Tag: myeloma

NF-kB: Dr. Jekyll or Mr. Hyde?

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A blog reader and I recently had an interesting exchange about this transcription factor, which is so important in myeloma…in a negative sense, unfortunately. Our discussion gave me the incentive to read more about it. My good friend Sherlock (grazie!) sent me a study published in January (2008) in “Experimental Biology and Medicine,” titled “Nuclear Factor-kB Activation: From Bench to Bedside,” and co-authored by Prof. B. Aggarwal (abstract: http://tinyurl.com/2m6j2g).

This transcription factor, discovered in 1986, was called NF-kB “because it was found in the nucleus bound to an enhancer element of the immunoglobulin kappa light chain gene in B cells.” Okay, wrap your brain around that!  But seriously, if you reread the quote slowly, it begins to make sense: it’s a thingie (protein complex or transcription factor) sticking to the “kappa” gene inside a B cell’s nucleus.

Under normal circumstances, our immune system needs NF-kB to fight off diseases and infections. And until it is needed, this transcription factor follows my cats’ example and takes a lot of very long naps. I don’t want to go into its mechanisms of action (complicated stuff!), at least not today. Let it suffice that, once it has accomplished its task, it settles back down for another nap.

The study informs us that NF-kB is present in every type of cell, not just B cells as was first thought. Researchers have in fact discovered that it is located in the cytoplasm (the watery environment surrounding the cell nucleus) of all types of animal (from the fruit fly to us) cells. Another important finding is that it moves, or translocates, to the cell nucleus only when activated. Otherwise, it stays in, or (once it has finished its task) goes back to, the cytoplasm.

Things change with cancer. That’s when NF-kB turns into Mr. Hyde: it goes bonkers for a variety of reasons and ends up being active ALL the time, or constitutively active. And when this happens, NF-kB remains inside the cell nucleus, that is, it doesn’t return to the cytoplasm. No more naptime!

Skipping the technical parts about heterodimers, polyubiquitination and nuclear localization sequences (!), let me get to what we are really interested in: how does this transcription factor get activated in cancer cells? The study provides an answer: “NF-kB is activated by many divergent stimuli, including proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), epidermal growth factor (EGF), T- and B-cell mitogens, bacteria and lipopolysaccharides (LPS), viruses, viral proteins, double-stranded RNA, and physical and chemical stresses.” Radiation and chemotherapy also activate NF-kB. Speaking of which, the study tells us also that "Cells that express constitutively activated NF-kB are resistant to various chemotherapeutic agents and radiation treatment.” Vicious circle?

Another key sentence: “In tumor cells, different types of molecular alterations may result in impaired regulation of NF-kB activation. In such cases, NF-kB loses its transient nature of activation and becomes constitutively activated. This leads to deregulated expression of NF-kB– controlled genes.” NF-kB, the study continues, plays a critical role in cancer cell survival, inflammation, growth and so on. It regulates genes that are implicated in cancer cell proliferation, including TNF-alpha, IL-6, to name just a couple that we know are essential growth factors in multiple myeloma. It also regulates some of the cell cycle-regulatory proteins such as cyclin D1, also involved in myeloma (see my page on Ursolic Acid or my December 4 2007 post for more info on this gene, which has recently been associated with disease activity and progression).

Activated NF-kB is also implicated in the control of anti-apoptotic genes, that is, genes that keep cancer cells healthy and alive, such as survivin and Bcl-2 (again, see my post on ursolic acid). Furthermore, it regulates matrix metalloproteinases, or MMPs, which are proteases (protein-dissolving enzymes) that, among other things, promote cancer cell growth and angiogenesis. Okay, so there is no question that constitutively active NF-kB is not a good thing.

That’s enough for today, but I would like to end with a question: if we systemically inhibit NF-kB in order to stop our cancer from progressing, doesn’t that leave us more susceptible to infections? (More on this topic SOON!)

The myeloma tap: part II

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Day before yesterday, in part one, we saw that the only myeloma cells capable of cloning themselves are the ones that do not express CD138. The following excerpt from the Johns Hopkins study says it well: “multiple myeloma cell lines and primary bone marrow contain small populations of clonotypic B cells that do not express the characteristic plasma cell surface antigen CD138 and are capable of clonogenic growth and differentiation into multiple myeloma plasma cells in vitro and in vivo.”

