ARE UNSATURATED FATTY ACIDS WORTH CONSIDERING?

One of the 'advantages' (how strange to use that word) of EHE resulting from a single genetic mutation is the possibility that there might be single actionable targets. Somewhere down the road it might be possible to use gene editing to specifically remove or reduce the expression of the fusion gene responsible for EHE. It's likely a long time until gene editing techniques like CRISPR cas 9  are sufficiently safe and effective for use in humans. Meantime, we can think of interfering with signaling pathways upstream of YAP/TAZ but there's a concern that 1) constitutive activation of the fusion means it's always turned on and therefore not susceptible to upstream manipulation and 2) inhibiting intermediate signals could further activate other upstream paths that are no longer attenuated by feedback inhibition. So, lets look to third way: 

Might it be possible to find a way to accelerate degradation of YAP/TAZ in a way that effectively deactivates them? Well, a recent paper from China suggests that omega-3 polyunsaturated fatty acids (w-3PUFA)might do just that. Kun Zhang et al report in a paper published in Scientific Reports last May that w-3PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce fibrosis in a mouse model of liver damage and fibrosis caused by carbon tetrachloride. This phenomenon is similar to cirrhosis caused by alcohol and is mediated by activation of YAP/TAZ. They further show that EPA and DHA reduce cellular content of YAP/TAZ and that this results from the increased degradation of these proteins. Note that DHA and EPA are common constituents of fish oil. So, could consuming fish oil accelerate degradation of YAP/TAZ in a state like EHE where these proteins are otherwise always active?  I'm not ready to start recommending fish oil all around; after all, we still don't know what this would do to those upstream signals. BUT, it's certainly something worth testing when we have that mouse model of EHE. Or possibly for someone with aggressive EHE when other treatments don't appear to have any benefit.  

 

More on Metabolism

You are all probably aware of the important connection between cancer and metabolism. By the way, you might ask, "What is metabolism"? It means the sum total of all chemical reactions in your body. That's a pretty big topic! Interestingly, when I was a student, almost every laboratory had a large wall poster of 'metabolism' showing many of the classical biochemical pathways, some of which you might know, like the citric acid cycle. However, by the 80s basic biochemistry had become somewhat passe, as many considered we knew it all. Besides, molecular biology was just coming in to its own and as more and more papers on genomics and gene expression were published, fewer scientists were interested in studying biochemistry which had become very 'old school'.

But lets flash back even further to the 1920s when the study of biochemistry was in full swing as many of the aforementioned classical pathways were being worked out. An amazingly prescient scientist, Otto Warburg, made the observation that cancers had a unique biochemical signature he referred to as aerobic glycolysis. Glycolysis is the conversion of glucose to pyruvate which when there's enough oxygen around enters mitochondria where it can be further metabolized to stoke oxidative phosphorylation which makes our currency of energy (ATP).  In the absence of oxygen, pyruvate stalls outside mitochondria and is converted to lactate. Cancers, Dr. Warburg observed, have very accelerated glycolysis and convert most of the resulting pyruvate into lactate even in the presence of oxygen...hence, aerobic glycolysis (note this is a slight misnomer given that glucose - pyruvate covers glycolysis; maybe accelerated, aerobic, glycolytic lactate production would be more accurate...whew). Anyway, the amazing thing is that Otto was right!!! And as this signature has been confirmed again and again for a variety of cancers, more and more interest is accumulating in studying the biochemistry of cancer. That means, all those old-school wall posters of my youth are coming back to the laboratory! Now, we're looking at an intersection of biochemistry and molecular biology in many cancer-focused laboratories....and some of these are likely to have real importance for EHE. 

