Carphoria

Carphoria noun (karforeeah) OLD ENGLISH 
The experience of exhilaration felt while driving home in your wife's convertible roadster with the top down in 65 degree mid-December weather from your Velcade (chemotherapy) injection appointment which is then augmented by having the general euphoria that comes 8 hours after ingesting large doses of steroids (Decadron) which makes you slightly hypo-manic prompting the playing of rock music at level 11; way louder than either your wife or audiologist would allow. Finally spiced by the wearing of shades, fedora and a care-worn leather jacket with the setting sun scene in the rear view mirror.

Speaking of Velcade, I have learned a few things about how best to receive it. First, and foremost, get it injected subcutaneously. It is just as effective and has less peripheral neuropathy complications. (see review on AmmyloidHope.org) Second, ask the nurse to inject it deep. The very first time I got it, the nurse placed the needle under the skin superficially by inserting the needle at an angle as she entered. This resulted in the drug both irritating the dermal layer of the abdominal skin and also getting absorbed into the skin lymphatic system. Within three days this caused severe skin inflammation with red-purple lines tracking to the groin where the now inflamed lymphatics drain. 
The next week I asked the nurse to push the 1/2 inch needle perpendicular to the skin and all the way to the hub. I actually grab my abdominal wall to give them a deeper target so that it doesn't hit muscle. It's almost painless. The area still turns faint red is is mildly painful to touch, but it resolves in a few days instead of two weeks. Since I often have a different nurse each week, I offer a gentle reminder before they take the plunge.

Little things can make a big difference.

Kevin

When the New Normal Becomes the Old Normal.

Sonoma Coast

In the midst of the anxiety surrounding the decision to undergo the bone marrow transplant I asked a question that hitherto I had not broached. Nor have I asked since. Before asking I was aware that doctors our lousy fortune tellers, but that didn't stop me. As Dr Schrier and I discussed the details of our joint decision to proceed with the procedure I asked him to predict my future. "If the stem cell transplant works, how long can I expect to live?" I asked, hoping for hope. "Well, generally after four years the disease tends to come back," he reported. Immediately I said,  "I was hoping for ten years."
Where did that number come from? Why not twenty? I see numbers in everything and ten years resided at the corner of pragmatism and optimism; facts and faith.
After the stem cell transplant, but before I knew that it failed, I wrote a fictional story of a man who knew exactly when he was going to die. (Link to Solids) There was no pre-planned allegory or moral that I was trying to convey. It was just a story. Over the years I ascribed many things into the meaning of what 49 year old me was feeling as 54 year old me re-read it. What I see most now is the consummate importance of the unknown. We metaphorilize the future unknown as darkness, yet is it only the place where the light has yet to shine; and we hold the beacon.
Two and a half years ago I stepped down as chief of my department. It was hard to fulfill all of my responsibilities while working only three days a week with mounting side effects of my varied chemotherapy drugs. I was often sick for extended periods of time. I remained on disability and closed my practice to new patients. I focused on a referral practice to treat prostate cancer with radioactive seeds and continued stone lithotripsy on Fridays. Dr. Troxel asked how much longer I expected to work. Given my knowledge of the natural progression of amyloidosis I said I figured to work two more years assuming by then things would have worsened.

The future had a different plan for me.

I continued my chemo. Slowly, I better adapted to the predictable outcomes of my drugs and their side effects seemed less onerous. My disease responded better than expected as the treatment repelled and tamed my bad clones. The tiger remained, but was now quietly curled in the corner just barely out of sight.

Just over two months ago Barbie observed that I hadn't been sick for a long time. I realized that she was right. She added that maybe I should consider going back to work, not only in extending my work hours, but also to take on full duty responsibilities. As such, I would do many more of the types of surgeries that I was trained to do. This would also include call. There have been many times in our marriage when Barbie will suggest something that would completely change the course of where I thought we were going and immediately I know that she is right. It was time to eschew the safety net of disability and move forward with the goal to continue working until I am old enough to retire, just like everyone else does.