Myeloma stem cells, therefore, don’t have CD138 sticking to their surfaces. Herein lies a big difference between regular myeloma cells and myeloma STEM cells: the former have CD138, the latter don’t. Enough said on CD138. Let’s look at other findings now.

I mentioned in my January 12th post that the capable-of-cloning-themselves myeloma cells are resistant to chemotherapy AND look like normal memory B cells AND also display "cellular properties characteristic of normal stem cells, suggesting cancer and normal stem cells share multiple mechanisms that promote drug resistance.” In fact, according to the 2008 stem cell study, both myeloma and normal stem cells have “intracellular detoxifying enzymes,” enzymes that, as I understand it, shoo away the chemo toxins, thus protecting the stem cell from apoptosis. This would provide a good explanation for why myeloma eventually becomes resistant to chemotherapy agents.

So, in sum, what does all this mean? In the researchers’ words, “Because cancer stem cells are a relatively low frequency population in most tumor types, the true inhibition of these cells is likely to be difficult to assess early after treatment, and a prolongation of disease remission would be required to establish such activity.” Well, that doesn’t sound very encouraging, does it?

Back in the middle of November, in a private exchange, a blog reader compared myeloma to a tank of water with a tap and a drain, an analogy he took from the film "Lorenzo’s oil," (those interested can go read a 2007 update on the real ALD story: http://tinyurl.com/2yjyjx). Anyway, the blasted paraprotein shoots out of the "tap," and the drain hole (our kidneys) gets rid of it. Myeloma cells, he was told by his haematologist, have a half-life of 5-6 weeks (I have been trying to find an online reference to this, but so far, on the UK freelite website, I found only that the “the serum half-life of intact immunoglobulin IgG is 20-25” days, so I will ask my haematologist about this in February). In other words, the cells stay in the body for that time and are then expelled via the kidneys.

Point is, are stem cells our "tap"? If so, how can we turn it off? I sure would like an answer to those questions! I would like to add that during yesterday’s meeting, Dr. Benelli suggested another "tap" theory to me, which I will be looking into in the next few days. Interesting times.

Concluding remarks. In the short term, yes, this stem cell research is exciting news but that’s what it remains: news. It has little relevance to us patients. For now. It holds promise for the future, though, indeed let’s hope the very near future. A finding that may prove to be useful is that “the developmental signaling pathway Hedgehog is up-regulated in multiple myeloma stem cells and regulates cell fate decisions.” So we meet again, Mr. Hedgehog! Back in early August, on August 2 and 3 to be precise, I wrote about cyclopamine, a poison contained in corn lilies that was found to be a Hedgehog pathway inhibitor (see my page on cyclopamine).

A couple of days ago, in a private exchange, an MMA list member asked me if the stem cell study had changed my supplement plans for the future. I answered yes, it has, in the sense that I hadn’t really thought seriously about taking parthenolide until I read about myeloma stem cells and how parthenolide and DMAPT (water-soluble form of PTL) annihilate leukaemic stem cells in vitro. So parthenolide shot right to the top of my supplements-to-try list. I am now planning to test parthenolide in March, after the Biocurcumax experiment has ended.

Summary of the main points made in the stem cell study, from my point of view:

  1. clonogenic myeloma stem cells do not express the characteristic CD138 antigen.
  2. myeloma stem cells constitute less than 2% of the myeloma "population."
  3. myeloma stem cells look like memory B cells.
  4. myeloma stem cells display normal stem cell characteristics that protect them "from toxic injury."
  5. like normal stem cells, nearly all myeloma stem cells (>98%) studied were in the quiescent (dormant, inactive) state, which is possibly another "major mechanism of drug resistance."
  6. conventional chemotherapy doesn’t affect myeloma stem cells.

The myeloma tap: part I

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This post was way too long so I decided to cut it in half. I will post the second part tomorrow. Only then will today’s title make complete sense.

Anyway, I have it, I have it! Yes, the FULL recently published Johns Hopkins myeloma stem cell study that I mentioned a couple of days ago. Okay, I confess that I have had it in my possession since last Sunday, when a very kind blog reader (thank you thank you thank you!) sent it to me, but just haven’t gotten around to writing a post about it. The study, by the way, was conducted by a team led by Dr. William Matsui and published in the January 1 2008 issue of “Cancer Research.” You can view the abstract here: http://tinyurl.com/2yuru9.