Interestingly, although it was assumed that transformation of cells to cancer causes the acceleration of glycolysis typical of cancers, it's recently been considered that the reverse is true, too: acceleration of glycolysis could promote cell proliferation typical of cancer. For example, it was recently shown that metabolic flux through one of the several enzymes required for normal glycolysis, phosphofructokinase (PFK), seems to turn on TAZ....the protein that is active in EHE. Although this effect is 'upstream' of TAZ, it's conceivable that dampening glycolysis could also slow down this signaling pathway and reduce one of the signals activating TAZ.....possibly even TAZ that is mutated by the disease-defining translocation of EHE. OK, that ice is somewhat thin, since upstream signals might be irrelevant to a mutation like the one in EHE, that constitutively (persistently) activates TAZ. However, let me go out even further onto the thin ice......some people, like Kris Karr believe in the benefits of a special diet. I don't hold with holistic medicine, but I wonder if there might something there. Is it possible that funneling tons of simple carbs down the glycolytic pathway causes PFK to turn on TAZ? Is it possible that the opposite is true: by eating well she's taming the effect of glycolysis on TAZ?

EHE GRAIL

It is important for EHEers to know the scientific goals that will allow us to tame or possibly cure this disease. This goal, our grail, is not out of reach given that the most important step has already been achieved: establishing the cause of EHE. We can even say that the second necessary step has also been taken: establishing how the underlying genetic alteration(s) in EHE cause cell transformation. Both steps were accomplished in Dr. Rubin’s lab and insofar as the EHE community supports his research, we can all pat ourselves on the back for helping him establish that mutations resulting in persistent activation of either YAP (~10%) or TAZ (~90%) and their resulting transcriptomes cause the proliferation of endothelial cells that we see as EHE. Sorry for the verbosity…… but what’s next?

We need at least 1) a cell model to screen and test drugs for their ability to suppress YAP/TAZ-driven expression; 2) an animal model of EHE to learn more about the disease and to test promising drugs identified in the screen and finally; 3) biomarkers of EHE to follow activity of the disease. So 3 is the magic number.

An example of 1) could be a cell system that allows high-throughput testing of drug effects on YAP/TAZ by computer analysis of immunofluorescence imaging (antibodies against that glow under a microscope). This could identify drugs that keep YAP/TAZ out of the nucleus (the only place they’re active) or that reduce mRNA levels resulting from YAP/TAZ binding of TEADs. Such systems have already been published and even identified drugs with possible activity against expression of the transcriptomes.  The only way we’ll know for sure if these drugs could alter EHE progression is by testing them in an animal model of EHE.  

The most workable animal model for EHE is a genetically engineered mouse (GEM). This is possible because EHE is caused by a single gene abnormality. Dr. Rubin is currently working on this project and is optimistic about having a good EHE GEM within the year. This would allow us to learn more about the biology of EHE, to test drugs against the disease and to test possible biomarkers. It’s exciting to contemplate now what treatments we might test in the EHE GEM. Keep thinking!

EHE is certainly a weird type of cancer. Unlike almost every other cancer, the extent of disease and number of organs involved are not good predictors of outcome. People live for long periods despite wide spread (or as we prefer to say, ‘systemic’) disease because it often remains dormant for years. The benefit of a biomarker is that we might use it to follow disease activity and thereby intervene at an early stage to suppress growth before the diseasebecomes clinically apparent or problematic. Possibilities include either a protein produced by YAP/TAZ activation, or EHE tumor cells or even EHE-specific DNA that could each be identified in a blood sample. The latter would allow so-called ‘precision medicine’ since it could be calibrated to identify only that DNA sequence specific to each patient’s mutation.

So, lots of good things to look forward to. Stay tuned.      

 

MTOR!

I want to give our community a little background on the potential use of mTOR inhibitors like rapamycin for EHE. There has recently been renewed interest and some practical experience in the clinic that shows some promise, so here’s a  little summary to let know a bit of the rationale behind that. Note to the cognoscenti: For the sake of simplicity, I am going to use ‘mTOR’ to refer generically to what might be considered the classic regulatory functions of mTORC1.

mTOR, the mammalian target of rapamycin (or mechanistic target of rampamycin) is a protein complex that integrates information about cell status (especially nutrient levels and energy status) to regulate cell growth and division (proliferation). Sensing the levels of various nutrients is an important job of mTOR which is activated when these are high; essentially mTOR says, ‘It’s OK to start making proteins because we have enough nutrients and energy”.

