EBV and myeloma stem cells. Chapter 3

January 23, 2018 / Margaret / 3 Comments

Back to the Ph.D. thesis. Dr. Biswas tells us, on page 28, “that the tiny percentage of cells that harbor virus are [sic] stably maintained over months or years.” Years?

Could it be maintained for decades, too? Hmmm. At my request, I was tested a few years ago for EBV, but the only thing we found was that I had some anti-EBV antibodies…nothing at all useful…

Anyway, here’s something interesting on page 31: “EBV infects B cells both in vitro and in vivo.” In vitro, EBV makes these B cells immortal. What happens in vivo, however, isn’t that clear. In people who aren’t affected long-term by EBV, as mentioned previously, the virus doesn’t cause any real harm. What triggers it to wake up and initiate the development of different types of cancer?

On page 46 we find “that in myeloma, EBV persists in a latent form in the 47 CD19+CD138- B-cell progenitor population and undergoes lytic reactivation in tandem as the cell becomes a CD19-CD138+ plasma cell.” So something has to happen within the B cell, the CD19 positive cell that is, in order for EBV to wake up and jump into action.

It’s actually on page 46 where my brain almost exploded. Lytic reactivation? 😯 I had absolutely no idea what that meant, so I looked for an “easy” explanation, which I found, finally (if you are interested, have a look here: http://goo.gl/pg8Q6r ).

This study tells us there are two ways in which a virus, nothing more than a “parasite,” can infect its host cell: 1. actively, by causing “a lytic infection characterized by the release of new progeny virus particles, often upon the lysis of the host cell,” (lysis refers to the destruction of a cell, the host cell in this case), or 2. inactively, which occurs when the virus just sleeps, without reproducing itself.

“Reactivation” occurs when a sleeping virus wakes up and reproduces, stimulated by internal or external factors…but that gets into too much detail, so let’s skip that part.

Here’s another clue: in order to be reactivated, EBV needs the help of a protein called Zta, as well as a transcription factor called Rta (remember NF-kappaB?). Not easy to describe a process that I barely comprehend myself, but, in a few words, a transcription factor (XBP-1) activates this pesky Zta, which then rushes over to hug its buddy Rta. The two of them, fortified by their love, then activate other genes, in what is called a “cascade.” (Phew…wiping the sweat off my brow…)

At the end of this process, EBV gets reactivated, which means it’s fully awake and ready to do its evil deeds. And in fact this is discussed in the Ph.D. thesis, too, on page 13, if you want to have a look. Yes, I’m jumping a bit back and forth, but it’s inevitable, especially when things aren’t too clear. [I just hope I’m not making any mistakes…Please correct me if I am! Thanks!]

An important aside (p. 48): EBV doesn’t become a target of T cells because it hides its “viral gene expression during latency.” Aha!!!

Another aside: the EBV myeloma lines are different from those of Burkitt lymphoma and lymphoblastoid cell lines, but are similar to chronic lymphocytic leukemia or CLL cell lines. The EBV-infected CLL B cells, however, do not become immortal and only grow for a short time. Bit of a difference there.

So, okay, back to us: in myeloma, B cells get activated and become plasma cells, thanks to the help of transcription factors (Blimp-1 and the above-mentioned XPB-1, etc.). In this process of transformation, in this cascade of events, EBV disappears. That is, it is no longer present in the newly-created plasma cell. Since plasma cells cannot reproduce themselves, it doesn’t have to be. It has already done its damage.

And now let’s get to something that I thought could be very useful, potentially at least: if you interfere with the cascade, with the process of transformation, EBV cannot reactivate itself.

This is important because, as we can see on page 93, “The investigations presented here show that although the cells that harbor EBV are only a tiny percentage of the cells in culture, EBV is an important driver for the proliferation of the cultured cell population considered as a whole.”

Margaret’s simple (simplistic) solution: we need to block the reactivation of EBV…keep it asleep, like Fluffy, the three-headed dog in Harry Potter. We need to block these transcription factors.

Shortly after I began this umpteenth EBV-MM journey (but, THIS TIME, with PROOF of the association!), I went to see our family doctor, who is a real genius. I’d sent him the main EBV-MM association studies, which we discussed briefly. Then I asked him to prescribe an anti-EBV drug for me.