Today was that day. I began the first day of my new old life as just a regular urologist working with my partners again to take care of whomever needs our care. It was wonderful. The patients I met today will be my patients for a long time. I truly have no idea of how long I will live nor do I think about it much. I have returned to the masses who live in blissful ignorance of their own mortality. It's a wonderful neighborhood.

How many times have I used the lesson of the importance of accepting the new normal unaware that my old normal lay in the unseen reaches where time takes us all. When the new normal becomes the old normal it uncovers the magnificent adventure that it is to fall forward into the unknown we call future.

"Ten years? Sounds like someone is bargaining with God." Dr Schier had told me.
We are still on good terms.

Kevin

NEOD001

Last Saturday I drove to the quarterly Northern California Amyloidosis support group held at the Walnut Creek Kaiser. It was wonderful to reconnect with so many friends and fellow patients. Charlesetta looks great after her bone marrow transplant. She's like me, first a heart then BMT. Dena had invited the chief science officer from Prothena to speak about their new drug in phase 1 clinical trials to target amyloidosis, NEOD001. THIS IS REALLY IMPORTANT. Never has a company targeted a drug to only treat amyloidosis. Most of our current drugs we borrow from the world of multiple myeloma. The main paradigm shift is that we can now focus, not just on the plasma cell, but rather the toxic light chain proteins themselves.

This is tricky. The light chain has two parts: The hypervariable region and the constant region. The hypervaiable region is like a snowflake; no two are alike. Concomitantly each patient's bad light chain is also different, likely arising from a random  mutation in this same region. As such, no one drug (antibody) could target them all. Additionally, if you designed the drug to attack the constant region, it would attack all of our antibodies, both the good, the bad and the ugly. Alas, how do we correct this conundrum? Aha! The cleverness of y'all. First you ask, "What is common to all misfolded light chains? Answer: they are misfolded. When normal good-guy antibodies correctly fold they hide, or physically cover a region that is common to all light chains. Misfolded bad light chains swing open, like a gate on a hinge and, Viola! the cryptic epitope is now exposed and visible. NEOD001 is an antibody that is designed and produced in manufactured cell cultures. It specifically targets this previously hidden amino-acid sequence, activates the immune response and the terminator arrives to clean up the mess. The toxic villains are neutralized and removed from both the serum and the tissues. The normal, good-guy antibodies are unaffected because this target sequence is still hidden deep inside; unavailable to the drug. Wow, what a concept.
One of our group members in currently in the study and shared that he seems to be doing just fine with no untoward effects. We thanked him for doing this for us.

This changes everything, if it works. 

Until now, I have always considered amyloidosis incurable. My current fight is not to be cured, but rather to shut down my plasma cells with drugs so that fewer light chains are floating around to attack my new heart. 

Now, by detoxifying the rogue light chains, it isn't exactly the definition of cure, but it feels the same. It is possible that we will stop using the term fatal with this disease. We will manage our disease and move on with our lives.

That would be nice

Kevin

P.S. I like that the Prothena logo looks like a gamma-globulin (antibody) designed to look like a "P"

