Untangling #Amyloidosis at ASH 2015!

I am pleased to announce the upcoming Untangling Amyloidosis Friday Satellite Symposium on Friday, December 4th 2015 in Orlando, Florida prior to the American Society of Hematology Annual Meeting.  A stellar faculty will discuss the latest recommendations regarding diagnosis and management of amyloidosis, including sessions on emerging protein- and fibril-directed therapies. AND – thanks to the Amyloidosis Foundation – we are able to offer five (5!) student/trainee travel grants which will cover the airfare, lodging, and registration costs associated with attending the symposium and the ASH 2015 annual meeting! Applications are being accepted until 11:59 pm on October 1st 2015. 

A Lecture I Recently Presented at the Summit on Lymphoid Malignancies & Multiple Myeloma 2015

I recently had the opportunity to speak at a lymphoma and multiple myeloma conference in Whistler, British Columbia. Yes, the attendees (and speakers who weren’t recovering from Influenza B, as I unfortunately was) skied. But the agenda for the program was quite ambitious, and it included sessions on special populations and emerging therapies, which is where my talk fit in. 

Below are the slides from my talk. In this presentation, I cover the traditional therapeutic approach to treatment of AL amyloidosis, then move into an overview of new fibril-directed therapies currently in development. I included a few slides from a trial involving NEOD001, an anti-fibril mAb. The fully updated trial results were recently shared in an oral presentation at ASCO 2015 by Morie Gertz (Mayo). Click here for a link to the abstract. 

One of my posted slides (the one about anti-SAP therapy) suffered Grade 1 formatting abnormalities likely attributable to file embedding, not attributable to anti-SAP therapy or to the truly fabulous (but absurdly expensive) Manhattans at the Mallard Lounge and Terrace at the Fairmont Chateau Whistler.   

Game Changers for ATTR Amyloidosis?

I originally started this entry a year ago, having recently attended the huge weekend symposium for patients with familial amyloidosis in Chicago (here are the details) with a planned trip to Rio for the International Symposium on Familial Amyloidotic Polyneuropathy.  Maybe it was the easy lure of Twitter. Maybe it was too many caiparinhas in Rio. Whatever the reason, I lost my blogging mojo, and put it away until now. Despite this, internet-trolling ‘bots have remained extremely interested in my blog, with over 15K hits originating in Russia, Ukraine, and China alone during this year-long absence. Hopefully I can lure some amyloidosis-interested humans back to the site with insightful analysis and witty banter.

I just attended the International Amyloidosis Society’s XIV Symposium taking place in Indianapolis. Tuesday, April 29th, was largely dedicated to ATTR (transthyretin) amyloidosis, so it seems timely to discuss an important publication describing a novel new therapy for ATTR amyloidosis. I hope to briefly discuss some of my favorite oral and poster presentations from the symposium in the near future. Here is a link to the abstract book for those of you who just cannot wait.  

The paper, published in the New England Journal of Medicine at the end of August, describes the use of RNAi (RNA interference) as a means of selectively inhibiting production of transthyretin (TTR) but not other proteins. 

Before discussing the paper, some background on the biology of protein synthesis. Cells make proteins in a multi-step process. The coded template (the gene) for each protein is found in your DNA in the nucleus of each cell. When the cell wants to make a protein, the gene for that specific protein is copied as messenger RNA (mRNA). This is called transcription. The mRNA leaves the nucleus, and then is translated into protein in the cytoplasm (the part of the cell outside of the nucleus). In ATTR amyloidosis, misfolded transthyretin produced predominantly by liver cells (hepatocytes) aggregates into larger insoluble fibrils of amyloid which deposit in various organs, injuring them.  Protein synthesis is summarized below. 

If You are interested in a more in-depth discussion of this, click here.  

Dr. Coelho and colleagues conducted two sequential Phase 1 studies evaluating siRNA targeting ATTR synthesis. “siRNA” stands for small interfering RNA, which (together with a multi-protein cluster called RISC) finds, binds, and grinds a specific mRNA, thereby selectively shutting down production of the protein the mRNA encodes. Your basic silver bullet. The siRNA was packaged for delivery to liver cells (where transthyretin is produced) in lipid nanoparticles.  The two studies reported by Coelho look at two different nanoparticle preparations to deliver the same siRNA payload. The two preparations are called ALN-TTR01 and ALN-TTR02. The second one (ALN-TTR02) has since moved forward into clinical studies as the I.V. drug patisiran. There is also a subcutaneous formulation in development. 

