After chatting with the organizers, I realized that the primary reason to have the meeting in Disney Paris was financial—similar hotels in downtown Paris would cost twice as much. In addition, there is a grand chateau nearby that is undeniably French.
On 9/16, the lectures were mostly on progress in basic and clinical research. Regarding basic research, it seems rather clear that there are two “clusters” in pheo pathogenesis. The clusters concept is not entirely new (I wrote on the clusters before) but now the molecular details are worked out to a large extent. The scheme of pheo pathogenesis is a labyrinth of interconnected molecules. As I also do basic research myself, I am sometimes sarcastic about this kind of scheme. If everything affects everything else, how do we break the pathways? We need to figure out what the “driver” molecule is. But is there such a driver?
Some researchers reported the results of experimental targeted therapy in cell models, animal models, and in patients. The animal models are particularly intriguing and are real breakthroughs.
This meeting is very heavy on characterizing patients with SDH mutations and their individual mutations. The European countries are leading this effort. I have always wondered if SDH mutations are more common in Europe. In this meeting, I saw again some small countries reporting hundreds of patients with SDH mutations. I myself have not seen many patients in the US with clear familial paraganglioma syndromes. An alternative explanation is the difference in health care system. I cannot tell you how many patients I no longer follow due to their change of insurance plan. The national insurance system in Europe is a blessing to patients with rare and complicated diseases like pheo.
During the meeting, especially around 3 am when I was suddenly awake and trying unsuccessfully to go back to sleep, I reflected on the big picture of pheo patient care and where we should direct our research resource. I will elaborate my thoughts in later posts.
Dr. Pheo
Saturday, September 17, 2011
Friday, September 16, 2011
Report from ISP 2011 Part I
The 3rd International Symposium on Pheochromocytoma (called “ISP 2011” by the organizers) is being held in a Disneyland Hotel outside Paris. I am here attending this meeting. It is a 4-day meeting but most academic activities are concentrated on Sept 15 and 16.
The specific Disneyland hotel is kind of an odd choice of venue for an American attendee like me. I would pick a downtown Paris hotel on the left bank. Apparently my European colleagues are tired of Paris and prefer a place on a theme park. The hotel is full of little cute girls and boys dressed in Disney costumes, or pestering their parents to buy them a set or 2 of. The hotel is so serious about the Disney theme that you see Monsieur Mickey everywhere, including on shower curtain. At one moment today, I felt I was at home until someone said Bonjour to me. And a bottle of coke costs 3.5 Euros.
The meeting itself is simply fantastic so far. Today’s lectures and posters are actually very educational to me even though I believe I knew a few things about pheo before the meeting (I indeed presented a poster on pheo clinical care). Really great is the discussion with colleagues. All the big shots on pheo are here, including most doctors I recommended as pheo experts in a post 2 years ago. I am pleased to say that we share similar experience and opinions on many controversial issues. Patient support groups also have a prominent presentation.
The following is an incomplete list of new things I learned today:
1. Practical half-life of plasma metanephrines is longer than most people thought. Plasma metanephrines can linger for one month after complete pheo resection.
2. Most attendees agree on the importance of preoperative preparation even when the patient does not have hypertension at the time of diagnosis.
3. First-hand accounts of the discovery processes of the novel pheo genes TMEM127, SDHAF2, and MAX, by the discoverers themselves.
4. The 3 novel genes, however fascinating for studying pheo pathogenesis, probably have limited value in clinical care for most patients.
5. Apart from family history and clinical predictors, pheo markers and pheo tissue staining can also predict specific mutations.
6. No real progress in pathological diagnosis of malignant pheo. Basically even an expert pathologist cannot accurately tell if a primary pheo is benign or malignant.
7. Surgical indications of head and neck paragangliomas.
8. Still there are no commercial labs that can do plasma methoxytyramine in the US.
9. More and more people realize that pheo causes heart damage. I have observed that for many years and it is nice to see people now agree.
10. Some new vagaries of pheo. For example, cardiomyopathy can have a waxing-and-waning course even after phenoxybenzamine.