My idea was: block the EBV = block the MM.

Well (I should have known it), my doctor told me it’s not that simple. Sure, he could prescribe a cycle of acyclovir for me, but:

For how long?
What should the dose be?
Would it work?
What about the side effects?
Did I really want to take the risk?

Of course I had no good answers, except to question e. (I’ve taken risks before, so, no biggie). And so I gave up, but only for the time being.

I just have to do some more research. There must be a way, a non-conventional way. Any ideas?

Hmmm, I just read that bortezomib (Velcade) kills EBV. Not that that gives me an incentive to start conventional treatments, mind you! But 1. if you are already on Velcade, AND 2. if EBV might have initiated your myeloma, well then, two birds with one stone, right?

Anyway, proteasome inhibitors in general have an effect against EBV, including, tada!, curcumin.

Food for thought.

Okay, I think I have enough fodder for a Chapter 4, then I’m done with the Ph.D. thesis. Take care, everyone! Ciao!

New…or rather, perhaps not so new: a “new” long-term follow-up study on MGUS

January 22, 2018 / Margaret / 3 Comments

Ah, here we go again. A bunch of useless statistics (as usual, this is JMO).

A Mayo Clinic study just published in the New England Journal of Medicine states that people with MGUS will ALWAYS be at risk of progressing to multiple myeloma or a related blood cancer, even if they have been stable for 30 years. You will find the abstract here: goo.gl/3Gsihd

I learned about this study after reading the rather ominous title of an article published in Science Daily on January 18, 2018: “Patients with blood cancer precursor at risk of developing cancer even after 30 years.”

Yikes!!!!

Except…there aren’t any Yikes!

We already knew this.

In an earlier follow-up study published back in 2004, Dr. Robert Kyle et al came to the exact same conclusion, and I quote: “The median survival rate of study patients with MGUS was only slightly shorter than that of a comparable US population. Risk of progression of MGUS to lymphoplasma cell malignancy is indefinite and persists even after more than 30 years of follow-up […]”

So yes, sure, there is a risk of progression, even after 30 years, or 40, or 50, or 1000. But, as I said, what’s new, here? Not much, except that the number of people with MGUS residing in Olmsted County, Minnesota, is higher compared to the 2004 study, 1384 versus 241.

That said, I managed to get my hands on the full study and will go through it with more care in the next few days, so there might be some surprises or interesting tidbits. Probably nothing earth-shattering…and, almost certainly, nothing that would justify that ominous title.

Well, actually, here’s a quick tidbit: in the Discussion part, these researchers tell us that it is MUCH more likely that people with MGUS will die from something else than from myeloma or a related disorder. I mean, the difference is overwhelming.

So if we have stable MGUS, we should be MUCH more worried about slipping and falling down in the kitchen and hitting our head on the floor, for example…

Well, I’m disappointed. I mean, I’m sure that these researchers find it very interesting to carry out these follow-up studies, but at least in this case I find it a waste of time and money…It just confirms something we already know.

Let’s spend the money elsewhere, like on finding a way to neutralize EBV inside myeloma cells, and, indeed, inside other types of cancer cells. That would be so much more useful!

In conclusion…As a U.S. myeloma expert once told me, statistics are useful only to specialists who wish to compare the results of their own statistical studies. He told me that as far as patients are concerned, statistics are useless.

I concur.

EBV and myeloma stem cells. Chapter 2.

January 18, 2018 / Margaret / 1 Comment

One thing Dr. Biswas discovered is that the subset of EBV-positive (as opposed to the EBV-negative) myeloma cells are the blasted stem cells, which have CD19 on their surface. What does that mean? Simply that we’re not talking about plasma cells here, but about B-cells that have the ability to REPRODUCE themselves, turning into plasma cells (which do not have that ability, btw).

Confused? Well then, let’s have a look at something different.

On page 12, Dr. Biswas discusses the 90% percentage that I mentioned in my previous post. While EBV “is benign in acute stages and latent in chronic stages […], in some cases, EBV has been demonstrated to be involved in the development of many malignancies, both hematologic and epithelial.”