Unwind, Find, Bind, Grind. Repeat as necessary. 

In the NEJM article, the authors showed that even a single dose of ALN-TTR02 could induce >85% knockdown of transthyretin levels. Even 4 weeks after the dose, TTR levels were still partially knocked down (albeit less so). The trials included patients with ATTR amyloidosis (the ALN-TTR01 trial) and healthy volunteers (the ALN-TTR02 trial). Side effects were manageable, with about 20% of patients experiencing infusion reactions that could be handled with steroids, temporary interruption of the infusion, and resumption of the drug at a slower infusion rate. 

Reliable reduction in TTR levels after ALN-TTR02 administration.

This week, at the ISA symposium, Dr Ole Suhr and colleagues (including Dr. Coelho) presented some data from a Phase II study of ALN-TTR02 in patients with Familial Amyloidotic Polyneuropathy, an inherited form of ATTR. Here is a copy of the abstract:

Note: Alnylam is the pharmaceutical company that makes ALN-TTR02 (patisiran)

Analysts ponder whether 85% reduction in TTR production is adequate to alter the clinical course of FAP, and that of course remains to be determined. Here is a link to an insightful blog discussing the implications of this in terms of drug development. 

Also presented at the mtg in Indy was an update regarding the status of ISIS-TTrx, another transthyretin mRNA-targeting agent using a different platform (its an antisense molecule). Here is the abstract:

ISIS-TTRx is a product of ISIS Pharmaceuticals

The actual oral presentation made by Dr. Ackermann focused on her company and the general technology of antisense therapy.  

As more information regarding both patisiran and ISIS-TTRx enters the public domain, I’ll update this topic. 

Japanese Scientists Debunk Longstanding Avian Behavioral Theory

Recent research published in the Journal Amyloid casts doubt on the widely accepted concept that chickens cross the road merely to get to the other side. It appears that at least some of them may actually be searching for an amyloidosis specialist. 

Tomoaki Murakami and colleagues describe their research related to an outbreak of AA amyloidosis occurring at a Japanese poultry farm. Avian AA amyloidosis is well characterized (as indicated by its inclusion in Table II from the most recent amyloid fibril nomenclature committee guidelines). AA amyloidosis has been described in waterfowl (due to chronic inflammatory conditions) and chickens (due to bacterial infections or repeated vaccinations). AA amyloid has also been detected in the livers of force-fed ducks and geese used for foie gras. 

A photomicrograph of a hepatic venule from a sample of commercially-available foie gras
(top panel, h/e stain; middle, congo red stain under polarized light; bottom IHC confirming AA amyloid).
Ref: http://www.ncbi.nlm.nih.gov/pubmed/17578924

The authors studied four breeds of chickens, one of which has previously been shown to have a propensity for developing systemic AA amyloidosis after repeated vaccinations for Salmonella enteritidis (SE) and/or Mycoplasma gallisepticum (MG). In this study, chickens were inoculated with a single dose of one of two SE vaccines (“SE(a)” or “SE(b)”) or an MG vaccine. Then some of the chickens were also given a dose of an AA amyloid fibril solution which the authors had prepared from the livers of other chickens with AA amyloidosis. Additionally, there were some chickens who received only vaccine without AA fibrils, only fibrils without vaccine, or neither.

The findings: 

  • 29 out of 38 chickens (all breeds studied) who got both vaccine SE(a) and a dose of AA fibrils (either orally or intravenously) developed AA amyloidosis. If the AA fibrils were administered orally, then the amyloidosis tended to develop in the chickens’ spleens; the chickens who got the AA fibrils intravenously developed more widespread systemic amyloidosis (including the birds’ intestines). 
  • ZERO out of 113 other chickens developed systemic AA amyloidosis.
  • Serum AA precursor protein levels (SAA levels) did not correlate with risk of developing systemic AA amyloidosis. The SE(a) vaccine did not induce an increase in SAA in any subgroup of chickens (including those who developed amyloidosis) and the MG vaccine did induce a rise in SAA (with no cases of associated amyloidosis).
The scientists (and another author providing commentary in the same issue of the journal) concluded that the outbreak of avian AA amyloidosis was likely the result of chickens ingesting amyloid-contaminated feed and/or droppings after having had industry-standard vaccinations which may have pre-disposed them to developing amyloidosis. 