To be continued…
Dr. Pheo
The specific Disneyland hotel is kind of an odd choice of venue for an American attendee like me. I would pick a downtown Paris hotel on the left bank. Apparently my European colleagues are tired of Paris and prefer a place on a theme park. The hotel is full of little cute girls and boys dressed in Disney costumes, or pestering their parents to buy them a set or 2 of. The hotel is so serious about the Disney theme that you see Monsieur Mickey everywhere, including on shower curtain. At one moment today, I felt I was at home until someone said Bonjour to me. And a bottle of coke costs 3.5 Euros.
The meeting itself is simply fantastic so far. Today’s lectures and posters are actually very educational to me even though I believe I knew a few things about pheo before the meeting (I indeed presented a poster on pheo clinical care). Really great is the discussion with colleagues. All the big shots on pheo are here, including most doctors I recommended as pheo experts in a post 2 years ago. I am pleased to say that we share similar experience and opinions on many controversial issues. Patient support groups also have a prominent presentation.
The following is an incomplete list of new things I learned today:
1. Practical half-life of plasma metanephrines is longer than most people thought. Plasma metanephrines can linger for one month after complete pheo resection.
2. Most attendees agree on the importance of preoperative preparation even when the patient does not have hypertension at the time of diagnosis.
3. First-hand accounts of the discovery processes of the novel pheo genes TMEM127, SDHAF2, and MAX, by the discoverers themselves.
4. The 3 novel genes, however fascinating for studying pheo pathogenesis, probably have limited value in clinical care for most patients.
5. Apart from family history and clinical predictors, pheo markers and pheo tissue staining can also predict specific mutations.
6. No real progress in pathological diagnosis of malignant pheo. Basically even an expert pathologist cannot accurately tell if a primary pheo is benign or malignant.
7. Surgical indications of head and neck paragangliomas.
8. Still there are no commercial labs that can do plasma methoxytyramine in the US.
9. More and more people realize that pheo causes heart damage. I have observed that for many years and it is nice to see people now agree.
10. Some new vagaries of pheo. For example, cardiomyopathy can have a waxing-and-waning course even after phenoxybenzamine.
To be continued…
Dr. Pheo
Tuesday, July 19, 2011
"Pheo interest group"
As pheo is a rare disease, it is no surprise that many doctors have little experience on pheo. Ideally patients with suspected pheo should be seen at large centers with extensive experience such as Mayo Clinic or National Institute of Health. On the other hand, most patients with suspected pheo do not actually have pheo and the management of pheo is not that complicated in most cases. Having traveled long distances, many patients with suspected pheo would feel that they probably could have saved the trip if their primary doctors had simply communicated with the experts in large centers about their conditions. A recent paper addresses the above situation somewhat, albeit indirectly.
In this paper, doctors at one center examined whether a "pheo interest group" could improve the diagnosis and treatment of pheo. The pheo interest group is nothing more than a group of doctors with a common interest in this rare disease. A few of the doctors have a large personal experience with pheo. The doctors compared the diagnostic accuracy and management of pheo before and after the formation of the pheo interest group and found that the quality of care improved after the group formation.
It might be expected that quality of care of course would be higher if the patients were seen by pheo specialists. This paper, however, shows that the pheo specialists do not have to see the patients directly. A phone call or email exchange between the primary doctor and a pheo specialist often does the job. The pheo specialist would review the clinical history, lab test, and imaging results (if available) provided by the primary doctor and arrive at a conclusion. The specialist only communicates with the primary doctor, without seeing the patient. The medical responsibility still rests in the primary doctor's hands. The primary doctor chooses to adopt the opinions of the specialist or not. As alluded in this paper, most primary doctors would adopt those opinions after they have had positive experience with the pheo specialists.