Before I go on, though, I wanted to mention that another blog reader posted an interesting New York Times article on the controversy surrounding the cancer stem cell theory and other interesting info, so if the issue of stem cells is your cup of tea, please go read Carla’s comment on my “Stem cells and myeloma” post, Jan 12th.

Back to us. I have to admit, reading this stem cell study was not exactly as fun and easy as reading one of the Harry Potter books, but I found it almost as engrossing. The study begins by providing a bit of background, including this: “Early studies examining a murine model of multiple myeloma suggested only a minority of cells were capable of clonogenic growth.” Hmmm, so only a tiny percentage of myeloma cells can clone themselves…I didn’t know that. I thought they were all capable of creating clones. Live and learn.

Myeloma stem cells are mentioned in a 1977 study (full text: http://tinyurl.com/2d8z3n), which, by the way, shows black and white photos of myeloma cells for those who might be interested. Anyway, according to the Johns Hopkins investigators, this early study showed that “the cloning efficiency of primary multiple myeloma specimens was 1 in 1,000 to 100,000 cells. To date, it has remained unclear whether these clonogenic cells are distinct from the plasma cells that constitute the majority of tumor cells.”

Then, in 2004, Dr. Matsui et al published a study (full text: http://tinyurl.com/2233wp) in “Blood” on clonogenic myeloma cells. Clonogenic, by the way, has two meanings: 1. “giving rise to a clone of cells” and 2. “arising from or consisting of a clone.” I went through the 2004 study, which reported that “highly clonogenic cells from both human MM cell lines and primary patient samples do not express CD138, but rather markers that are characteristic of B cells.” This rather baffling sentence will, I hope, become clearer after the upcoming section on CD138 (and part II, which I will post tomorrow, should also help in that sense). The 2004 study also suggested that, like chronic myeloid leukaemia or CML, “MM is another example in which cancer stem cells are a rare cell population that is distinct from the differentiated cells that comprise the bulk of the disease.”

CD138. Now I am going to delve into some rather difficult material that has to do with this thing called CD138. Also known as syndecan-1, CD138 “is “a heparan sulfate proteoglycan expressed on the surface of, and actively shed by, myeloma cells.” I know, I know…Let’s see if this will clarify matters: proteoglycans are “glycoproteins but consist of much more carbohydrate than protein; that is, they are huge clusters of carbohydrate chains often attached to a protein backbone,” according to Prof. Kimball’s Biology Pages. (Hmmm, lots of carbs plus some protein…pasta with meat sauce! )

Seriously though, it doesn’t really matter if we don’t completely grasp what CD138 is. What’s important is that we understand the following excerpt from the 2004 Johns Hopkins study. CD138 “is the most specific marker for normal and MM plasma cells. However, normal CD138+ plasma cells appear to be terminally differentiated and unable to proliferate, and there have been few studies using this marker to study the proliferative capacity of MM cells.”

Not the easiest stuff to digest, eh! Well, let’s see if I can explain what CD138 is in a few simple words (if I make any mistakes, please let me know): in sum, CD138 is a thingie (ok, a proteoglycan) sticking to the surface of regular myeloma cells—the ones, that is, that are NOT able to clone themselves. These are the CD138 "plus" myeloma cells. Patients whose myeloma cells release, or "shed," CD138 (CD138 "negative" cells) into the serum have a worse prognosis than those whose myeloma cells still have it. Hence it is a helpful prognostic marker (for more info, see this 2002 “Blood” study: http://tinyurl.com/2h26uq). CD138 levels can be measured in MGUS patients, too (see this 2006 "Neoplasma" abstract: http://tinyurl.com/yr9vzd).

A September 2007 “Blood” study (see abstract: http://tinyurl.com/2slg3t) confirms that “High levels of shed syndecan-1 in myeloma patient sera correlate with poor prognosis and studies in animal models indicate that shed syndecan-1 is a potent stimulator of myeloma tumor growth and metastasis.” So again we see that if CD138 is shed into the myeloma “microenvironment,” this is bad news for us (poor prognosis etc.). Interesting aside: this is true for CLL patients as well (see this January 2008 abstract: http://tinyurl.com/3ap8ba). Connections, connections.