A brief glossary note is indicated: inputs are considered ‘upstream’; effects exerted are ‘downstream’; and the specific signal molecules (usually proteins) are called ‘effectors’. The classic upstream inputs for mTOR are (positive) insulin signaling (occurs when insulin binds a cell surface receptor) and (negative) AMPK, an important sensor of cell energy status that is activated when the cell energy level is down – this puts the brakes on mTOR signaling. Effects of mTOR activation include protein synthesis and progression through cell cycle that together allow the cell to grow and divide. Mutations in upstream regulators of mTOR that leave it constitutively (always) ‘on’ result in growths and tumors that can be treated with mTOR inhibitors. You can look up tuberous sclerosis for example to learn more. This is why rapamycin might be considered a potential generic treatment for all sorts of cancers, including EHE.

However, there is theoretical (and serious) concern with a general application of this approach since the downstream targets of mTOR play a role in regulating and controlling growth responses through ‘negative feedback’ to upstream systems. To engineers, this is called a servo-mechanism; to the rest of us, this is just a way to keep things from getting out of control. The problem is that when mTOR is inhibited indiscriminately, many upstream systems become active or very sensitive; this could turn on other growth systems parallel to mTOR, essentially defeating the purpose of mTOR inhibition. However, there is now circumstantial evidence that suggests mTOR is specifically turned on in EHE, thereby providing a rationale for using rapamycinin EHE.   

The amino acid, leucine, is one of the key upstream activators of mTOR. Teleologically, it makes sense that a high intracellular concentration of an important amino acid means the cell is ready to synthesize proteins (which after all are made of amino acids). Going even more upstream, both YAP and TAZ are potent stimulators of the amino acid transporters that bring specific amino acids, including leucine, into the cell. This means that YAP and TAZ are both indirect stimulators of mTOR. So, when either of them is turned on all the time, leucine levels will be high and mTOR should be activated, too. This might provide an explanation for a possible benefit of mTOR inhibition in EHE. We should also look at the possibility of using specific inhibitors of the leucine transporter. More on this at a latter blog.

Homologs

I discussed in a previous post the relevance of the genetic concept, heterogeneity, to EHE. Specifically, the two most common types of EHE-causing genetic alterations involve transcription co-activators, YAP and TAZ. These two genes are very similar, making them homologs. There are two types of homologs: paralogs and orthologs.

Paralogs: a pair of genes that derives from the same ancestral gene and now reside at different locations within the same genome. Gene duplication is a very common evolutionary event that allows variation by mutation within a particular gene without losing its (possibly essential) function. There are many examples: hemoglobin is made of a tetramer of globin proteins, two each of Hb A and Hb B. These are each synthesized from the Hb A and B gene templates: closely related but diverged from one another at some point as a result of duplication of an ancestral globin gene and subsequent mutations in each daughter gene. Hb A and B are paralogs, just as YAP and TAZ are. 

Similar to globin, YAP and TAZ are highly conserved throughout evolution - they are transducers of a signal system, Hippo, that is well known and first described in detail in Drosophila (fruit flies). The Hippo system is responsible for controlling organ size by causing cells to stop proliferating when they touch each other (contact inhibition). YAP and TAZ are the vertebrate versions (orthologs) of the Drosophila gene, Yorkie. Orthologs are genes in different species that evolved from a common ancestral gene by speciation. So, orthologs and paralogs are closely related gene sequences (homologs), separated by speciation and therefore are in different species (orthologs) or duplication and mutation but in the same species (paralogs).

You might think this is way too much detail about EHE. But a better understanding the biology of this disease will help us get more quickly to the goal of a cure.