Not an unprecedented finding. Fecal transmission is suspected to contribute to the high incidence of systemic AA amyloidosis in captive cheetahs (like cheetahs don’t have enough problems). Also, the same scientists who discovered amyloidosis in foie gras fed it to amyloid-susceptible mice and found it accelerated the rate at which systemic AA amyloidosis developed. They concluded foie gras was a potential Amyloid Enhancing Factor (AEF), and that 

“It would seem prudent for children and adults with rheumatoid arthritis or other diseases who are at risk for [AA amyloidosis] to avoid foods that may be contaminated with AA fibrils. 

Then, citing studies such as one in which formation of a specific type of amyloidosis (AApoAII) could be accelerated in predisposed experimental mice by intravenous injection of any of several different types of human amyloid fibrils (AL, ATTR, Abeta2-MG, and others), they suggest

“…that it may be hazardous for individuals who are prone to develop other types of amyloid-associated disorders, e.g., Alzheimer’s disease or type II diabetes, to consume such products.”

Which nags at me. I don’t so much wonder about whether my father, the son of a woman who died of Alzheimer’s disease, should enjoy foie gras as much as he does (though maybe I should – it’s Fathers’ Day). I worry a little bit about whether diet could be affecting the outcome of my patients with documented systemic amyloidosis. Is our carnivorous American diet full of AEFs? Possibly. An examination of the kidneys and other organs from 302 apparently healthy cattle slaughtered for meat revealed AA amyloidosis in 5% of the animals (take a look). The incidence was lower (0.4% – 2%) in other studies. A largely vegetarian diet has been cited as a possible explanation for the virtual absence of secondary amyloidosis in leprosy patients in India compared to the fairly high incidence amongst leprosy patients in the United States, Malaysia, Brazil, and other countries.  Check out this 1965 article by Amyloid Guru Alan S. Cohen and colleagues which explores this very topic.  At this time, though, there is no compelling evidence for transmission or acceleration of amyloidosis (AA or any other type) in humans from ingestion of AA-containing bovine meat or organs.  Additionally, a search of the medical literature did not turn up any studies looking at the impact of diet on prognosis in AL amyloidosis. So for now, I’ll just worry a little bit. Comments welcome. 

Digoxin Sensitivity and AL #Amyloidosis

Last week, I learned something. Since learning new things is a good habit to get into, I thought I’d share – especially since the pertinent data were actually a little difficult to track down. 

A patient of mine with long-standing AL amyloidosis was admitted to the hospital with congestive heart failure occurring in the setting of rapid atrial fibrillation (“AFib”). For non-medical folks, this means the top chambers of the heart  (the atria) were beating extremely fast and irregularly, driving the bottom part of the heart (the ventricles) to do the same. This is not a kind thing of the atria to ask of the stiff, thick, amyloid-filled ventricles. 

The situation was particularly difficult because of the patient’s chronically low blood pressure.  His typical BP of 90/50 was running even lower due to the abnormal heart rhythm.  Some of the medications one might normally employ to control the Afib – like beta-blockers or calcium channel blockers – could not be used here because of the BP.  I suggested to the medical residents that we try using digoxin, which would not be expected to lower the blood pressure.  An hour later, the team called me back to let me know they had decided against that because the risk of digoxin toxicity was too high in this patient. I asked why they felt he was at risk for this, and the answer surprised me.

“His amyloidosis.”

A search of PubMed using the search terms “digoxin” and “amyloidosis” yields only 8 references, at least as of the afternoon of May 18th, 2013. Of these, one of them was a case report of a person who was diagnosed with cardiac amyloidosis after developing fainting spells on digoxin.  Another article describing two cases of familial transthyretin (ATTR) mentions in the abstract that such patients are prone to digoxin toxicity, but does not state that the patients in that report experienced this. I have thus far not been able to track don a copy of the actual article text. The other 6 references that came up were not relevant to my specific patient’s case. 

I tried another strategy and pulled up a review from cardiac amyloidosis guru Dr. Rodney Falk. Here is his commentary on the use of digoxin in AL amyloidosis patients: 

“There is no role for digoxin in patients with cardiac amyloidosis who are in sinus rhythm. However, for patients with atrial fibrillation, cautious use of digoxin may aid in heart rate control although the risk of digoxin toxicity may be increased, possibly related to abnormal binding of the drug to amyloid fibrils.”