Ok, that’s it for today! Phew.

MD Anderson Curcumin Myeloma Clinical Trial Results: Preliminary Comments

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First, a blog notice: yesterday I sort of updated my "Curcumin in the News" and "Italian Curcumin References" links. My New Year’s Resolution number 2861 (!) is to keep these links a bit more updated, and the same goes for some of my more sadly neglected blog pages, such as the recipe one.

I was waiting to read the full MD Anderson report before discussing the curcumin-myeloma trial results here, but Chris’ comment on yesterday’s post, on top of all the private messages I have received to this regard, made me decide this morning to go ahead and write a post even though, I repeat, I don’t have ALL the facts and numbers. I will certainly have more to say on the topic as soon as I read the full study, which hasn’t been published yet. In the meantime, for what it’s worth, here goes!

Oh, before proceeding, though, I wanted to mention that you can view Prof. Aggarwal’s ASH presentation on the International Myeloma Foundation’s website: http://tinyurl.com/yw4m7y One important thing he points out is that, even when as little as TWO grams of curcumin were administered to some of the myeloma patients in the clinical trial, after four weeks a downregulation of the evil (I added the "evil" part) transcription factor NF-kappaB was observed. After 24 weeks, no NF-kappaB could be detected in some of these patients. Not even a glimpse. And they were taking only two grams. How about that?

Prof. Aggarwal also says that cancer treatment requires the inhibition of more than a single pathway, which makes curcumin an ideal agent since it inhibits several different pathways involved in cancer progression. A key sentence: “Although this study was very interesting and we did find the downregulation of various markers for cancer in MM pts, no objective responses were noted. So, in the future, I think that it would be interesting to combine curcumin with some of the existing treatments.”

A few introductory comments of my own: we know from the huge number of studies published on curcumin that this biologically active compound has extraordinary anticancer properties in vitro. Frequently, however, extraordinary properties do not work as well, or indeed at all!, when applied in vivo. It’s one thing to inject curcumin directly into some cancerous cell cultures, quite another for us to swallow a capsule or pill and hope that eventually our myeloma cells will be blasted by enough active curcumin. As we know, when taken orally, most of the swallowed curcumin gets transformed into (probably) less powerful, perhaps even useless metabolites (first-pass metabolism etc.). The issue of bioavailability pops up, again.

So the big question is: how do we get enough still-active curcumin delivered right smack into our cancerous cells? Eh. Still working on that!

ASH abstract. Thanks to the kindness of someone who sent me the abstract presented by the MD Anderson curcumin myeloma trial researchers at the American Society of Hematology (ASH) meeting held in December 2007, I was able to read some of the preliminary clinical trial data. Jan 15 UPDATE: here is the link to the abstract: http://tinyurl.com/26mjb7

The abstract tells us that the MD Anderson clinical trial (which is still recruiting patients, by the way) consisted of 29 myeloma patients with asymptomatic, relapsed/refractory, or plateau phase disease. They took curcumin capsules without bioperine, 2, 4, 6, 8, or 12 grams/day in two divided doses, OR curcumin capsules with bioperine, 10 grams, again twice a day. The abstract tells us that “At least 6 pts are enrolled at each dose level; 3 on the curcumin arm and 3 on the curcumin + bioperine arm.” Conclusions: “Of the 29 evaluable pts treated so far, no objective responses have been seen. Twelve pts continued treatment for more than 12 weeks and 5 (1 patient at 4 grams, 2 pts at 6 grams, and 2 pts at 8 grams dose levels) completed one year of treatment with stable disease.”

Key words: “stable disease.” These patients remained STABLE. My glass is half full, not half empty. Always. 

Most of the people with whom I have corresponded privately have focused on the “disappointing” trial results, that is, not one of these myeloma patients experienced a decrease in her/his myeloma markers. But that is precisely what I expected since my own results from my capsule experiments have been similar. So I am not disappointed. Not at all. Sure, it would have been great to see a decrease at least in one patient since I (myself) did experience a fluky IgG decrease in September of 2006 that may or may not be ascribed to my curcumin capsules with bioperine intake (update: my parents pointed out to me that the way I worded this last sentence makes it seem as though my September 2006 IgG decrease has been my ONLY decrease to date. That is not the case, of course. I have experienced decreases  while taking curcumin powder. So I thought I should clarify that I was referring to capsules here). I say "fluky" because at the time, pre-blog era, I wasn’t keeping good records on my intake, and when, months later, I repeated the capsule with bioperine experiment my results were stable, that is, there was no decrease. Hmmm.