The moral: an inexperienced doctor should seek help from pheo specialists for diagnosis and management of pheo. Will the specialists be happy to answer the questions from non-specialists? They should. Take me as an example. I have been approached by doctors in my practice area and from remote places for pheo-related questions. I am happy to answer them. First of all, these questions are not very frequent so do not cost a lot of time. Second, I often learn new things on pheo from my colleagues who have questions in pheo. Last, it is rewarding for me to help my colleagues and patients (indirectly). I always make sure to emphasize that my opinions are "friendly" and non-binding. It is the primary doctor's responsibility to decide what to do.
Dr. Pheo
In this paper, doctors at one center examined whether a "pheo interest group" could improve the diagnosis and treatment of pheo. The pheo interest group is nothing more than a group of doctors with a common interest in this rare disease. A few of the doctors have a large personal experience with pheo. The doctors compared the diagnostic accuracy and management of pheo before and after the formation of the pheo interest group and found that the quality of care improved after the group formation.
It might be expected that quality of care of course would be higher if the patients were seen by pheo specialists. This paper, however, shows that the pheo specialists do not have to see the patients directly. A phone call or email exchange between the primary doctor and a pheo specialist often does the job. The pheo specialist would review the clinical history, lab test, and imaging results (if available) provided by the primary doctor and arrive at a conclusion. The specialist only communicates with the primary doctor, without seeing the patient. The medical responsibility still rests in the primary doctor's hands. The primary doctor chooses to adopt the opinions of the specialist or not. As alluded in this paper, most primary doctors would adopt those opinions after they have had positive experience with the pheo specialists.
The moral: an inexperienced doctor should seek help from pheo specialists for diagnosis and management of pheo. Will the specialists be happy to answer the questions from non-specialists? They should. Take me as an example. I have been approached by doctors in my practice area and from remote places for pheo-related questions. I am happy to answer them. First of all, these questions are not very frequent so do not cost a lot of time. Second, I often learn new things on pheo from my colleagues who have questions in pheo. Last, it is rewarding for me to help my colleagues and patients (indirectly). I always make sure to emphasize that my opinions are "friendly" and non-binding. It is the primary doctor's responsibility to decide what to do.
Dr. Pheo
Tuesday, June 21, 2011
All those exons and MAX
It is now a good time to do translational research on pheo. A clinician/researcher myself, I am following pheo research closely and I can tell that translational research on pheo is getting great results.
Translational research directly addresses mechanisms of human diseases. Translational research is the interface between basic and clinical research. The recent boom in translational research, in my opinion, is driven by two forces: patient advocacy groups and new technologies. Patient advocacy groups are more like corporate now. They usually hire MBAs to manage their operations and use more sophisticated strategies to advance their causes. New technologies are being developed almost every day. The new technologies need to find applications to show they are worthwhile in answering medical questions. With the synergy of those two forces, new technologies are more and more applied to less common diseases. Compared with common diseases, less common diseases, such as pheo, are more easily studied with the new technologies because they are more homogeneous. For example, there are so many types of prostate cancer, making a common etiology less likely. While pheo, by virtue of its rarity and uniform pathology, share more common features between each other.
One such new technology, exonomics, sequences almost every exon of the genome. Exons are the DNA stretches that actually encode proteins. (Introns, on the other hand, are DNA stretches that do not.) Because proteins are the doers and movers of biology, sequencing the exons likely yields insight of genetic causes of diseases.
Today, I noted a paper just published online which identifies a new tumor suppressor gene for pheo called MAX. The Spanish doctors include 3 families of familial pheo who do not have any mutations in known genes important for pheo. The exons of a lot of genes are sequenced in this study and MAX mutations appear to cause pheo in the 3 families. Now the list of pheo genes is getting even longer: RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2, NF1, TMEM127, and MAX. Does this mean we have to sequence every gene in all patients? Of course not. Each patient’s unique family history and pheo presentation are still the basis for clinical care. Rather, this study demonstrates the power of careful translational research. For such research to be successful, the clinicians must identify a group of patients that share key common clinical features. Scientists, on the other hand, must know all the details of the technology and sieve through the data to find the real molecular deficit. The importance of patient participation of such research cannot be overemphasized.