Writing is Hard

Writing is hard. Writing a book is really hard. I mentioned to Barbie the other day that I believe that everyone has at least one book in them; the story of their own life. Some would write it as an autobiography while others would fictionalize it, as did Harper Lee with "To Kill a Mockingbird". What keeps everyone from writing a book? It's not easy. Well, it wasn't easy for me. I am sure that there are many writers that can sit down every day and bang out five to eight thousand words. The thinking part is easy. I wrote the book a hundred times in my mind. Yet the application of fingers (that is two index fingers) to keyboard has always been very difficult for me.
It took three years to write. And yet if I counted the number of days that I actually wrote it would be less than 50. When I switched from Revlimid to Velcade two years ago I suffered many new side effects. One of which was a lack of motivation. However, I could be guaranteed that at least one day a week that motivation would return. This occurred on Wednesday evenings when my high dose of steroids was in full force. This is when the hypomania portion of my drug induced bipolarity bubbles to the surface. However, the motivation produced is also accompanied by a certain degree of disinhibition which allows for a more soul-baring and uncensored writing.
My two greatest challenges in the process were first: how do I truly paint a picture with words that conveys the full emotional impact of the moment? And second: how do I fuse the retrospective narrative with the prospectively written blogs to maintain continuity while avoiding redundancy. In the latter, Barbie was immensely helpful. She read and re-read the manuscript offering invaluable input.
Then one day in January it was done. Writing is just the beginning. Now you have to get it published. Ten years ago I would have been at the mercy of literary agents and the big publishing houses. We now enter the world of self-publishing. In January I knew nothing of this world. It has now become my new hobby.
First yo go to the source of all useless knowledge (and some very useful knowledge: Google.) I found a book called A.P.E and downloaded it to Barbie's Kindle. It teaches the novice author how to Author, Publish and market (Entrepreneur) a book. I followed the steps, doubling back on certain blind pathways, and ultimately decided to have the book self published through CreateSpace, a subsidiary of Amazon. They provide a publish-on-demand service such that the physical book is only printed when someone orders it through Amazon. What a concept; no inventory.
First, though it had to be edited. When my editor, Sarah Bringhurst Familia, sent me revised manuscript, it was bleeding red on every page. Yet, as I clicked and accepted her changes, it became a real book.
Next was designing a cover. This was really fun. I found a website www.99design.com that, for $299, will create a contest where designers compete to build you the perfect cover. Ultimately I had 19 designers submit 64 designs. The last day of the contest Barbie called me to say a new design came in that was awesome. I immediately knew that this as yet anonymous designer had captured my vision and that we had found our cover. In the end it was a graphic design professor from the University of Viterbo, near Rome, Italy, that one the $200 prize. The longest process was the internal book design done by CreateSpace to format the interior. And now it is done.
I have learned so much in that last six months about writing and publishing. We live in a world where so much more is available to us because of the internet. Seemingly impossible things are not just possible, but relatively easy. No one needs to forgo their dreams anymore. You just need to know what question to ask and to whom.
The book is now out there; for some I hope that they may find in it comfort and hope in their struggles. For others, I just hope it is a good story. For me it is a testament to miracles.

Kevin

Hard Questions -- Good Questions

Social media allows for the interactive dissemination of information without boundaries. The possibilities then extend beyond the limits of  our personal understanding and credulity.  One must just find the right question.
For many years two questions have plagued me. Both relate to the process and results of a stem cell transplant (SCT) or to as it is sometimes referred, a bone marrow transplant. I have read numerous scientific articles describing the outcomes of SCT for AL amyloidosis but found that many of the reports did not differentiate the survival rates, or even include data regarding how many patients, and for how long, were spared the need of continued use of  chemotherapy after their treatment.
Since my SCT failed, (at least based on my blood tests that immediately showed not only no decrease in my light chain levels, but rather a doubling of those bothersome proteins,)  I was also keen to understand why at the cellular level.
I have learned that often the best source of discovery regarding a rare disease is from the people that live with it every day. So I went to that repository of combined life experience and wisdom, the patients. In the past I had joined an online amyloidosis support group and recently felt to reconnect there. As I began to read many of the comments, old personal questions began to resurface. Finally today I wrote the following.

There are two questions to which I wish I knew the answers. First, does a SCT fail because the Melphalan fails to kill all of the plasma cell clones in the bone marrow? Or is it that survivable clones are re-implanted with the stem cells? Second, my goal for stem cell transplant was to be free of chemo for at least two years. (I don't like taking dexamethasone.) What percentage of patients that have a SCT remain off chemo for at least two years? 

I was encouraged at the number and caring quality of the responses that I received. But three in particular had important insights that taught me things that I needed to learn.
First was from a man whose experience was  a major reason that I wrote the questions. I had met some amyloidosis patients that had complete responses from their SCT, they were successes, yet their oncologists still kept them on chemotherapy, just in case. Tim wrote the following.