Heterogeneity

Heterogeneity is an important term for all genetic diseases and EHE, like all cancers, can be considered a genetic disease. Only in EHE, unlike most cancers, there is a single responsible genetic alteration (mutation) that starts the disease in each person - I say it this awkward way because each cell can obviously later develop additional mutations. Heterogeneity refers to the fact a range of different mutations can lead to a single type of disease. For instance, hundreds of different mutations can lead to dwarfism (disproportionate short stature), or hemoglobinopathy. Within any given category of disease you can slice the distinctions with an ever sharper blade and still come up with variations in the particular mutations that cause that disease. So, even within a type of hemoglobinopathy, like sickle cell, you might find that most patients have a specific mutation that leads to the most common amino acid substitution in the beta-globin molecule, but there are other, rarer beta globin mutations that also lead to red cell sickling. Thus heterogeneity means it can be important to know what specific mutation a patient has because it will affect their clinical course and possibly their treatment. This is especially true for targeted therapy or precision medicine since the treatment will depend on the specific mutation.

This all leads up to pointing out that EHE is heterogeneous. The most common mutation (~90%) result from a balanced, reciprocal translocation (see future 'words of the day') that fuses the gene coding for TAZ (a transcritional co-activator) to that coding for CAMTA1. The other 10% are caused by a similar fusion between YAP (a close relation to TAZ) to TFE3. We don't know yet if the different mutations result in different clinical outcomes. Or whether they might be similar in terms of response to different treatments. These questions are an important part of future research. Furthermore, if we can find a way to use 'precision medicine' to stop the expression or effects of a particular fusion protein, then we will clearly need to define the underlying mutation for each EHE patient. 

ENCYCLOPEDIA

I am very glad to tell you that Jane Gutkovich at EHEFoundation announced today the publication on their site (fightEHE.org) of the EHE Encyclopedia. Thank you, Jane and all the volunteers and contributors!! This is essentially a patient-driven registry and contains the stories of almost 180 patients to date. It is a living document insofar as people will continue to add to and update their stories and new patients will be added over time. Assembling this is a monumental undertaking that required tremendous perseverance and a lot of hard work by Jane and volunteers. It will be very useful for a variety of reasons, not least that EHE patients can review the stories to find similarly affected individuals. Everyone is different, but not so much that we can’t learn from each others’ experiences.

This enterprise grows from the work by Cynthia Pollak who established the HEARD registry, a similarly robust and useful on-line, patient-driven registry. We analyzed that database several years ago and published our findings in the journal Chest (see below). I will cover our findings in detail in another blog post. Suffice to say that we made a few important observations. One is that there EHE appears in a number of reasonably well-defined patterns of clinical disease and, more importantly, the extent of metastasis and the number of organs involved doesn’t seem to have much bearing on clinical outcome. This is important since it distinguishes EHE from almost all other cancers. Since discovery of the underlying genetic alteration and resulting biology of EHE, this finding makes a lot more sense.

In summary, please take advantage of the encyclopedia and contribute your story if you haven’t already. Finally, if you have trouble spelling encyclopedia, just go here.

Clinical Patterns and Outcome in Epithelioid Hemangioendothelioma With or Without Pulmonary Involvement Insights From an Internet Registry in the Study of a Rare Cancer

Kenneth Lau , MD ; Malek Massad , MD , FCCP ; Cynthia Pollak ; Charles Rubin , MD ; Joannie Yeh, MD; Jing Wang, PhD; Guy Edelman, MD; Jenny Yeh, MD; Sunil Prasad, MD; and Guy Weinberg , MD

ABSTRACT. Background: Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm of endothelial origin with clinical behavior intermediate between hemangioma and angiosarcoma. The natural history of EHE is highly variable. This study uses an Internet registry to identify clinical patterns with prognostic significance in EHE.

Methods: Cases from the International Hemangioendothioma, Epithelioid Hemangioendothelioma, and Related Vascular Disorders (HEARD) Support Group were evaluated based on demographics,organ involvement, disease progression, presence or absence of pleural effusion, and treatment. Survival among various cohorts was compared using log-rank analysis of Kaplan-Meier plots.

Results: Two hundred sixty-four patients were identifi ed from April 2004 to November 2009. Fifty-eight cases were excluded because of inadequate information or wrong diagnosis. EHE was more common in female patients (61%). Male gender and age _ 55 years were associated with decreased survival. The most commonly affected organs were liver, lung, and bone. No specific organ or combination of organ involvement differentially affected survival, and survival was no different between patients with multiple vs single organ involvement. However, pattern B, defined as lesions without distinct borders (eg, pulmonary infiltrates, pleural effusion, ascites), hemoptysis, or involvement of more than two bones adversely affected survival in all cohorts.