A reference for last statement not provided, so more digging was needed.  Turned up the following additional references, not identified by original search:

A 1961 article from one of Michigan’s own in the Annals of Internal Medicine which described two amyloidosis patients who seemed to have problems stemming from digitalis (a drug structurally related to digoxin, but with a longer half-life in the blood: 5-7 days, compared to 1.5-2 days). Pt #1 was a 58-yo farmer with jaundice and hypoalbuminemia (low serum protein levels) and atrial fibrillation who developed severe bradycardia (slow heart rate) of approximately 30 beats per minute after a 0.8 mg loading dose of digitalis followed a couple of days later by a 0.1 mg dose. Although it is not entirely clear from the text, it appears the patient had a liver biopsy proving he had systemic amyloidosis a few days before dying of liver failure.  No information was provided regarding kidney function. On autopsy, multiple organs were confirmed to be infiltrated with amyloid, including the heart. Amyloid fibril typing was not performed.  Pt #2, on the other hand, almost definitely had AL amyloidosis complicating a plasmacytoma. She was in sinus rhythm but had symptoms of congestive heart failure and exam findings suggesting cardiac tamponade (compressive fluid around the heart). She was treated with 1.3 grams of an older digitalis preparation (digitalis folia) over 60 hours. I cannot find a good reference with a dosage equivalency table to put this into current medical context. Also, again, no information on kidney function was provided. After dosing, the patient developed cardiac bigeminy (paired heart beats) with a rate of 70 beats per minute. The patient then developed severe hyperkalemia (high serum potassium levels – 8.3 mEq/L in this case, or about twice the normal level, after originally starting in the normal range). The patient suffered heart rhythm disturbances typical of this potassium level, and she died. On autopsy, the patient was found to have cardiac amyloidosis and a pericardial effusion (fluid around the heart) was confirmed. In 1961, serum digitalis levels were not obtainable.

A second article from A. Pomerance of London’s Central Middlesex Hospital’s Department of Morbid Anatomy and Histology was received at the British Heart Journal on Aug 17th, 1964, and was ultimately published in 1965. It turns out that at the exact same time, the Beatles were at work trying to get the tracks for Beatles for Sale! recorded and mixed. Busy time for the British. Pomerance’s article is an autopsy series of 21 elderly patients with “senile amyloidosis.”  At the time, the composition of the fibrils had not been characterized; today we know that most if not all of these cases were likely ATTR (wild type) amyloid.  The report is actually pretty fascinating from a historical standpoint, and it summarizes what was known at the time about systemic amyloidosis citing even older literature. As far as the cases, 3 of 21 patients were reported to have been “sensitive to digitalis” during hospital admissions prior to the terminal ones. No information about digitalis dosing, serum levels, or kidney function was provided. Two of the three patients had had prior myocardial infarctions. 

So, 6 total cases of amyloidosis patients experiencing “digitalis sensitivity.” One of the cases provides sufficient detail to justify this diagnosis.  One (pt #2 from the 1961 Cassidy article) almost certainly did not experience digitalis sensitivity but died of hyperkalemia-induced arrhythmia in the setting of pre-existing cardiac tamponade. There is insufficient data on the other four patients (from Pomerance’s report, and from the original PubMed search I did) to reach any conclusions one way or the other. 

What about the last part of the cited text from the Falk article? The best support for this was a brief report by Dr A. Rubinow, Martha Skinner, and Alan Cohen from Boston University published in 1981. They describe a laboratory experiment in which they added digoxin to pellets of amyloid fibrils isolated from the spleens of three patients with amyloidosis, and also to samples of ground up tissues: normal human liver, normal human heart, and human heart affected by amyloidosis.  They demonstrated that both pellets of pure amyloid fibrils or heart tissue from a patient with amyloidotic cardiomyopathy bound digoxin, whereas the control tissues (the ones without amyloid) did not. 

Ref: http://circ.ahajournals.org/content/63/6/1285.long

The authors discuss cardiac glycosides’ mechanism of action, and – citing the relevance of cardiac tissue levels of the drugs rather than serum levels – postulate that binding of digoxin by amyloid-laden cardiac tissue may increase effective drug levels where it counts. However, they (correctly) point out that it is unknown whether amyloid-bound digoxin retains its pharmacologic activity. Their conclusions? 

“Therapeutic judgement regarding the cautious administration of digoxin in patients with cardiac amyloidosis still rests on clinical grounds.”

My conclusions? The same. Patients with amyloid cardiomyopathy are known to be at risk for potentially fatal arrhythmias – its what accounts for the dismal outcomes seen in patients with cardiac stage 3 AL amyloidosis.  It is also clear that patients with structural heart injury from any cause may be at risk for digoxin-induced arrhythmias. So caution is warranted.  A critical review of the literature, however, does not make the case that digoxin can never be used in patients with systemic amyloidosis.  