I had an SCT in July of 2011 at xxxxxxxx xxxxxxxxx (had consults at mayo as well). I had VelDex as a front line treatment prior to  transplant and achieved near complete response after transplant. My doc wanted to see if we could get to complete response so we resumed VelDex in November of 2011 and continued treatment until June of 2012. I was getting really run down from chemo so voluntarily stopped after a consult at mayo where the specialist there said that they would not have treated at all and would have just waited to see. Flash forward nearly a year and my numbers remain stable and I'm hoping to be chemo free for at least a year. I feel good off the chemo teat and will be wary of getting pushed back on in the future.

Another woman described her story with the preface that she generally did not respond on the site because her story is 'discouraging'. Yet her story was my story. Her SCT failed and she remains on chemotherapy.  I felt connected with her and shared my hope that new treatments are already available and on the horizon. It is a good time to be alive.

But the one that affected me the most was from woman who also failed the SCT and her light chain levels remain elevated. But her doctors are not treating her with chemo. This is the question that Barbie and I have been asking for four years. Is the chemo adding days to my life? What would happen if I stopped it?
This woman, named Jan, offered the following after describing her numbers, which were my numbers; except that she is not on chemo.

But as someone said, we are all different. And for us as individuals, the
statistics are meaningless. We either had a response or not. We either need more
treatment or not.

I totally agree with you. I really would like to avoid chemo if I can. So far I
can...I live from 3 month check up to 3 month check up, always knowing it could
change. Hoping the best for you.

Ultimately, Muriel Finkel, the site administrator found the answers through her connections at the Mayo clinic.

To question 1: The SCT doesn't always kill all of the bad clones in the bone marrow.

To question 2: 80% of patients with a successful SCT remain off chemotherapy for at least two years.

This news was very encouraging to me. Generally, scientific studies speak of success in terms of overall survival (who's still alive at 5 years) and disease free progression (who has no evidence of disease progression at 5 years) These numbers refer to quantitative success. They often don't report on whether those patients were on adjuvant (or continued) chemotherapy, (qualitative success). This is what I want to know as this is what makes our days miserable while we wait to add to the survival statistics. Living a long time is great. Living a long time off chemo is outstanding.
So what's next? For now I will remain on chemo. But I am encouraged by those that have chosen a different path having asked these hard questions. Not with just their words, but with their minds and bodies.

Kevin

Where do we go from here?

The first week after receiving the diagnosis of amyloidosis is the most confusing. Everyone that knows you wants to help. Suddenly dozens of voices are offering advice and it is difficult to see which way to turn. These are good voices of people you trust and who care about you; but you just don't have all of the facts yet. Not to mention, you feel like crap.
The internet only makes it worse. Initially, you find sites that only speak in vague generalities and appear to be copy and pasted from some unknown literary progenitor. Finally, you find and abstract written in medical jargon that offers more details, but you cannot read the whole article unless you pay for it.
Your primary care doctor make an appointment with a hematologist/oncologist, but they have only had one prior amyloidosis patient in the last 18 years. Besides, how do you know what questions to ask them? It is a very confusing week. It was for me and I am a doctor.
My sister works with cancer patients and has vast experience with chemotherapy and bone marrow transplants. I told her that my Kaiser doctors had suggested that I go to the Mayo Clinic for my work-up. Her colleague, a professor at the University of Washington said, "No, he needs to go to Boston University, they are the best at treating amyloidosis." I felt torn. Do I go back and tell my doctors that they are wrong in their recommendation? Or do I trust them implicitly?
Finally, around week two - three a groundwork is laid. The smoke clears and you find your advocates. The doctors, nurses, social workers and caregivers who light the first part of the path so that you can move forward. A plan is proposed and it feels right. You take the first step.
Every amyloidosis patient has a story of their delay-in-diagnosis. Unfortunately, this is the rule, not the exception. It is an uncommon disease with common symptoms. It is not easy to diagnose. Someone has to think about it. Notwithstanding, once diagnosed, and properly verified. We need to forget past delays, miscommunications and annoyances and move forward. This need no longer be a fatal diagnosis, and to the doctors that recommend getting our affairs in order we could respond, "with all do respect, I suggest the same for you, doctor." Doctors are terrible at predicting when someone will die if it longer than a month.
Where you receive your care is an emotional decision affected by many factors: the burden of travel, family issues, work issues, money, cost of care, insurance coverage. These limitations are set against the understandable desire to get the best care that we can. It truly can be a matter of life and death. What I have learned as a physician, and now as a patient, is the power of the team. No one person can be at the top of their game 100% of the time. With a team, each person specializes in certain aspects of the process so fewer things are missed, Teams tend to use protocols and 'best practices'; learning from the successes of others. Teams are not necessary for all diagnoses, just the really complicated ones. Often these teams are referred to as centers of excellence. They are everywhere.
Amyloidosis centers of excellence are found throughout the country. Although, we all owe a great debt of gratitude to the pioneers in our diagnosis that have laid the groundwork, done the research and written the papers so that all can learn from their collective experience. The Mayo Clinic and Boston University and others, stand out as giants in this area. We owe them our lives. Those who find new treatments for multiple myeloma also help immensely as so many drugs that start there transfer to us.
All of this knowledge, available to all and administered through centers of excellence can truly assuage our anxiety such that we know that the place that we are at is the right one for us. This is not a time for doubt, but for trust.
I no longer consider my diagnosis fatal. Yes, I will die and yes, it will likely be from complications of amyloidosis. But I am still alive and I shouldn't be. Since each day is, for me, a gift, the need to live a long life is no longer the goal. Rather, the goal now is to learn every day and to give love through service every day. This is where we go from here and the journey continues.