Dr. Pheo
Translational research directly addresses mechanisms of human diseases. Translational research is the interface between basic and clinical research. The recent boom in translational research, in my opinion, is driven by two forces: patient advocacy groups and new technologies. Patient advocacy groups are more like corporate now. They usually hire MBAs to manage their operations and use more sophisticated strategies to advance their causes. New technologies are being developed almost every day. The new technologies need to find applications to show they are worthwhile in answering medical questions. With the synergy of those two forces, new technologies are more and more applied to less common diseases. Compared with common diseases, less common diseases, such as pheo, are more easily studied with the new technologies because they are more homogeneous. For example, there are so many types of prostate cancer, making a common etiology less likely. While pheo, by virtue of its rarity and uniform pathology, share more common features between each other.
One such new technology, exonomics, sequences almost every exon of the genome. Exons are the DNA stretches that actually encode proteins. (Introns, on the other hand, are DNA stretches that do not.) Because proteins are the doers and movers of biology, sequencing the exons likely yields insight of genetic causes of diseases.
Today, I noted a paper just published online which identifies a new tumor suppressor gene for pheo called MAX. The Spanish doctors include 3 families of familial pheo who do not have any mutations in known genes important for pheo. The exons of a lot of genes are sequenced in this study and MAX mutations appear to cause pheo in the 3 families. Now the list of pheo genes is getting even longer: RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2, NF1, TMEM127, and MAX. Does this mean we have to sequence every gene in all patients? Of course not. Each patient’s unique family history and pheo presentation are still the basis for clinical care. Rather, this study demonstrates the power of careful translational research. For such research to be successful, the clinicians must identify a group of patients that share key common clinical features. Scientists, on the other hand, must know all the details of the technology and sieve through the data to find the real molecular deficit. The importance of patient participation of such research cannot be overemphasized.
Dr. Pheo
Thursday, March 24, 2011
Adrenal biopsy and pheo
Adrenal tumors are fairly common. Diagnosis and follow-up of adrenal tumors can be costly and inconvenient. So a reasonable question is "why don't we biopsy an adrenal mass to get a definitive diagnosis?" Here I will try to convince the readers that adrenal biopsy is seldom necessary or useful except in one situation. Most important to me is the one particular safety issue of adrenal biopsy: biopsy of a pheo can be catastrophic.
The one situation where we need adrenal biopsy is to determine the staging of a cancer. For example, one unfortunate patient has lung cancer and an adrenal mass. If the adrenal mass is benign, then the patient's lung cancer is of a lower stage. If the adrenal mass is lung caner metastasis, then the same lung cancer is of an advanced stage. Only biopsy of the adrenal mass will give definitive staging information of the patient's cancer.
Adrenal biopsy is not needed for the vast majority of adrenal masses because the diagnosis of adrenal mass can be confidently made in most patients without biopsy. Let me explain why. How do we know someone has an adrenal mass? Either the patient has clinical symptoms (e.g. paroxysmal hypertension) with suggestive biochemical test results (e.g. elevated plasma metanephrines) so that a functioning adrenal mass (e.g. pheo) is suspected, or CT or MRI is done on the abdomen for some other purposes (such as abdominal pain or cancer staging). In both cases, the imaging characteristics of the adrenal mass tell a lot about it. The size, density, enhancement, and appearance on various MRI protocols all matter. With additional biochemical testing, a good doctor is able to make the correct diagnosis of the adrenal mass.
One may wonder, OK, adrenal biopsy probably is not needed, but will it give important additional information? This issue is a little complicated for non-specialists. For the most common clinical question whether an adrenal mass is adenoma or carcinoma, adrenal biopsy can not answer. Regarding pheo, we just simply do not biopsy a pheo to confirm the diagnosis because doing so is too risky without any benefits.
Although generally very safe, adrenal biopsy can be potentially lethal if done to an unappreciated (or worse, suspected) pheo because of the risk of hypertensive crisis. Here are the basic facts: 5% of all incidentally identified adrenal masses are pheo and the percentage is higher if the mass is pheo-like on imaging. In addition, 6-24% of adrenal masses suspected to be malignancy or metastasis are actually pheo. It is not that every attempted biopsy of a pheo will result in hypertensive crisis. It happens in about 15% of times. Although this number does not sound very high, the extreme danger and the total avoidability of hypertensive crisis makes adrenal biopsy unacceptable in any patients without negative pheo test results.