Well, anyway, in my view, the following trial results are even more important than disease stability (which is important enough!): “Oral administration of curcumin significantly downregulated the constitutive activation of NF-kB (at 3 months a median reduction of 77%, p<0.0001) and STAT3 (69%, p<0.001), and suppressed COX2 (66%, p<0.0001) expression in most of the pts at each of the monthly time points.”

Check out those percentages! Accipicchia! Excellent! This means that curcumin is able to inhibit all the overly active transcription factors that make myeloma cells proliferate…and this happened IN VIVO! That is, in spite of its low oral bioavailability, curcumin was still able to inhibit these bothersome pathways in myeloma patients. In vitro translates to in vivo. That result is not at all disappointing but very very exciting. To me, at least. Oh, I can’t wait to read the full report.

Curcumin won’t cure myeloma (or perhaps it could, but it would have to be injected directly into each cell, I am afraid…), but if it can keep me and others, I hope!, stable or even decrease my/our counts until someone finds a way to exterminate the cancerous STEM cells (DMAPT trial, where art thou?), well, that’s fine by me. As Earl (Beth’s blog reader, see yesterday’s post) wisely declares, “always believe you can do it…if you think you can, you can…if you think you can’t, you can’t.”

I think I can.

My Cocoa Mass And Curcumin Recipe In English And Italian

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Yesterday I went to see my family doctor, who was absolutely thrilled to see my most recent test results. Almost as thrilled as he was to get a big bag of my Xmas cookies, hehe. And some Slitti chocolate. Oh, I just have to fly my own kite for a second: he told me that MY cookies are the best he has EVER had. Ever!  Anyway, he wrote down my chococumin recipe and also asked if I had posted about it on my blog. Since I couldn’t remember the exact date and am too lazy to look it up, I decided to post the recipe again. It’s not even a real recipe, since I don’t measure anything!

Anyway, here goes (I will translate this into Italian, too, see following paragraph): I use one and a half or two small squares of cocoa mass, or 100% chocolate (not cocoa powder, mind you). Cocoa mass looks like a regular chocolate bar, and you don’t need but a small bit. I melt it over very low heat, but you could use a double boiler, if you prefer. I add a couple of heaping teaspoonfuls of dark organic honey, otherwise it’s too bitter to swallow, in my opinion. As soon as these two ingredients have melted (be careful not to burn the mixture, as I have done a couple of times in the past!), I take the pan off the stove and add two grams of quercetin powder and my eight grams of C3 Complex curcumin powder. Stir quickly and eat the mixture even more quickly since it has a tendency to harden. Important note: I put small blobs of it under my tongue, where there are a TON of blood vessels. My idea is to get the dissolved curcumin into the bloodstream without much ado. It would seem that this approach works, which is why I am SO curious to see my next test results.

Ricetta in italiano: prendere un quadratino e mezzo oppure due (dipende dalla grandezza; ad esempio, se è pasta di cacao Slitti ne basta uno e mezzo; se è Domori ce ne vogliono due) di pasta di cacao. Mi raccomando, che non sia cacao in polvere (non so perché, ma mi dà l’idea che funzionerebbe peggio), ma pasta di cacao, che assomiglia alle tavolette di cioccolato normali. Praticamente si tratta di cioccolato al 100%, senza zucchero insomma. Aggiungere due cucchiaini da té stracolmi di miele biologico, il più scuro possibile (tipo, castagno). Scioglierlo a fuoco bassissimo oppure a bagnomaria. Attenzione a non bruciarlo sennò fa veramente schifo (lo so per esperienza, eheh!). Aggiungere due grammi di quercetina in polvere e otto grammi di curcumina, sempre in polvere. Io uso la curcumina C3 Complex. Una volta sciolto e mescolato il tutto, ne metto un po’ sotto la lingua e lo faccio sciogliere piano piano. L’idea è che da lì entra velocemente in circolo nel sangue senza passare per lo stomaco e l’intestino dove viene aggredito in malo modo da diversi enzimi. Ultima cosa: siccome questa specie di pastone cioccolatoso si indurisce rapidamente, bisogna mangiarlo velocemente e, soprattutto, mentre è caldo.