So EBV doesn’t normally cause any terrible mischief. but remains inactive (quiescent) once it gets inside its host cell. But, in some cases, EBV doesn’t keep sleeping like Fluffy (Harry Potter reference: Fluffy, the three-headed sleeping dog)…That is the case with myeloma, as we have seen, but it happens in other types of cancers, too, such as Burkitt lymphoma, Hodgkin and non-Hodgkin lymphomas.

Even though it’s difficult to keep up with the technical gobbledegook, what is clear is that other factors have to be present in order for EBV to initiate the development of cancer (the image in my brain is of Fluffy waking up when the music stops…the music would be the “other factors”…). Anyway, that will be fodder for my third chapter, methinks.

So, summing up: 1. in MOST cases, EBV causes no long-term harm but simply remains dormant inside its host cell; 2. In some cases, unfortunately, it is associated with the development of cancer; 3. In myeloma, EBV DNA is present only in a small subpopulation of MM cells = the myeloma stem cells; 4. EBV doesn’t cause just one type of cancer, but quite a few, and 5. As for other types of cancer, EBV is present in EVERY SINGLE tumor cell, so myeloma really stands out in this group of EBV-associated malignancies. Yaaay, we’re special! Um. 🙄

A question just popped into my head (actually, it’s been in my head for a while now): would it make a difference if you took antiviral drugs such as acyclovir as soon as you receive an EBV diagnosis? Hmmm.

When my EBV infection was diagnosed, I was given nothing, e.g. Nothing. Just told to go home and rest…

But after going through all these new EBV-myeloma studies, I wonder if I would have ended up with MGUS (more than 18 years ago!) if I had immediately taken acyclovir or something similar? And I wonder this not just for myself but for all the people who have EBV-associated cancers.

Well, perhaps it’s because there wasn’t much research on this topic back then (the EBV-MM studies are quite recent, as we have seen). Perhaps EBV is too insidious to be targeted by any existing drug on the planet…even acyclovir has its limits, I have read. Perhaps it’s because nothing can be done once the process has begun, but I can tell you that I’d have been “relieved” (with lack of a better word) to have known the cause/s of my cancer. It would have eliminated all these years of wondering where I got this thing (well, not wondering obsessively…you know what I mean).

And another thing: with all we know about EBV now, it seems absolutely astounding that everyone diagnosed with MGUS, SMM, or MM doesn’t get immediately tested for EBV. I mean, NOW (not 20 years ago).

Or am I wrong? Was anyone here tested for EBV?

Okay, enough for today. I seem to have more questions than answers…

My next chapter is going to be a bit more technical. I’m sure you can’t wait, eh! 😉 I’ll try to tone it down… 😎

More on EBV and myeloma stem cells

January 16, 2018 / Margaret / Leave a comment

A few months ago, before all the kitten chaos began in our lives (read: when I had a bit more free time!), I came across a 2013 Johns Hopkins University Ph.D. thesis titled “Persistence of EBV in the cancer stem cells fraction of multiple myeloma,” by Sunetra Biswas. [Reminder: EBV is the acronym for Epstein-Barr Virus, about which I’ve written a bunch of posts, most recently in October 2017…A connection has finally been established between EBV and MM in SOME patients.]

I began reading, and drafting a post about, Dr. Biswas’ thesis, which is very interesting but also quite technical here and there…well, okay, it’s technical everywhere! 😉 Now, I might repeat some stuff, but that’s because there are some repetitions in the thesis, as you will see if you are brave enough to go have a peek. I apologize for the repetitions…I just took one out, in fact, and I’ve only re-read this post at least five times! 😉

Here’s the link: goo.gl/fgANzE

In the abstract, Dr. Biswas states that “EBV is present in some multiple myeloma cell lines and patients and when present, it is detected in a subpopulation of cells.” This subpopulation has “a mature B cell phenotype.”

But EBV just doesn’t sit inside the cell and do nothing. Nope, it helps MM cells grow.

However, check this out: when EBV is taken out of the MM cells (using a viral inhibitor), their growth slows down. On page iii, she talks about the growth of myeloma STEM cells. Oh how I wish I’d known all this when I became infected with EBV, decades ago!!! This viral inhibitor business gets reiterated on Page 8, btw.

On Page 2 of the Introduction, she states something that I already knew (but reminders aren’t a bad thing, eh): some B-cells infected by EBV become IMMORTAL. Just like cancer cells.