To prevent hypertensive crisis from happening, ask these following questions before adrenal biopsy:
1. Is this adrenal biopsy really needed? (Answer: only needed for cancer staging.)
2. If adrenal biopsy is needed, have pheo markers been tested? (Answer: please test pheo markers and only do biopsy if the markers are considered negative.)
Dr. Pheo
The one situation where we need adrenal biopsy is to determine the staging of a cancer. For example, one unfortunate patient has lung cancer and an adrenal mass. If the adrenal mass is benign, then the patient's lung cancer is of a lower stage. If the adrenal mass is lung caner metastasis, then the same lung cancer is of an advanced stage. Only biopsy of the adrenal mass will give definitive staging information of the patient's cancer.
Adrenal biopsy is not needed for the vast majority of adrenal masses because the diagnosis of adrenal mass can be confidently made in most patients without biopsy. Let me explain why. How do we know someone has an adrenal mass? Either the patient has clinical symptoms (e.g. paroxysmal hypertension) with suggestive biochemical test results (e.g. elevated plasma metanephrines) so that a functioning adrenal mass (e.g. pheo) is suspected, or CT or MRI is done on the abdomen for some other purposes (such as abdominal pain or cancer staging). In both cases, the imaging characteristics of the adrenal mass tell a lot about it. The size, density, enhancement, and appearance on various MRI protocols all matter. With additional biochemical testing, a good doctor is able to make the correct diagnosis of the adrenal mass.
One may wonder, OK, adrenal biopsy probably is not needed, but will it give important additional information? This issue is a little complicated for non-specialists. For the most common clinical question whether an adrenal mass is adenoma or carcinoma, adrenal biopsy can not answer. Regarding pheo, we just simply do not biopsy a pheo to confirm the diagnosis because doing so is too risky without any benefits.
Although generally very safe, adrenal biopsy can be potentially lethal if done to an unappreciated (or worse, suspected) pheo because of the risk of hypertensive crisis. Here are the basic facts: 5% of all incidentally identified adrenal masses are pheo and the percentage is higher if the mass is pheo-like on imaging. In addition, 6-24% of adrenal masses suspected to be malignancy or metastasis are actually pheo. It is not that every attempted biopsy of a pheo will result in hypertensive crisis. It happens in about 15% of times. Although this number does not sound very high, the extreme danger and the total avoidability of hypertensive crisis makes adrenal biopsy unacceptable in any patients without negative pheo test results.
To prevent hypertensive crisis from happening, ask these following questions before adrenal biopsy:
1. Is this adrenal biopsy really needed? (Answer: only needed for cancer staging.)
2. If adrenal biopsy is needed, have pheo markers been tested? (Answer: please test pheo markers and only do biopsy if the markers are considered negative.)
Dr. Pheo
Sunday, January 23, 2011
Pheo in pregnancy
Pheo in pregnancy is very rare. Most people with pheo are diagnosed after they are 40. If they know they have pheo, younger women would have the tumor removed before becoming pregnant. When pheo does occur in pregnancy, it usually is a big surprise and can have serious consequences to the mother and the fetus. Pheo in pregnancy is one of those “cannot afford to miss” diseases. Once suspected, diagnosis and treatment are usually straightforward and the mother and fetus can expect great outcomes.