Successful #Amyloidosis Foundation Benefit: Art, Autos, and Amyloid

Tonight, I attended a fine benefit event which raised funds for the Amyloidosis Foundation. I was joined by two other people from the Karmanos Cancer Institute Myeloma and Amyloidosis team (Silva Pregja and Christy Houde). The event was held at the Inn at St. John’s in Plymouth, MI. Here is a picture of the room: 

The Atrium Ballroom at the Inn at St. John’s. Image downloaded from the I@SJ’s website: http://www.stjohnsgolfconference.com/index.cfm

Very nice night with strolling dinner and a silent auction. Over a hundred people in attendance. The event Co-Chair was the daughter of one of my former patients. I had the opportunity to say a few words at the start of the evening describing the good work the Foundation has been doing for the last decade (educating patients and their physicians about amyloidosis – see link to video of GREAT symposium the Karmanos Cancer Institute and Wayne State University co-sponsored with the Amyloidosis Foundation; funding Junior and Senior level research grants to the tune of three-quarters of a million dollars in total).

Also while there, I had the opportunity to speak with some folks from Millennium, Alnylam, and Prothena – All sponsors of the event, and all in the business of developing amyloidosis therapies (Millennium – Bortezomib, Ixazomib; Alnylam – ALN-TTR02, ALN-TTRsc; Prothena – NEOD001).  

As for the auction, I made a successful run at at a nice piece of art:

Aptly named “Horses” (pardon less-than-professional-quality photo).
A nice little pic for the house and a few bucks for a good cause. 

Patient Page: Why is AL #amyloidosis bad for kidneys?

“Amyloidosis” refers to any one of several diseases in which abnormal protein fibrils accumulate in a person’s organs. The most common type is called AL amyloidosis, and the protein fibrils are made up of fragments of antibody proteins called light chains. I posted a slide which illustrates what a light chain is in a previous post (“Why is AL amyloid bad for hearts?“). In AL amyloidosis, the levels of light chains (usually lambda type, but sometimes kappa type) in the blood and urine are elevated.  Light chains are made by plasma cells in the bone marrow, and current AL amyloid therapy targets these plasma cells. 

Any organ’s function can be compromised by amyloid deposits.  The kidney is one of the most commonly affected organs, and patients with injured kidneys may have symptoms, including swelling (edema) of the legs, decreased urine output, and lightheadedness due to sudden drops in blood pressure. 

In order to understand how amyloid injures the kidneys, it is helpful to understand how the kidney works. 

A summary of kidney anatomy and function relevant to amyloidosis:

  • The kidney is made up of a million microscopic filtration units called nephrons. 
  • Each nephron has a filter called the glomerulus, which filters the blood.
  • Some parts of the blood, namely water and electrolytes (sodium, potassium, etc), flow through this filter into a tube system where it is processed further. The material that eventually comes out of the end of all this tubing is urine
  • Other components of the blood, like red blood cells, do not pass through the filter.  
  • Although under normal circumstances there is essentially no protein in our urine, it is not because proteins do not pass through the filter. Filtered protein may be reabsorbed (taken back up into the body) in the first part of the tubing system.  The part of the tubing where this takes place is called the proximal tubule.
  • The part of the tubing further down the line is called the distal tubule.
  • All of these structures, as well as blood vessels within the kidney, are surrounded by tissue which serves as scaffolding to hold it all together. This is the interstitial space, or matrix.  (Its the Jell-O holding all the little pieces of fruit in place in that dessert your mother used to make on Thanksgiving) 

If you want to know more about normal kidney function, see the clear, easy-to-understand post by my friend, nephrologist Joel Topf, in his blog Precious Bodily Fluids.

Light chains can injure the kidneys in a number of ways.  Like albumin, normal light chains are filtered through the glomerulus and then taken back up in the proximal tubule.  The receptors along the lining of the tubule which do this are actually the same for albumin and light chains (cubilin and megalin, if you were wondering).  Problems develop if the light chain levels are abnormally high or if the light chains have an abnormal tendency to form clumps of strands.
  • Amyloid light chains, in addition to being filtered, form deposits in the glomerulus itself. This is because these abnormal light chains are taken up by cells within the filter called mesangial cells. Mesangial cells do not take up normal light chains. After the abnormal amyloid light chains are snagged by these cells, they get processed and deposited within the matrix of the filter in strands called fibrils. When a pathologist is looking for amyloid in a kidney biopsy, s/he applies Congo Red stain, which makes these deposits look red under normal light and green under polarized light. As amyloid accumulates in the tissue around the mesangial cells in the glomerulus, the filter is damaged. It becomes “leaky” and the amount of protein lost through the filter increases. 