Kevin

Small Victories-

Eagle River, Alaska

I looked on Yahoo news, but I didn't find it. I did find out that two celebrities were wearing the same dress at the same event and that another sports figure did something stupid. But there was no mention of the woman that called me on the phone today. She wanted to tell me that she had received a new heart and that she was a changed person. This is huge. She was going to die very soon and now she will not. I did not wonder why this was not big news in all of the major venues. She is not famous. She is just like the rest of us. And what a blessing that is.
I met her and her husband in February. She was an inpatient and was placed on the transplant list that very day. I was there for my semi-annual heart biopsy. She had heard of me and wanted to ask me some questions. She has primary AL amyloidosis and was in much worse condition that I had been prior to my new heart. But, she was initially afraid and did not want a heart transplant. Finally, with her doctors' urging and her husband's support, she acquiesced and agreed to go on the list. But she was still nervous. When Barbie and I entered her room she was surprised to see how healthy I looked. We answered her questions and named her fears such that they no longer lurked in the darkness of uncertainty. When we parted she was visibly relieved and increased in hope.
I knew from what she told me of her symptoms that without a heart transplant she would not be long for this world. I silently prayed that the heart would come soon. It did. Within a month I got word from her husband that she had an uneventful surgery and recovery. She had an early heart rejection, but this was reversed with ridiculously high doses of I.V. steroids (Solumedrol: nasty stuff) and has done well since.
She called me today to ask when she should be rechecked as to the status of her amyloidosis. We discussed this and her new side-effects. She spoke of a wicked 'Prograf' tremor (Prograf is the major anti-rejection medicine that we take everyday, forever.) This causes a bad 'intention' tremor. This type of tremor gets worse as the effort at fine motor movement increases. So when the spoon begins at the bowl, it is not that bad. However, when it finally reaches the lips it is like eating soup on a roller coaster during an earthquake with a magnitude of 7.2 on the Richter scale. It is messy. I reassured her that this would greatly improve in 9 - 12 months. I gave her suggestions on managing her light-headedness after sitting for long periods. Barbie and I reminisced on how we never knew what the cause of all of my early side-effects were and how it would have been nice to have someone to call. The doctors tried, but patients understand these thing better; we live through them every day.
It was amazing to hear her describe her new life. She is no longer short of breath; no more oxygen tanks. The defibrillator vest is gone. No more pain when eating. And the nasty swelling in the legs is gone. She now walks a mile a day. What a miracle.
This should be momentous news; such an amazing event. But it happens to regular folk every day all over the world.
Fame is a funny thing. Some people actually seek it, but they are always disappointed.They often proffer some salacious tidbit that immediately vaporizes into cyberspace as they remain unsatisfied. Fame is an empty promise. I define fame as when 51% of the people who have ever heard of you have never met you. I would rather be famous among 50; within a small group whose lives you have touched while becoming better for having met them, either physically or through our ever expanding virtual world.
In this group we know each other. We share our stories and listen and understand. We give hope to each other and enlighten the path for those that follow. In this group we are each enriched as we share our small victories