Conclusion: A novel staging system with prognostic value for EHE is proposed. Pleural effusion or other signs of uncontained tumor growth, hemoptysis, and osseous involvement of more than two bones implied worse survival than did localized and discrete tumors, regardless of number of organs involved. A lay registry can provide useful insights into the clinical behavior of a rare cancer. CHEST 2011; 140(5):1312–1318

 

 

two fusions

A translocation that brings together the genes for TAZ (WWTR1) ahd CAMTA1 is responsible for ~90% of EHE cases while 10% involve fusion of YAP, (a paralogue, closely related gene of TAZ) with TFE3. A new paper from Korea (citation below) analyzed 18 EHE specimens and found that while all of them were positive for the TAZ-CAMTA fusion, 5 of them also had the YAP-FTE3 fusion. Note that one possible explanation for sudden conversion of dormant EHE to aggressive disease could be the occurrence of a second mutation. Could this fusion of paralogous YAP be an example of such an activating mutation. They also try to make a connection between the TFE3 fusion and clinical presentation at an earlier age with a tendency to larger, single tumor. There could be something I'm missing, but their analysis of the data and conclusions seem to me of limited practical or scientific value in terms of treating patients or having a better understanding the disease. By the way, the word, compossible used in the title was new to me, so I thank the authors for that. It means what it sounds like: two things that can exist together or, compatible.

Epithelioid hemangioendotheliomas with TFE3 gene translocations are compossible with CAMTA1 gene rearrangements Seok Joo Lee, Woo Ick Yang, Woo-Suk Chung and Sang Kyum Kim Department of Pathology, Yonsei University Medical Center, Seoul, South Korea

ABSTRACT: Epithelioid hemangioendotheliomas (EHEs) are vascular tumors of intermediate malignancy that can undergo high-grade malignant transformations. EHEs have been characterized by tumor-specific WW domain-containing transcription regulator 1(WWTR1)-calmodulin-binding transcription activator 1 (CAMTA1) translocations, and recently, a novel Yes-associated protein 1 (YAP1)-transcription factor E3 (TFE3) gene fusion was identified in EHEs. In this study, we examined the expression levels of TFE3 and CAMTA1 via immunohistochemical staining and identified chromosomal alterations using fluorescence in situ hybridization (FISH) assays and RT-PCR tests. Although all of the EHEs were CAMTA1-positive in immunohistochemical staining, only five out of 18 EHEs (27.78%) positively expressed nuclear TFE3. The five TFE3-positive EHEs exhibited TFE3 gene break-apart in FISH assays. YAP1-TFE3 gene fusions were confirmed by RT-PCR. Interestingly, we observed CAMTA1 gene break-apart in all of the five TFE3-positive EHEs via FISH assays, and four out of the five TFE3-positive EHEs exhibited WWTR1-CAMTA1 gene fusions via RT-PCR. These results indicate that these two chromosomal alterations are not mutually exclusive but compossible in EHEs. Finally, primary tumor sites in TFE3-positive EHEs consistently contained single masses (P = 0.0359) with larger sizes (P = 0.0550) compared to TFE3-negative EHEs. Similar to previous reports, we observed well-formed vessels more frequently in TFE3-positive EHEs than in TFE3-negative EHEs (P = 0.0441). In addition, TFE3- positive EHEs tended to more frequently demonstrate high-grade nuclear atypia (P = 0.0654) and hypercellularity (P=0.0987) than TFE3-negative EHEs. Thus, we have now established two clinically distinct subgroups of EHEs: TFE3-positive and TFE3- negative EHEs.