On Page 8 she begins looking at multiple myeloma and at myeloma stem cells, and then states that her research “suggests that EBV persists in cancer stem cells in MM patients and in four out of seven commonly studied MM cell lines.” More than half…wow.

Further on, Dr. Biswas states what we already know: “Multiple myeloma is a neoplasm of the plasma cells that has not been previously shown to be associated with EBV.” Indeed, in the past, whenever I asked a MM expert about this possible connection, all I got were denials and eye rolls. Well, now we have more than one study showing that there IS a connection…for SOME of us, at least.

Can’t be denied now. No more eye rolls expected… 😉

Now, even though she “identified EBV in 4 out of 7 multiple myeloma cell lines, EBV wasn’t present in every single myeloma cell, but only in a subset of cells, that is, a small population of cells, which makes it different from other EBV-caused cancers. And yes, the subset of cells happen to be myeloma stem cells.

Time for a mind-boggling statistic: the B-cells of 90% of the world’s population are infected with EBV. So here’s a good question: since Epstein-Barr is such a common viral infection, why don’t more people have myeloma or other types of cancer associated with an EBV infection? Clearly something else must be going on, otherwise practically everyone in the world would have some sort of EBV-associated cancer…

There must be other factors involved for an EBV infection to lead to MGUS and so on…

I hope to find the answer to that question by the end of this post (but I may not…there may be no answer as of yet), which I am going to divide into “chapters”…although if I skip a lot of the technical stuff, and the repetitions, I might end up with less material than originally planned… 😉 …

Oh, okay, drat, Pixie and Pandora have woken up from a nice cat nap and are becoming way too interested in what I’m doing at the computer, so I have to stop for today…Meeeeow! I mean, Ciao! 🙂

Holly Butcher: her letter goes viral after she dies at age 27

January 12, 2018 / Margaret / Leave a comment

Many thanks to Cynthia for posting about a letter written by a young Australian woman, Holly Butcher, who died on January 4. She had Ewing’s sarcoma, a rare type of bone cancer that usually affects young people and children.

I was quite touched by parts of it, so I decided to write a quick post. Before I forget, here’s the link to an Australian news article about Holly (and you can get to and read her full letter there, too): goo.gl/sLEYd8

In Holly’s letter, I recognized some of the feelings I myself have/have had…For instance, the irritation that I feel at times because my girlfriends don’t want to turn off their cellphones while we are playing cards. These weekly get-togethers, which last a couple of hours or so, are an important moment for all four of us. It’s therapeutic, too, for all of us. We chat up a storm, we laugh, we are silly, we eat homemade goodies, we make fun of one another, and so on. It’s OUR FUN TIME TOGETHER. But it can also be our serious time whenever one of us has a problem to talk about and try to solve. Before the cellphone era, there were no interruptions. But now the cellphones have to be turned on (not mine, by the way. Mine is always OFF).

It’s all the more annoying when I consider that, just a few years ago, those cellphones didn’t even exist…Our generation grew up with rotary dial phones, which then became cordless phones. Cellphones entered our lives in the late 1990s (if I am not mistaken). Before then, we weren’t connected to the world every single nanosecond of the day…but hey, we managed to survive anyway. So why is it that nowadays we are obsessively and almost physically attached to those little, annoying devices (useful in emergencies, I’ll grant you that)?

Anyway…Sorry for the rant. That was just a thought that popped into my head as I was reading the part about girlfriends having their hair done and so on.

Like Holly, I have always been frustrated that certain subjects are taboo. Death, she writes, is treated as a taboo subject, as though it will never happen to us, and that is certainly true.

Cancer is also taboo. Here in Italy people always die after “a long illness” or “an incurable illness” and similar euphemisms. Very rarely does someone mention the dreaded word, “cancro.” Even now, in the 21st century! Whenever I hear that a friend’s relative has died after a long illness, I always ask “was it cancer?” If the answer is yes, and it almost always is, then I ask, “what type of cancer was it?”

I’m not afraid to use that word anymore. But many years ago, the situation was quite different. When I was first told I had multiple myeloma, I thought I was going to die at any minute. But if cancer hadn’t been such a taboo subject throughout my life, I’m sure I would have had an easier time dealing with this terrible diagnosis.