Kevin

All Things Being Equal

I am fascinated with words, even more so with phrases. I wonder how they get crafted and adopted. All things are rarely equal. But it helps to attempt equality when deciding between things. Currently all things are going well, and yet they aren't. I am reminded of this in the blog post that Rebecca so courageously shared yesterday about dealing with a miscarriage. a-wretched-life
I am proud of Rebecca and Jason for their faith and perseverance. We so love our children and want them to be happy. But there will always be days that are sad.
I continue to do extremely well with my health. No changes of note. I still get Velcade weekly along with my Decadron. There are, however, some promising new drugs on the horizon that may change the course of my disease. I will keep you updated. Work is going well and I will be working with Kaiser to develop a video for patients newly diagnosed with prostate cancer. I wrote the script and will be in front of the camera. I'm trying to lose 10 lbs so that I look better on computer screens around Northern California.
Barbie has been working consistently in temporary positions as an RDH and is considering some more permanent options. She is a great hygienist.
We recently returned from a very romantic cruise to the eastern Caribbean. We visited Turks and Caicos, San Juan, Puerto Rico, St Thomas and a private island that Holland America owns called Half Moon Cay. We had such a relaxing week with 7 days of no cell phones, no Internet and no schedule. The sea was a beautiful clear turquoise, the water was warm and the few fish that we saw enough to say we snorkeled.

Half Moon Cay

The basement of the Provo house was finally finished and Caitlin and  Ben moved in on Monday. It is not a typical BYU basement apartment. Barbie's friend, Wendy Ormsby is an interior designer and, working with her contractor, Jeremy Brown, were able to take Barbie's vision and create a wonderful 'space'. Caitlin is delighted to have a little more room for her womb as she is now in her 17th week and wants to nest. Once I get the before and after shots of the basement, I'll post them.
With the book done and a grandchild on the way, my previous bucket list had officially expired. While watching the ocean from our stateroom balcony I penned a new one. It has some fun stuff like reading Dickens, learning French, doing a culinary experience in St Helena, CA and riding the Orient Express from Paris to Istanbul.
I hope to continue writing, both here on our blog and other places as well. Maybe if the prostate cancer video plays well, I might get a call from Kaiser Hollywood.

Kevin

Deconstructing Amyloidosis

Each of us surviving amyloidosis, in ourselves or a loved one, can help the rest of us in often profound ways. Muriel Finkel is the maven of information. She supplies us with incredible articles and access to information that define the cutting edge progress in this disease. I say thank you to her with all of my heart. Her most recent update includes the current report by the team at the Mayo Clinic on 10 year survival data on 74 patients that underwent an autologous SCT from 1996 to 2001. The results showed that 43% of patients lived beyond 10 years. Some might scoff at that number and say, "Only 43%, that's dismal." Of course, context is everything.
Glass half empty, eh? (Actually, the glass is always full; the sum of the liquid and gas equals one.)
Ten year survival is a wonderful thing and more common than I previously thought. The article then goes on to talk about significant baseline characteristics that might predict a better prognosis. There were four, but one stood out, the number of organs involved, although heart septal wall thickness also contributed. Post therapy lowest light chain level and degree of response also correlated. I, of course, inserted my numbers, both baseline and post SCT and I clearly will not be in the long term survivor (LTS) group. Yet, for me the glass is still full. I have had a heart transplant, so it is apples to lacrosse sticks. As such, I have designated myself the current president of my own long term survivor club. With continuous chemotherapy I have only succeeded in pushing my light chains to the median level for the non-LTS group.
What was most interesting to me was what I learned from the introduction to the article. Sufficient to entice me to attempt to translate it into common American English.