 

 

A Huge donation

This past weekend, Hugh Leonard posted on the FB EHE page that he donated $180,000 to Dr. Rubin's laboratory at the Cleveland Clinic. This is a monumental event since that type of money can substantively advance the EHE science we all want to see. Every dollar can make a difference since it means we can obtain needed equipment and supplies for experiments that will have a real impact on our understanding of EHE. Large sums make an even bigger impact since that means Dr. Rubin can hire technical or scientific support (read, post-doctoral fellow). That, in turn, allows experiments be done more rapidly. In short, more resources and suppies translates into more science and answers.

I'm in awe of Hugh's accomplishment since CRAVAT Foundation has been raising money for Dr. Rubin over the past 5 years, and while we've done well, we're not at that level (yet)....and Hugh did it over a very short period of time. I hope to have him contribute to the blog soon so that he can share his special, I mean especially effective, methods of fund raising.

REBOOTING THE BLOG

There has been enough scientific progress in EHE-related research and sufficient development of the EHE community over the past two years to warrant re-establishing a blog on the topic. I hope to include a wide variety of sources and especially the voices of key people in our community. I'm not sure exactly how it will develop over time (that's the nature of evolution) but I bet it will be interesting. Please stay tuned.

What's in a Name?

By Any Other Name....WWTR1=TAZ, and Why That's Important. You may know that Brian Rubin, an acclaimed, first-rate molecular pathologist at Cleveland Clinic and the key scientific researcher in EHE discovered a few years ago that the genetic alteration underlying EHE is a 'fusion' of two genes: WWTR1 and CAMTA1. Til now, there's been very little interest in the basic science community to do research on EHE because it is so rare.  However, I believe that will change soon. It turns out that WWTR1 has another name: TAZ. So, just to this clear up WWTR1=TAZ but there is another (entirely different) gene called TAZ (http://en.wikipedia.org/wiki/Tafazzin) so the TAZ that is altered in EHE is sometimes called YAP/TAZ to avoid confusion since those two genes (YAP and TAZ) are very similar highly conserved paralogues that both promote cell growth and are normally inhibited by the Hippo signaling pathway. Note the recent publications showing that fusion in YAP can also cause EHE. So, abnormal cell growth in EHE occurs because the fusion protein is not inhibited by Hippo and therefore continually signals for cell growth to occur. OK, enough background. 

Significance of TAZ The little lesson in nomenclature is important because TAZ is now becoming a highly researched gene since mutations in it are found at very high rates in common cancers (e.g breast). I expect that EHE should no longer be the super rare thing no one wants to study. My hope is that we can bring TAZ people over to EHE and I've been focusing on this for the past several months. It's definitely new hope since it appears that big Pharmas are now assembling TAZ teams to find targeted drugs. Also TAZ knock out mice aren't really very sick, meaningTAZ  inhibition shouldn't be too adverse for patients (hopefully). 

Upstream and Downstream Targets. There are two theoretical ways to inhibit activity of the mutant TAZ in EHE.  TAZ is a transducer for Hippo, but it also responds to a number of other important signals: Wnt, f-actin, mevalonate, etc. If the problem wiht the fusion is that the TAZ signal becomes perpetually active will it be sensitive or insensitive to alterations in upstream signals. Some people think the fusion will remain active no matter what. I think (believe, hope) that inhibiting upstream activators could reduce activity of the fusion. This is important since there are many drugs available now that target these upstream signals. However, if inhibiting these upstream signals don't change TAZ activity there's still the possibility that we can discover drugs that inhibit activity downstream of TAZ where it promotes cell growth by interaction with DNA. 

What We Need Now: Cell and animal models will allow us to screen for and test drugs (upstream or down) that could treat EHE. So, developing such models is a VERY HIGH PRIORITY for us. Could one of the drugs already on the shelf be 'the one'? Won't know til we get a cell or animal model.