Kidney biopsy stained with Congo Red stain. Top image is the view under normal light, and the bottom one is the same slide viewed under polarized light.  Everything that turned fluorescent green in the second image is amyloid!
Images snagged from http://www.pathguy.com/lectures/imm-iii.htm
  • Increased protein delivery to the proximal tubule is bad for one’s kidneys. The receptors to reabsorb albumin and light chains can become overwhelmed. Excess albumin is lost in the urine, and it can make the urine appear “foamy.”  Very low blood albumin levels are what cause the swelling (edema) and low blood pressure (hypotension) amyloidosis patients experience. Even though I.V. albumin solutions exist, it is not feasible to replace it because infused albumin suffers the same fate as the patient’s “home-grown” albumin: flushed. Excess light chains can also cause problems, as they can bind to other proteins in the urine and form casts (clumps that clog up the distal tubule, which in turn causes problems upstream). Cast formation is the leading cause of kidney injury in multiple myeloma, but less of an issue in amyloidosis.  I posted about cast nephropathy previously (check that out). 
  • Inflammation plays a role in amyloid kidney injury. Abnormal light chains, when taken up by the cells in the proximal tubule actually injure the cells in that part of the kidney. Excess albumin in the tubular system and abnormal amyloid light chains in the cells lining the tubular system trigger inflammation and eventually scarring of the interstitial area. This is why AL amyloidosis patient with persisting heavy albuminuria (albumin in the urine) due to filter damage may have continued worsening of their renal function even after the amyloidosis has been treated and the light chain levels are no longer elevated: albumin-mediated kidney injury. In my own practice, this is a common and frustrating problem. One glimmer of hope: it is possible that one of the treatments commonly used in the treatment of AL amyloidosis – the proteasome inhibitor bortezomib (Velcade) – targets this inflammatory pathway.  Other drugs in this same family (carfilzomib (Kyprolis) and ixazomib (MLN-9708)) are currently undergoing testing as therapy for AL amyloidosis. These drugs may not only kill bad-acting plasma cells, but also help the kidney dodge some albumin-mediated damage. Friend and colleague Meletios Dimopoulos has published extensively on this topic; check out this article describing the improvement in kidney function seen in myeloma patients who received bortezomib therapy. 
Kidney transplant has been undertaken in a limited number of patients with myeloma and/or amyloidosis. A major concern is that the same disease-related processes which caused the original kidneys to fail will recur in a transplanted kidney. Also, the fact that patients with these diseases often have limited survival independent of kidney function begs the question of whether precious  donor kidneys are best used in this situation. With newer therapies leading to higher remission rates and longer survival in both myeloma and AL amyloidosis, the idea that it may be time to revisit the conventional wisdom about organ transplantation is gaining traction (like here).

Lets call it a wrap. While I call this a “Patient Page,” I used a lot of medical terminology. I tried to define everything in common language. Even so, it is probably clear I expect a lot from my readers. If there is anything in this page which requires clarification, TELL ME. Email me, or post it as a comment. I want the content of this (and every) post to be as clear and helpful as possible. 

Calling All Bloggers

I am planning to add several new features to my blog in the coming weeks and months, and the first one I’d like to tackle is the development of a slide library which readers can peruse and download. 

I think I make reasonably nice slides. The few I have included in prior posts are personally made using PowerPoint. As an art-major-turned-oncologist, I take some pride in the graphics I create for my lectures. 

I inserted the images above as screen shots, not editable slides. It is important to me that the content be editable to make it as useful to users as possible.  What I am envisioning is essentially an amyloidosis/protein folding disorder/myeloma/hematology/cell biology reference deck one can use in his/her own talks.

No plans to upload entire lectures complete with copyrighted survival curves or tables snatched from journals. 

The question at hand: best way to do it? Advice from blogging gurus out there? Looking at SlideShare currently, but it seems like I would have to load slides in as multiple one-slide files. A friend suggested I also take a peek at Google Docs. 

Any other suggestions? Anybody create something similar to this to which they can point me?