And that’s my point here, really: we have to bring these topics out into the open. Of course, not ALL the time, duh! I mean, who wants to talk about cancer and/or death all the time? Yikes! Not I, for sure!!! 🙂

Anyway, I haven’t died (yet), and, as the years have gone by with no great shake-ups, I have followed some of the suggestions mentioned in Holly’s letter…For example, Stefano and I have become birdwatchers (although we still say “hey, look, there’s a BIRD over there!” hehehe, still rather terrible at identifying birds, we are…), we travel as much as possible (not lately, but I hope that will change soon). And so on.

And then there’s the part about stopping to watch/listen to Nature…to cuddle with your pet (a dog, in her case…cats, in mine)…to listen, really listen to music…to eat the cake – zero guilt…to say no to things you really don’t want to do…

Oh yes, indeed. I do try…although life does get in the way sometimes, as it has recently when I’ve had to deal with a few stressful personal items. But…life goes on, and I’m certainly not a “whinger.” Uh-uh. No way. I deal with the stress, do my best, and get on with it!

In sum, there are a lot of really good suggestions in this letter, and that is why I decided to post this link, even though, yes, it’s always sad, very sad, to read about someone’s death, particularly that of a young person.

But her letter is actually very upbeat, as you will see, and that’s how she wants to be remembered…as will I, too, someday!

🙂

Touch of the flu…and carfilzomib

December 31, 2017 / Margaret / 5 Comments

I began feeling a bit “off” right before Xmas…Fatigue (I mean, I couldn’t keep my eyes open…), immense fatigue…and a low-grade fever: those were my main symptoms. Nothing major, as you can see, but it was enough to slow me down at a time that is normally quite busy for me, including frenzied Xmas cookie baking and that sort of thing.

The low-grade fever turned into a proper fever after Xmas, so I gave up fighting it and just slept. And slept and slept. Then, a day or so ago, the fever was gone. The main symptom is gone, but I’m still super fatigued. Bummer.

That said, I’d much rather be fatigued than have THE DREADED COUGH! So, truth be told, this touch of flu hasn’t been all that bad. Many of our friends and neighbors have had a terrible time with this flu (one of my friends had it twice!), so I can’t complain. Besides, I had the best nursing care ever. In addition to Stefano, of course, my adult cats made sure I was always warm and surrounded by purrs and love…Whenever I’d wake up from one of my comas, there they were…on top of me and/or around me. So comforting!

I’m still too exhausted to feel up to bringing in the New Year with our friends, so Stefano and I are staying at home with the kitties…Speaking of which, Pandora and Pixie are still in their quarantine room, mainly because their ear mite infection hasn’t completely cleared, and ALL WE NEED is for the other five adult cats to get ear mites (AGGGHHHHHH!!!). But just a few days from now the vet is coming to check them over, so it won’t be long before we will be able to let them out…It’s TIME. They’ve been isolated in that (big) room for almost two months now. Such good, patient kitties…but they really want to come out, now…And they’re getting BIG…I’ll try to post a photo or two tomorrow…

As for carfilzomib, well, the news isn’t all that great. Since some of you might be taking it or might know someone who is, I thought you might want to read about the recent discovery that a higher than expected percentage of patients on carfilzomib has been experiencing some severe cardiovascular issues. Not good. Here’s the link to the Science Day article where I read about it just this morning: goo.gl/vFcSvF

P.S. After publishing this post, I thought I’d double-check the carfilzomib news (I usually do the reverse!) and found out hat these cardiovascular problems have been known for years now. Years! Quite a few studies on this topic have warned about the toxicity of this drug (from 2013, possibly earlier). So this study simply confirmed what was already out there.

And this shows that I am not so up to date on conventional MM therapies…Then again, neither is Science Daily, hehe.

Okay, I need to go check on the mad kittens now (they are SO active!!!), and then go help Stefano with our New Year’s dinner, yum yum. I hope everyone has heaps of fun tonight AND heaps of good food and happiness!

HAPPY NEW YEAR – BUON ANNO, everyone!!! And may 2018 be a VERY HEALTHY YEAR FOR ALL OF US!!! 🙂