Pheo in pregnant women is usually subclinical before pregnancy. The metabolic changes during pregnancy and the growing uterus tend to make the tumor more active. In my experience, pheo-induced hypertension usually occurs later in pregnancy but it can occur much earlier. Clinically it is difficult to differentiate between preeclampsia and pheo. My suggestion to obstetricians is to have a low threshold to test pheo. If the blood pressure is hard to control or there are paroxysmal symptoms such as palpitation, sweating, and headache, I would test pheo just not to miss it. In the vast majority of pregnant women, the test results are negative and pheo is ruled out. In those with clearly elevated pheo markers (the markers are usually markedly elevated in pregnancy), abdominal MRI is then done and the pheo is usually in one of the adrenal glands. CT and MIBG scan are contraindicated in pregnancy due to the associated radiation to the fetus. If pheo is diagnosed in the 1st or 2nd trimester (< 24 weeks), the woman is treated with phenoxybenzamine and beta blocker for preoperative preparation and the tumor is resected laparoscopically. If pheo is diagnosed in the 3rd trimester, the woman is still treated with phenoxybenzamine and beta blocker. When fetus is mature enough, Cesarean section is done, followed by tumor resection.
As pheo in pregnancy is a dramatic disease, there are always a few case reports every year, each with a little different flavor in it. The conclusion of most cases is to consider pheo in a pregnant woman with unusual hypertension. The case brought up by reader DJPheo was about a 27-year-old woman. Biochemical diagnosis was very clear but initial abdominal MRI did not identify a tumor. She received a PET/CT scan which localized the tumor. As DJPheo points out, the case raised a few issues. First, it is surprising that the abdominal MRI did not identify the mass (which is sizable at 5.7 x 2.8 x 3.1 cm) adjacent to the spine. Second, what should be done next if the mass is not seen even by experienced radiologist on abdominal MRI? Most would recommend MRI of the pelvis, chest, and neck. Third, if no tumor is seen after MRI of neck and trunk, what should be done next? I would make sure the blood pressure is well controlled and wait until after delivery (probably safer by C-section) for MIBG scan or PET. At any rate, this case should not be construed as evidence supporting PET/CT scan for localizing pheo in pregnancy. Rather the moral is that you need to find a good radiologist to read the MRI images.
Dr. Pheo
Pheo in pregnant women is usually subclinical before pregnancy. The metabolic changes during pregnancy and the growing uterus tend to make the tumor more active. In my experience, pheo-induced hypertension usually occurs later in pregnancy but it can occur much earlier. Clinically it is difficult to differentiate between preeclampsia and pheo. My suggestion to obstetricians is to have a low threshold to test pheo. If the blood pressure is hard to control or there are paroxysmal symptoms such as palpitation, sweating, and headache, I would test pheo just not to miss it. In the vast majority of pregnant women, the test results are negative and pheo is ruled out. In those with clearly elevated pheo markers (the markers are usually markedly elevated in pregnancy), abdominal MRI is then done and the pheo is usually in one of the adrenal glands. CT and MIBG scan are contraindicated in pregnancy due to the associated radiation to the fetus. If pheo is diagnosed in the 1st or 2nd trimester (< 24 weeks), the woman is treated with phenoxybenzamine and beta blocker for preoperative preparation and the tumor is resected laparoscopically. If pheo is diagnosed in the 3rd trimester, the woman is still treated with phenoxybenzamine and beta blocker. When fetus is mature enough, Cesarean section is done, followed by tumor resection.
As pheo in pregnancy is a dramatic disease, there are always a few case reports every year, each with a little different flavor in it. The conclusion of most cases is to consider pheo in a pregnant woman with unusual hypertension. The case brought up by reader DJPheo was about a 27-year-old woman. Biochemical diagnosis was very clear but initial abdominal MRI did not identify a tumor. She received a PET/CT scan which localized the tumor. As DJPheo points out, the case raised a few issues. First, it is surprising that the abdominal MRI did not identify the mass (which is sizable at 5.7 x 2.8 x 3.1 cm) adjacent to the spine. Second, what should be done next if the mass is not seen even by experienced radiologist on abdominal MRI? Most would recommend MRI of the pelvis, chest, and neck. Third, if no tumor is seen after MRI of neck and trunk, what should be done next? I would make sure the blood pressure is well controlled and wait until after delivery (probably safer by C-section) for MIBG scan or PET. At any rate, this case should not be construed as evidence supporting PET/CT scan for localizing pheo in pregnancy. Rather the moral is that you need to find a good radiologist to read the MRI images.
Dr. Pheo
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