Rewarding Morning in Detroit

Since my last post, I attended the International Myeloma Workshop in Kyoto, Japan. I spent much of the first day of this 4-day symposium taking notes in the form of a draft blog post and simultaneously tweeting in real time from the conference. It quickly became evident that Twitter was better suited for disseminating info to those unable to attend. Please find me on Twitter (@amyloidplanet) if you want to see my feed from the conference.  Japan was excellent, and I am certain I’ll be in the mood for sashimi again sometime in the next year or two.

This weekend, I was able to participate in TWO very satisfying events.

First, I spoke at a CME conference organized by the Karmanos Cancer Institute focusing on cancer-related bone disease. Topics covered included myeloma, prostate cancer, and breast cancer, as well as specific treatment modalities – kyphoplasty, radiopharmaceuticals, external beam radiation, etc. 

Brochure from today’s symposium in Troy, MI: 130 registered attendees!

I discussed multiple myeloma with my colleague Muneer Abidi in a debate-style format:

Me (right) and my “opponent” (Dr. Muneer Abidi, left) squared off in front of colleagues, discussing myeloma-related bone disease. This is a PowerPoint slide from my talk, designed to lull him into a false sense of security from the outset. Not sure it worked. 

We discussed two questions which plague oncologists, even ones with particular expertise in myeloma:

  • Should all patients with active myeloma receive zoledronic acid as part of their therapy (even in the absence of bone lesions)? Traditionally, bisphosphonates (BPs) are used to treat hypercalcemia (high calcium) and to prevent skeletal complications in myeloma patients with either osteopenia or frank lytic bone lesions. The MRC IX Trial, which randomized myeloma patients treated with one of four different anti-myeloma induction regimens to additional treatment with either clodronate or zoledronic acid, found that patients treated with the latter not only had reduced skeletal events, but also modestly improved progression free survival (by about 2 months) and overall survival (by 5.5 months). Since this benefit was seen even in the third of patients without myeloma bone disease, recent updates of the NCCN guidelines and Canadian guidelines (the Alberta Health Services myeloma guidelines) recommend zoledronic acid or pamidronate (both potent amino-containing bisphosphonates, as opposed to the non-amino type, clodronate) for all myeloma patients receiving systemic anti-myeloma therapy. I was assigned the “against” side of debate, and the best argument against universal zoledronic acid use is a Cochrane Review from 2010 which did NOT show a definitive survival advantage related to zoledronic acid or any other bisphosphonate (though a 2012 update seems to, at least partially). Additionally, I find the fact that BPs don’t seem to modify the natural history of MGUS or SMM a strike against the use of these drugs in patients without bone disease. Also, there is the cost and the potential side effects like osteonecrosis of the jaw and subtrochanteric femoral fractures. Hard call.
  • Should any patients with MGUS or smoldering multiple myeloma (SMM) be treated with bisphosphonates? I was assigned the “yes” side of this debate and found it somewhat easier, because I believe its actually the correct answer. There is ample evidence that people with MGUS or SMM are at increased risk for osteopenia and – more importantly – fractures. A recent analysis performed by Kristinsson, et al., compared the incidence of fractures amongst ~5000 MGUS patients and ~20,000 matched controls from a Swedish health registry. MGUS pts had an increased fracture risk (HR: 1.74 @ 5 yrs, and 1.61 @ 10 yrs, not affected by M-protein Ig type or titer). Patients with fractures were not at higher risk of a subsequent diagnosis of  myeloma, which I found a bit surprising. Even though BPs do not reduce risk for progression of MGUS/SMM to frank myeloma, the risk of having lytic bone disease at the time of progression may be reduced. In my own practice, I make sure that I check bone density in MGUS and SMM patients, and – at the least – treat osteopenia/osteoporosis with BPs according to the standards for non-MGUS/SMM pts. If BPs are used, bone density needs to be tracked over time to assess efficacy of the intervention. 

The second event I attended was a meeting of the Southeast Michigan Amyloidosis Support Group. This group meets face-to-face twice a year in a conference room at Karmanos. The group is one of several around the country coordinated by Muriel Finkel and Amyloidosis Support Groups, Inc. Over 20 patients and caregivers were in attendance, along with Sue Smith – the moderator – myself, and Dr. Grogan (a cardiologist from Mayo Clinic, Rochester). The meeting was about 4 hours long, with breakfast and lunch served. We saw some slides describing the ways that amyloidosis affects one’s heart (see my prior post on that). As always, everyone shared their story and provided health updates since the last meeting. I always find the stories fascinating, and I learn something about amyloidosis every meeting. If I am the weekend rounder for our inpatient hematology service when our group is meeting, I will break rounds and attend the meeting with the residents. Invaluable learning experience. The list of meetings for the remainder of 2013 can be found at this link. (The amyloidosis expert(s) who will be attending each meeting also listed. I will be at the Denver CO mtg August 10th, the Detroit MI meeting Sept 21st (with the famous Dr. Robert Kyle!) and in Columbus OH Oct 19th. I also plan on attending the Familial Amyloidosis Support Grp Weekend in Chicago on Oct 25th, as a roving reporter).