I refer to the article below and reference it so that I may quote verbatim the first paragraph.


Ten-Year Survival After Autologous Stem Cell Transplantation
for Immunoglobulin Light Chain Amyloidosis
Stefan Cordes, MD, PhD1; Angela Dispenzieri, MD1,2; Martha Q. Lacy, MD1,2; Suzanne R. Hayman, MD1,2; Francis K. Buadi, MD1,2;
David Dingli, MD, PhD1,2; Shaji K. Kumar, MD1,2; William J. Hogan, MB, BCh1,2; and Morie A. Gertz, MD1,2
Cancer 2012


"INTRODUCTION
Systemic immunoglobulin light chain amyloidosis (AL) is a plasma cell dyscrasia in which monoclonal light chain protein aggregates and deposits in tissue as amyloid fibrils.1-3 Only a relatively small percentage of Ig light chains are amyloidogenic,as evidenced by the finding that AL amyloidosis occurs in only approximately 6% to 15% of patients with multiple myeloma. Amyloidogenicity is related to structural features such as the light chain isotype and the variable subgroup. The folding pathway of such amyloidogenic light chains is believed to pass through partially folded metastable conformations that aggregate either 1) at sufficiently high concentrations or 2) under specific environmental conditions."


Most of us know that AL or light chain amyloidosis is caused by the deposition of large quantities of abnormal proteins (light chains) that somehow band together in bundles and damage tissue. There are some pearls in the paragraph above of which I was previously unaware.


1. " Only a relatively small percentage of Ig light chains are amyloidogenic." 

It appears that a mere excess of light chains is not enough to cause the condition of amyloidosis. The evidence is in the following statement that only 6%-15% of patients with multiple myeloma show a clinical presentation of amyloidosis. The rest of the patients with multiple myeloma make massive quantities of light chains, but not the toxic type.
When a plasma cell goes rogue as either a cancer (Multiple Myeloma; the plasma cell clones don't die) or a dyscrasia (AL Amyloidosis; the cells die, but make toxic proteins before they do.), they make excess copies of a single protein. Somehow, this particular protein misfolds and combines with other proteins to create a fibril. This is a random event.

2. "Amyloidogenicity is related to structural features such as the light chain isotype and the variable subgroup."


Antibodies are incomprehensible in their awesomeness. 

The light chain is the short, lighter blue and orange protein shown on the outside of the bigger and heavier chain of amino-acids that make up this particular protein or immunoglobulin. The magic occurs in the orange part or variable subgroup. From the time we are born we have white cells that make and store millions of unique antibodies that differ in the orange tip region. A controlled fire of mutations allows for this library of antibodies, most of which may never be used. Usually, mutation is bad, however, here it is necessary for our survival. When we get an infection or any foreign protein (antigen) enters our bodies, millions of white cells, (B-lymphocytes) each presenting their own unique antibody go up and 'taste' the invader. Most don't recognize it and move on. However, one will have a unique shape that will allow it to stick, like a lock and key. An alarm goes off and the B-Cell becomes a plasma cell and dedicates it's life and the life of all of it's daughter clone cells to making that single unique antibody with it's unique light chain.
I am no expert, but it might be additional factors that cause the overproduction and misfolding of our unique light that make ours toxic and others not. This part I don't understand well. In other words, just misfolding and making fibrils out of any light chain won't cause amyloidosis. It may be a specific clone that is required. I would imagine that if you did amino-acid sequencing to get a fingerprint of each of the variable region our light chains for those of us that have this disease, they would all be unique. The commonality of the presentation is more likely related to characteristics shared by the final products; first, their preferred soil. Some fibrils have shapes, bonds and electrical polarities that favor heart muscle, while others prefer to clog up kidney tubules. Kappa light chains are monomers or single molecules, while Lambda are dimers, or double molecules. This means that they start out twice as big and this might effect there propensity for kidney damage. Regardless of the initial clonal type, the final common pathway is tissue damage.