Back to English. I am busily finishing research for a post and have other errands to run. Busy days, these! I apologize to those who have sent me messages and who are not receiving a reply. I do read every single message, but I probably won’t get to answering any of ’em until Sunday or so. Ok, off I go! Poof!

Another Celiac Disease Case Study

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Just a quick post today. These days I have heaps of things to do that are keeping me away from my computer and my research. Errands, work, cookie baking and whatnot. ‘Tis the Xmas season! Speaking of work, one of my students this morning wanted to say “I’m really sorry,” but what came out of her funny mouth was “Sorry davvero” (davvero means “really” in Italian). Yes, this was another merry teaching day. Oh dear, I just noticed that parts of my keyboard have turned yellow. Will I ever get the curcumin stains out? Hmmm.
 
Anyway, back to serious stuff. A friend (thank you!) sent me a case study published in 1980 and titled “Multiple myeloma and adult celiac disease.” It discusses the case of a 75-year-old woman with multiple myeloma (a bone marrow biopsy or BMB revealed 80% malignancy), a resident of Wisconsin, who “was admitted to the hospital because of diarrhea and abdominal pain.” She had had this kind of trouble for “25 years prior to admission.” So had a few close relatives. Her intestinal woes vanished after she began a gluten-free diet.
 
Keeping in mind that this study was written 27 years ago (!), let’s read the following: “The appearance of malignity in patients with celiac disease has been well described and several theories have been offered in explanation. An abnormal immune surveillance allowing for the development of a malignant clone of cells is most popular. Proponents of this theory cite the various studies demonstrating a defect in the immune apparatus, such as a reduction in the number of ‘T’ cells or immunoglobulins, or demonstrating a defect in immune function, such as impaired response to mitogens or reduced cytotoxicity. Other explanations include inherent genetic predisposition (celiac patients with malignancy have a higher frequency of having the histocompatibility antigens HLA-A1, HLA-B8, and HLA-B12), and the accumulation of dietary carcinogens because of the lack of detoxifying enzymes and appropriate cell turnover in the small bowel mucosa.” Hmmm. Detoxifying enzymes, eh? I must look into this when I have more time (hah!).
 
Further on, “Multiple myeloma, a malignant conversion of an immune functioning cell, had not been reported in association with celiac disease. It is tempting to speculate that chronic antigenic stimulation in a patient with abnormal immune response resulted in the plasma cell dycrasia. In patients with multiple myeloma who have persistent, unexplained diarrhea or steatorrhea, endoscopy and biopsy are indicated to rule out amyloid or celiac disease.”
 
Plasma cell dyscrasia, by the way, is a group of diseases characterized by the proliferation of a single clone of plasma cells. This clone produces a huge amount of a single antibody, or monoclonal antibody, known as M-protein. Multiple myeloma is part of this group and so are other plasma cell malignancies, such as Waldenstrom’s macroglobulinemia. And MGUS. I think it’s always good to review this stuff (sometimes I forget specifics, too!).
 
I don’t know if I have gluten intolerance. I certainly don’t have any of the harsh symptoms that I have seen described here (and there). But I want to take the antigliadin antibody test just to rule it out. Like Web Admin, I had a terrible diet for years, especially in college and grad school, when I couldn’t be bothered with cooking. I ate a lot of pasta and chemical-ridden sweets. Tons of gluten, in other words. At any rate, if it turns out that I have the slightest intolerance to gluten, I don’t think it would hurt for me to send it into exile forever. Even if my myeloma markers don’t decrease. Okay, I have more errands to run, so off I go! Ciao a tutti!

Myeloma: An Acute Form Of Celiac Disease?

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A topic that has been discussed recently on a couple of websites, that is, Cancer Compass (http://tinyurl.com/2daxza) and Beating Myeloma, is the celiac disease-myeloma connection. There are a ton of studies on celiac disease, also known as gluten intolerance. According to this one (abstract: http://tinyurl.com/2hk8jj), it is: “an autoimmune inflammatory disease of the small intestine that is precipitated by the ingestion of gluten, a component of wheat protein, in genetically susceptible persons. Exclusion of dietary gluten results in healing of the mucosa, resolution of the malabsorptive state, and reversal of most, if not all, effects of celiac disease. Recent studies in the United States suggest that the prevalence of celiac disease is approximately one case per 250 persons.” Now, I grew up in Italy on a pasta diet. I LOVE pasta and cannot imagine my life without it. But this topic concerned me enough to buy some gluten-free pasta and think about going on a gluten-free diet at some point early next year. Let’s have a look at a few of these studies.