 

Margaret Mead and EHE

I was reading the FB page today (if you haven't yet, you must join EHEcancer group if you have an interest in EHE) and two things occurred to me about the effort to find a cure for EHE or at least a solution to it clinical management. First, is the famous quote by Margaret Mead, “Never doubt that a small group of thoughtful, committed, citizens can change the world. Indeed, it is the only thing that ever has.”  It is the best description of our group imaginable. We might not always know where we're going or always agree with each other on the best means of achieving our goals, but we are certainly getting closer every day to taming the beast, thanks to the tireless efforts of our small, thoughtful, committed group. Those of us who've been involved with EHE for a while as well as the 'newbies' must all recognize the tremendous value of pooling efforts, and learning and working together that is made possible by the FB group. A fantastic example of this is provided by the story of Sue Byrnes who created the LAM foundation after her daughter was diagnosed with lymphangioleiomyomatosis, a rare lung disease that only afflicts females. Starting with a letter writing campaign she was able to leverage her friends' and family's support into a movement that essentially forced the NIH to fund research on LAM which has since led to major breakthroughs in our understanding and treatment of the disease. Her inspiring efforts could form a template we can use to advance our cause. I encourage you to learn more about her story and success since it has direct relevance to achieving our goals.  

The second interesting point to me is that the main movers in the FB group are women. Very reminiscent of Sue Byrnes, the force behind the original EHE movement, HEARD, was Cynthia Pollak. She single-handedly did so much to move the field forward, including the establishment of the HEARD registry from which we learned so much about EHE - it still informs and guides the current efforts at creating an EHE registry. The current group, started by Dawn has seen other women, like Jane and Gayla take on major leadership roles. Almost all the posts each day on the FB page are made by women. So, in keeping with Margaret Mead's role as a cutting edge, prescient and consequential woman, the EHE group has embodied not only the credo exemplified by her famous quote but continues to show female leadership. More than a paean to women, I hope this spurs male readers to accept the challenge and try to do as much as the mom's, sisters and daughter are.

Dichotomies: Finding Balance

It occurs to me that in EHE as in life in general, maintaining equilibrium requires that one must choose a path between extremes. These dichotomies appear over and over again throughout the EHE journey and provide useful topics for consideration insofar as considering how to avoid 'banging the rails' can help sustain some semblance of normalcy along the way.

The first dichotomy strikes most of us shortly after hearing the diagnosis: once we're recovered from the shock of the 'C' word and getting over the 'What the Hell is EHE' phase (each a good blog topic in itself), we're faced with the question, 'What do I do now'? People often answer either by hiding or kicking into super-action. I offer that neither is optimally adaptive because this is a long road that requires engagement AND stamina. You have to become involved....but last long enough to make a difference. 

In a 15 round prize fight, the boxers pace themselves and so must we. I think in that first rush, patients and family can go nuts trying to talk to every doctor, read every book, surf every site, find every other patient, consider every treatment option...it's only natural that after a scary diagnosis you want to do everything you can to improve your chances. However, when even the best intentions lead to 'over action' you can end up trying to do too much - this is potentially mal-adaptive if it leads to burn out.

So, take the long view. It's important to commit to the cause but in a reasonable fashion. Inaction isn't really defensible since even when the disease is dormant we have to consider our response if/when it reappears. However, running around trying to accomplish an army's worth of work 24/7 isn't healthy either. Try to pace yourself to stay in the game and active at that.

Second opinion? Yes!!

This is pretty much a no-brainer. The hard part is often convincing a new EHE patient that it's OK to seek another opinion....or finding the right person for giving that opinion.

The key is that EHE is so rare, virtually only a handful of doctors in the US have sufficient experience to be considered 'expert'. Therefore, as every experienced EHE patient knows, you MUST strongly consider getting a second opinion, unless of  course your primary doctor is one of the small cadre of experts (what are the odds?). Moreover, virtually all clinical input is tempered by the knowledge that there is little consensus on how best to manage 'systemic'  EHE. This is a term I just invented. I don't like the word metastatic since it carries an intention and meaning that applies to other cancers but not EHE since the number of organs involved doesn't really impact outcomes - this is substantiated in at least two published studies (Lau et al, Chest, 2011;  Thompson et al HPB, 2013); in fact in the latter, five year survival was improved in 'metastatic' vs single sight disease!). So, lets call it systemic when it involves more than one location....now back to the topic at hand.

