheo testing. He forgot to think about genetics. The family did find a doctor to do the test, and her son was diagnosed with metastatic pheo. Clearly something genetic is going on, but they are still unsure just what. One would have predicted that this would be a case of SDHB mutation, but both boys have tested negative for SDHB and other likely genetic causes.
Audrey from Canada had sent in her story of being diagnosed with a pheo after having had a stroke. Her doctor put her on blocker medications that make her spacey and keep her almost a zombie. She lives in fear of another stroke. The issue here is that blockers alone will not manage the effects of a pheo over time. She is working with a neurologist to determine whether she is a candidate for surgery.
Malinda S. from Pennsylvania told us of her 16-year saga, actively seeking medical help for symptoms that began with hypertension, sweating, and panic attacks. She was tested for many conditions, and was basically told to see a shrink. The symptoms escalated and the panic attacks became rage attacks. One doctor who worked with her later told her that he had considered a pheo, but for two reasons ruled it out: her blood pressure was high, but not spiking, and none of the descriptions talked about rage. A number of texts say that blood pressure should be spiking. Especially with hereditary pheos, it may be high all the time or in fact it can be low. And while the textbooks usually use words as strong as “angry outbursts”, Malinda would use the word “rage”. She lost weight and looked terrible. At 85 pounds the doctor felt that her liver seemed enlarged. The scan showed instead that it was being pushed out of place by a 9 cm pheo.
Once the tumor was removed and her body settled back to normal hormone levels, Malinda has completed a college degree and her family life is happy again. But those last three years before the diagnosis were rugged. She points out, though, that if the pheo had been diagnosed any time in those first 13 years of searching for a diagnosis, she would never have gotten to the point of rage. There were clues; there was plenty of opportunity for a diagnosis. But the available literature failed her and her doctor. There are new publications in the literature in the last 2-3 years that are trying to improve the information available to support doctors in making more timely diagnoses. The families need to help connect their doctors with this new information, some of which directly contradicts what they were taught in medical school.
Genetics and Kidney Cancer
On the second day of the conference Dr. Scott Plotkin of Massachusetts General Hospital told us about his work with Familial Tumor Syndromes, including VHL. He is working with a consortium of hospitals doing clinical trials for some of these diseases, trying to bring more options to his patients in Boston. In most cancer trials, there is one focal tumor and the objective is to shrink that one tumor. When there are multiple tumors, however, it is hard to choose one to focus on. How should we measure success? He is holding a conference in Boston November 29 on designing trials for people with tumor-suppressor syndromes like VHL, to determine what the specific goals of such a trial should be.
Dr. Daniel Cho of Beth Israel Hospital gave us an overview of the clinical trials available now for kidney cancer. Most are focused on metastatic disease, which we with VHL work hard to avoid. Sorafenib looked promising, but at the end of 18 months the benefits seem to wear off. Sunitinib (Sutent) approaches the problem from more angles and is showing promise. The angiogenesis effects do seem to wear down after a year, but the effects remain, and some promising agents are coming out that may prolong the effects. Temsirolimus, for example, works against cell proliferation. All three of these agents have now been approved “for advanced kidney cancer.” None has yet been explicitly approved for use with VHL. One active study is under way testing Sutent specifically for VHL. It should be noted that while there is response from these drugs with kidney tumors, there is no significant response reported for CNS tumors.
Dr. Othon Iliopoulos, head of the VHL Clinical Care Center at the Massachusetts General Hospital, shared his research on biomarkers for the identification of kidney cancer thru analysis of blood or urine. It would be great if there were an easy blood or urine test that could indicate the possible presence of kidney cancer – it would allow the doctor to identify people who need follow-up scans to determine whether kidney cancer were present, and it might help doctors measure the success of treatment – as the kidney tumor shrinks, the indicator levels go down; if the tumor recurs, the indicator levels go up again. A blood test is a great deal cheaper and easier than a scan.
Dr. Iliopoulos has done an extensive study of blood and urine samples from RCC patients, and has identified seven leading candidates for biomarkers – chemicals in the blood whose levels seem to correlate with levels of RCC disease. He worked to identify which chemicals rose, and which dropped, with the activity level of RCC in the body. The leading candidate seems to be CA9. Studies continue. Radio Frequency Ablation (RFA)
Dr. Nahum Goldberg of the Department of Radiology at Beth Israel Hospital in Boston spoke with us about Radio Frequency Ablation of VHL Renal tumors. This is an outpatient procedure performed with an image-guided probe – a very attractive alternative to open surgery for some situations. Ideally, the kidney tumors should be between 2 and 3 centimeters – large enough to be a good target, but small enough that it is still considered not to be in imminent danger of metastasis.
He explained the technology, showing how the heat probe is used, and the challenges of getting it to the right place without injuring other structures. Some tumors are harder to reach than others, and depending what other delicate structures they are sitting against (blood vessels, urinary ducts, bowel, or muscle) it may be necessary to inject saline to provide an insulating space to protect these structures, and to keep the flow of blood or urine from cooling the heat treatment before the tumor is fully cooked.
Dr. Goldberg presented his own experience, and data shared by Dr. Brad Wood at the U.S. National Cancer Institute, to give us an overview of the pros and cons of using Radio Frequency Ablation to treat kidney tumors. The promise of this technology is to stunt the growth of a kidney tumor without open surgery, keeping it from advancing and metastasizing. We now have eight years of data. A total of 325 patients have been reported in the medical literature. Dr. Wood and his colleagues have treated 112 tumors in 63 patients who have been followed for an average of three years after the treatment.
They conclude that RFA and other thermal therapies have much to offer for the treatment of VHL tumors. RFA for small tumors is safe and effective and can save kidney function as long as care is taken to minimize damage to surrounding structures.
Dr. Steven Libutti, head of the VHL pancreas study at the U.S. National Institutes of Health, gave us a status update of his research. See separate report. (Page 1)
At the Annual Meeting four new members of the Board of Directors were officially elected, and awards were presented to key volunteers: to Altheada Johnson, on completion of twelve years of service on the Board of Directors; to Tom Lusk on completion of six years of service on the Board of Directors; to Alexandra Morais of our Spanish language hotline, as our Volunteer of the Year; and to Fran Mott for her continuing service as chairman for Michigan.
Handouts and Videos of each presentation
As printed in the VHL Family Forum 15:3, September 2007. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org. |
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