A study (abstract: http://tinyurl.com/2hfhgz) published in “Leukemia Research” in December of 2006 points out that “it is well known that in sera of some patients with intolerance to gluten, with celiac disease, the IgA or IgG immunoreactivity to gliadin, and elevated levels of IL-6, could be present too.” Gliadin is a glycoprotein (a carbohydrate plus a protein) found in wheat, oats, rye, barley and other cereals.

Now, this is very interesting. Let’s see: 1. Gluten intolerance is associated with high levels of IL-6. But people with celiac disease also have high levels of IL-1beta, which strongly induces IL-6. Not good. 2. The immunoglobulins IgA and IgG are involved in the immune system reaction to gliadin. What a coincidence, huh? Hmmm.

This study is the first to report “that antibodies from some M-component could be directed to gliadin antigens.” Even though more research is needed, multiple myeloma could possibly be a “more severe form of gluten intolerance than celiac disease,” connected to our immune system’s reaction to gliaden antigens. In other words, those who have this particular food intolerance could possibly and eventually develop myeloma. Did I understand this correctly??? I am almost at a loss for words.

Another excerpt: “As IgA or IgG antigliadin immunoreactivity found in sera of patients with celiac disease is diminished in patients on gluten-free diet (GFD) and by some antibiotics, it could be of importance to consider whether the same approach in patients with MM (and with antigliadin immunoreactivity), applied at the end of conventional therapy would stop myeloma progression.” How about that? Go on a gluten-free diet, as some myeloma and MGUS folks in my acquaintance already have, and see if that is enough to stop myeloma from progressing. Who knows?

Another 2006 study, published in “Aging Clinical and Experimental Research (full study: http://tinyurl.com/ythyfm), tells us that “Although lymphoproliferative disorders and intestinal tumors are the most commonly seen malignancies, many other malignancies including multiple myeloma may develop.” The study examines the specific case of an elderly patient who was eventually diagnosed with celiac disease, after 15 years of diarrhea and other symptoms. “In our case, failure of diagnosis despite 15 years of symptoms played an important role in the development of malabsorption-related complications such as anemia, electrolyte imbalance and osteoporosis, as well as multiple myeloma.” I noticed a rather curious thing: the abstract tells us that the patient had plasma cell dyscrasia but not myeloma; then the full study states that the patient was diagnosed with early-stage myeloma. Odd. Oh well. Point is, though: this study affirms that myeloma may develop in patients with celiac disease.

A 1990 German study (http://tinyurl.com/yrlfa3) examined the fate of 52 people diagnosed with celiac disease: 15% of them developed cancer, including one case of myeloma. A 2004 Irish study (http://tinyurl.com/28gkm9), titled “Celiac Disease and Malignancy,” looked at 77 patients with celiac disease. One had myeloma. Interesting statistics, if nothing else. Could there be a gluten intolerance connection for some of us? Isn’t it worth at least getting tested?

Concluding remarks: I recall having an array of allergy tests done several years ago, and I distinctly remember that I was not allergic to wheat (etc.). But things change, so I am going to ask my haematologist what she thinks about it. After all, a simple blood test can determine if one has the antigliadin antibodies. Easy peasy!

Stress Involved In Myeloma Progression: Very Evil Growth Factor

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Today I will be putting back a couple of posts, including this one, which I posted on December 7, 2007. The original posts were gobbled up by the server, apparently, comments included. I will put the comments back as best I can. Sorry if they look funny! Not funny haha, funny weird. 😉

Other myeloma bloggers have posted about a recent study (abstract: http://tinyurl.com/2w4ndb) showing the link between myeloma and stress. My friend Sherlock sent me the full study, so I will try to provide some additional information. Conducted by a team of researchers at the Ohio State University Medical Center, this study was published in November 2007 in “Brain, Behavior and Immunity,” which by the way looks like a very interesting publication. I must keep my eye on it.