Most people with the diagnosis of EHE were originally told they had something else. This misdiagnosis is nearly always uni-directional. That is, people with EHE are given several wrong diagnoses before learning the truth. Almost no-one is given the diagnosis of EHE then told they have something else. Once having gone thru the wringer with an incorrect diagnosis (or many) and before they start making recommendations for treatment...the first thing the newbie should do is CONSULT AN EXPERT FOR A SECOND OPINION because the initial doctors just don't know enough about this rare disease. I mean, it's no knock on them but it's highly unlikely they've even heard of it, let alone seen it, before.

Finally, one important goal of identifying a small cadre of such experts is that together, in the aggregate, they generate an ever-expanding data base of knowledge that just isn't possible for 'singlet' oncologists, let alone primary care docs. This is the same goal as the registry and why we should 1) identify all the willing 'experts and 2) involve them all in posting to and using the registry.

Capiche?!!! Verstehen Sie?? Comprenez-vous?? Вы понимаете?

Now do it! No excuses!!

 

What to do about liver tumors

This is a very complicated question since EHE patients often have liver tumors that don't substantially affect life quality unless they cause pain which can be anywhere on a spectrum from nothing to severe. So, what to do about those buggers? What I can say off the top of my head is that for (the rare) patients with a solitary operable lesion, resection is best. However, as you know, most people with liver involvement (ie HEHE) have extensive disease (both lobes, multiple tumors); then, I believe most people think surgical excision is not advisable. Patients in this situation often decide to do nothing; especially since liver function (assessed by lab tests called 'LFTs' are often normal. Moroever, there's no evidence I'm aware of indicating that treating these exerts a survival benefit - maybe it does, we just don't know. In any case, many people decide it's best to kill the tumors and have used any of a variety of IR (interventional radiology) procedures. They involve different ways of killing tumor at the end of a catheter that is passed into the tumor under fluoroscopy either directly or via arteries that feed the tumor; these include: radiofrequency ablation = heat; electroporation = osmotic shock; yttrium 90 microsphere = radiation; chemo- or bland-embolization = cutting off blood supply. Finally, there's complete removal, ie liver transplant. the pro- con- of this decision is very complex and will be addressed in another post. Here, you're balancing lots of risks and benefits, for instance, all the risks of transplant (surgery, immunosuppression, etc) against a theoretical benefit and the unknown risk of leaving the tumors in place. One of the most important things to consider is that transplant is a one-way trip. Chemo, trematinib, RT, all those, you can start and stop. but transplant is different: it takes you to a new world and new way of life from which there is no return. For many people with symptomatic HEHE, this is good, cause they don't want to go back to where they were. The other good news is that there is a lot of experience with LTx in EHE (UNOS and European groups); moreover, LTx impacts quality of life a lot less than I expected or predicted it would. If you compare the survival (Meier - Kaplan) plots for LTx in EHE versus those without EHE, they look very similar. That is, the EHE seems to exert no influence on survival after transplant, suggesting that in a way you've reduced the disease burden or diminished somewhat the effect of EHE on survival...at least that's the way I view it. So, it's complicated and provides good food for thought. I think many people would be surprised to know that LTx, after a period of recovery, affects your life a lot less than you'd think....at least that's our experience.

Scanxiety: what's the best solution?

One of the frequent contributors to the FB page mentioned yesterday she gets  'scanxiety' - a perfect word to describe what we all experience before those big days. Everyone handles it differently. My approach: blissful denial in the days leading up; as in, 'oh, everything will be alright'. There's no downside since the approach won't change or avoid any actual findings. So, it's entirely safe and time proven as long as you don't stay in that mode if there's something that needs attention. Moreover, since radiologists nearly always 'over read' films (CYA-based reflex; this truism is based on our experience but appears very reproducible). So, if (there won't be...but) they see something, don't freak out - it could be an entirely normal thing but they just can't resist scaring you (I've been there more than once). I'lll address the whole, "Denial v Over-reaction" in another issue issue of this blog. Please don't hesitate to post if you have something to add.

There's a youtube on this topic from MSK: https://www.youtube.com/watch?v=BUPstSZDXFI