Weekends like this are part of the reason I find my work deeply satisfying: ample opportunity to teach others and learn from others.   

Patient Page: Why is AL amyloid bad for hearts?

AL amyloidosis is a disease in which abnormal bone marrow plasma cells secrete light chains (fragments of antibodies) which then coalesce into larger fibrils that deposit throughout different body tissues. 

PowerPoint slide I made illustrating what a light chain is: part of an antibody.
An antibody looks like a BBQ fork, but the business end functions more like a

key, fitting to a specific target. Amyloid fibrils are made up of aggregated light chains. 

Any organ can be affected, but heart involvement in particular drives survival. Generally, the more heart-involvement by amyloid, the worse the outcome. This is the basis of the cardiac staging system for AL amyloidosis developed by Dr. Angela Dispenzieri and her colleagues at the Mayo Clinic. The original version of this staging system used simple blood tests (NT-pro-BNP, and either cTnT or cTnI) to divide newly-diagnosed patients with AL amyloidosis into three groups:

Staging system using cardiac biomarkers to predict survival of patients with AL amyloidosis
(ref: http://jco.ascopubs.org/content/22/18/3751.long)

An updated version of this staging system incorporates another blood test, the serum free light chain measurement (FreeLite Test), resulting in 4 different stages.

When the heart is filled with amyloid, it becomes thick and stiff. The thickness can be measured using echocardiography (an “ECHO”). The affected heart often doesn’t relax normally after contracting (“diastolic dysfunction”). This can lead to congestive heart failure. The electrical conduction system of the heart may become compromised, and patients may be at risk for life threatening heart rhythm abnormalities or cardiac arrest. This latter problem is the explanation for the steep drop in survival in advanced stage patients the first year after diagnosis, and preventing arrhythmias can be one of the keys to survival. 

PowerPoint slide which includes a cross-section of a thickened heart affected by AL amyloidosis (top right). The cartoon next to it is designed to orient the viewer to what is being shown in the photograph. If you look closely at the two halves of the “figure eight” in the photo, you can see that one chamber has extremely thick walls, including the part between the two halves (the interventricular septum).  
It is widely held that the heart dysfunction in amyloidosis is the result of amyloid infiltrating the heart tissue – like impregnating the tissue with wax or concrete, making it impossible for the heart muscle cells (myocardiocytes) to contract, and disrupting the electrical circuitry of the organ. 

In medical school I imagined it like the La Brea Tar Pits – a sticky, stiff mire that eventually exhausted any living thing that got stuck in it. My daughter suggested that Frodo enmeshed in Shelob’s web would have been a cooler analogy. We debated this for a while, each of us conveniently ignoring our gnawing concerns that geekiness is potentially inheritable.  

Prehistoric elephant in tar pit, doing an impression of a cardiac muscle cell in an
amyloid-filled heart.  Low art, even by Neanderthal standards.
(Image ref: http://www.freeimageslive.co.uk/files/images006/mammouth_tar_pits.jpg)

At any rate, the actual story is a bit more complicated. It is not only the accumulation of amyloid fibers (made up of aggregated light chains) around the heart muscle cells which cause heart dysfunction. Researchers from Boston have shown that AL light chains themselves (ones that have not been incorporated into fibrils) are directly toxic to myocardiocytes. They reduce the  ability of the heart muscle cells to contract, and eventually they can cause the cells to die. This seems to be caused by activation of a signaling protein called p38-alpha MAPK inside the cells (click here to see the original article). Of interest, normal non-amyloid-forming light chains – ones made by normal, non-clonal plasma cells – do not damage heart muscle cells like this. Of even more interest is that various pharmaceutical companies are developing and testing p38-alpha MAPK inhibitors.  In theory, such agents could minimize the direct toxic effects of AL-light chains on the heart, and maybe – just maybe – improve the prospects of patients with advanced cardiac AL amyloidosis.