3. "The folding pathway of such amyloidogenic light chains is believed to pass through partially folded metastable conformations that aggregate either 1) at sufficiently high concentrations or 2) under specific environmental conditions."


Here the authors teach us that it is not just the high levels of our light chains floating around, but the environment around them. Tissue types, other proteins, cellular communications: many things may impact the toxicity, independent of our light chain levels. We all know that each of us have a different range where our light chains levels live, both on and off therapy. Yet, we cannot compare numbers like PSA for prostate cancer; because we cannot compare our respective environments. We do all agree that lower is better, though.


4. The second paragraph in the introduction has a line that states, "One of the rationales for the efficacy of such treatment is the remarkable observation that it is the growth of fibrils, in contrast to existing fibril load, that inflict cellular damage through transient defects in the cell membrane."


This was a new concept for me. Essentially, I interpreted this as these nasty protein fibrils do there damage as they break through the window, not while they vegetate inside the cell as couch potatoes. Therefore, the target of treatment is to prevent new break-ins rather than remove the loafers already living there. The blood tests that measures our light chains only detect the hooligans on the prowl, not the ones already in residence. That is measured by organ health, and it's ability to heal itself once the break-ins are curtailed.
We have SCT and chemotherapy the reduce our plasma cell numbers and prevent them from making more light chains of one particular flavor.

I hope that this explanation is clear enough to add to your understanding of this article and our shared lot in life.

May you all join my LTS club.

Kevin

If I have erred, please correct me so that we may all learn.

The Gift of Life-Have a Heart

Newly Trained Donate Life Ambassadors

Last Saturday I drove to Modesto to be trained as a Donate Life Ambassador for the California Transplant Donor Network (CTDN). As such, I have the opportunity to provide community outreach to DMV's , High Schools and Medical Facilities to encourage people to choose to be a donor when they get a drivers license or register online at the CTDN Website . It was very interesting for me considering that the majority of the other trainees present were families that had chosen to support their deceased loved ones wishes by donating their organs and tissues to other people. For them, from five to ten people benefited from this gift made during such a traumatic moment. I her multiple stories of the pain that they suffered from the loss of a son, daughter or husband, (they were all women.) And yet, they all felt a great sense of goodness as they talked of those who live and live better as a result of these shared organs. The woman to my left, Michelle, has become friends with the family of the man that has her husband's liver. Not all have had contact with their recipients or donors. The need to respect privacy is important and everyone grieves differently. I am fortunate to have written letter correspondence with my donor family.
I was so grateful to hear the process from their perspective. We all learned some very interesting things; such as the true definition of brain death, or brain stem death. For an organ to be donated there must be brain stem death before the heart stops pumping. The patient is no longer alive, however, the heart only continues pumping because the mechanical ventilator continues to provide oxygen to the heart. Hearts pump independently of the brain if you give them food and oxygen. Mine does.
I went to a picnic that night and asked everyone I saw, are you a donor? The two high school students were but most of the older adults were not. I was surprised. Most reported some myth to justify their response. I realized that it is important to share my story and educate, dispel myths and save lives.
There were two other women at the meeting that were liver transplant recipients. There was much interest for others to hear what it was like to be a recipient. They marveled at our courage, interestingly, we didn't feel courageous, we felt that without the transplant, we would not live. It wasn't a tough choice, if it was a choice at all.

Sometimes I say I am lucky, sometimes I say I am blessed, I just feel so grateful and humbled to wonder at why I have been so blessed. I have seen too many amyloidosis patients die too soon. This saddens me. I want to support organ donation, and more specifically, that more heart transplant centers consider amyloidosis patients for heart transplants. I know there are many out there that can be saved if their local center would consider them as candidates. How long do I have to live to justify getting a heart, a second life? Just one more day sounds poetic; but surgeons aren't poets. The actual number has been calculated to be 3 years 2 weeks 4 days and 13 minutes, ( +/- 2.5 years).

Are you an organ donor? Why not?

Kevin