The study is titled “VEGF is differentially regulated in multiple myeloma-derived cell lines by norepinephrine.” A couple of notes before proceeding. Noradrenaline, also known as norepinephrine (NE), is a hormone and neurotransmitter involved in alertness and concentration, among other things. It is involved in heart rate, blood pressure and blood sugar level increases. VEGF stands for “vascular endothelial growth factor,” and is an evil signalling protein that is linked to tumour progression, feeding cancer cells, etc. Read this excerpt from an IMF article written in 2001 (http://tinyurl.com/2yh49k): “Dr. Kenneth Anderson of the Dana-Farber Cancer Center mentioned that VEGF might not only be important for the formation of new blood vessels in MM but also has the potential to stimulate directly the proliferation and migration of myeloma cells. His group demonstrated that production of VEGF by myeloma cells can be stimulated by activation of the CD40 molecule on the surface of the tumor cells.” CD40, we meet again!…remember my CD40 post? I am not done yet with natural ways we can use to inhibit CD40, I just need to find the time to read the studies that Sherlock sent to me.

But let’s get back to VEGF. The Ohio stress study tells us that “VEGF is a crucial cytokine that directs and promotes tumorogenesis and potentiation in the marrow. VEGF levels correlate with overall prognosis and associated bone destruction, which contributes substantially to clinical morbidity.” I told you VEGF was evil! In fact, I suggest that from now on it be known, perhaps more appropriately!, as “Very Evil Growth Factor.”

The introduction begins: “There is evidence that psychological factors can affect the incidence and progression of some cancers.” And, in fact, there is definitely a connection between our IL-6 levels and chronic stress, which is actually a topic on my infinitely long to-be-researched list. That is one reason why I was most interested in the finding, reported in the Ohio study, that NE has been found to stimulate IL-6 and IL-8 in human melanoma cells. But these two cytokines are also actively involved in myeloma. We know all about evil IL-6, but IL-8 has also been connected to progression in myeloma. No comment necessary, methinks.

Discussing a previous study, the Ohio researchers report that stress can inhibit T cells from responding “to tumor-associated antigens on tumor cells of immunogenic tumors.” T cells, hmmm, that sounds familiar.. And the effects caused by stress may “may contribute to tumor progression independent of its effects on the immune system.” Well, we knew that stress is bad for us, but this goes a bit beyond “bad.”The researchers tested three myeloma cell lines in different stages of development. All three had “the potential to respond to NE,” but one in particular “exhibited the greatest NE-dependent response.” Interestingly, this cell line came from someone whose myeloma was aggressive but ”in the earliest (and comparatively longest) clinical phase—i.e., where disease is confined to the bone marrow.” This could mean that in early stages perhaps the blood supply to the malignant cells could be diminished simply by inhibiting NE, which would not kill the malignant cells, of course, but should theoretically slow down tumour growth and disease progression.

Toward the end of the study, we find the following: “Whether the stress-associated activation of the sympathetic nervous system results in the upregulation of NE levels in the bone marrow is unknown. However, observations described here suggest the potential for a stress-associated stimulation of proangiogenic properties of MM cells through the upregulation of NE levels.” The Ohio team adds that “the mechanism involved in the NE-dependent increase in VEGF release by MM cells is not known.”So let’s have more studies like these instead of inanities of the following sort (I glanced at this article this morning and could hardly believe my eyes): “new research suggests that the presence of other people may enhance our movie-watching experiences. Over the course of the film, movie-watchers influence one another and gradually synchronize their emotional responses” (http://tinyurl.com/299s5x). Ehhhh??? You’ve got to be kidding. Isn’t it common knowledge that if you go see a fantastic movie with someone you don’t like, most likely you will hate it, but if you go to see the same movie on your own or with a good friend, you will probably love it, blablabla? Do we really need actual STUDIES to look into this sort of twaddle? Come on!

I would like to finish by saying that I hope to have time at some point to look at the other NE-cancer studies. The one I read today deals specifically with myeloma, but the other NE studies examine other types of cancer. And then there is the whole related issue of beta-blockers, which the Ohio team suggests might be beneficial for myeloma patients (but more info is needed, they add). Anyway, that topic too complicated to get into today. Interesting, though. Okay, have a fun laughing weekend, everyone!