Myeloma: An Acute Form Of Celiac Disease?

December 14, 2007 / / 13 Comments

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!

TEST RESULTS IP IP URRA’!

December 13, 2007 / / 4 Comments

I wrote this post on Monday, December 10th, after receiving my November test results (here in Italy, we patients receive our test results, not our doctors, which I personally think is great). Since I received more than a dozen comments (that were gobbled up by voracious Mr. Server during the updating process), I decided to create one BIG comment instead of several individual comments. As things stand, it really looks as though I wrote all those comments myself, but I didn’t, I didn’t, I promise! Here is the original post:

Spettacolare!, as we say in Italian! And here I was, dreading the arrival of my test results since I took them during a period of (a bit of) stress, I had just begun my new job etc. Well, HURRAY definitely replaces DREAD! But let me proceed by degrees.

I will compare these tests, taken on November 19th, to my not-so-good-but-still-semi-okay September tests. My IgG has dropped from 34.3 (September) to 27.8 g/L (now). The normal range is 7-16 g/L. I have always been terrible at math, but that’s almost a 20% drop, no?

My IgA and IgM are as stable as rocks, haven’t moved a bit, but that is ok with me, even though both values are very VERY low. The important thing is that they didn’t go any lower!

My blood viscosity has dropped from 55 to 48 mm/hour, which is good. Keep in mind that this value has gone as high as 95! My white cells have climbed a bit, from 4.63 to 4.98; my red cells dropped just a teeny tiny fraction. My haemoglobin is stable in the region of 13, and my hematocrit has increased a bit, from 38.1 to 39.5 (normal range: 36.0-46.0). Creatinine is stable at 0.7, within the normal range; calcium is slightly up but still way within the normal range; albumin is still within the normal range (yippee). Bence Jones is NEGATIVE (yeah, yeah, yeah!). Beta-2 Microglobulin has gone down slightly, from 1.8 mg/L to 1.6 (normal range: 1.2-2.5 mg/L). Also good.

Not much really stands out in a negative sense. My serum iron, however, has dropped from 109 to 62 micrograms/dL (normal range 60-140 mcg/dL), so I will have to do something about that. Yikes. I see a few steaks in my near future. But my ferritin, which was 7 ng/mL in June, then 8 in September, is now 10 ng/mL (normal range begins at 15). Still low, but going in the right direction, at least. Oh, my total cholesterol went up somewhat (but so did my HDL, the good cholesterol, so that is good), but I expected that to happen, since for more than a month and a half I tested a concoction based on a dab of butter and either double cream or whole milk, so I suppose even curcumin couldn’t battle against THAT! Have I forgotten anything? Oh, my m-spike is also stable, in the 2 region.

In sum, all is well! SUPER DUPER WELL! Little dance of joy today! 🙂

Stress Involved In Myeloma Progression: Very Evil Growth Factor

December 13, 2007 / / 1 Comment

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!

Curcumin Restores T Cells

December 5, 2007 / / 9 Comments

Doing research for a recent post, as frequently happens, I came across an interesting abstract with some hard-to-believe news. My brilliant friend Sherlock (grazie!) kindly sent me the full study, published in the Journal of Biological Chemistry in June 2007. According to the abstract (http://tinyurl.com/3yqzc6), Administration of curcumin to tumor-bearing animals resulted in restoration of progenitor, effecter, and circulating T cells. Curcumin can reinstate our T cells at every stage of their development? No way! (Yes, way). Hmmm, the question arises: why should we care about T cells? Well, if we didn’t have any T cells, we would be like nude mice, yes, the sort used in lab experiments. We would have no way of fighting off disease. T cells, in a nutshell, are crucial players in our immune response to diseased cells.

Let’s take a look at the full study: In order to establish itself, a growing tumor must evade the immune system of the host. This contributes to tumor-induced immune suppression. A growing tumor can evade the proposed immune surveillance by several mechanisms. One of these mechanisms is to kill (induce apoptosis of!) our T cells. Reading on, we learn that Increased oxidative stress because of the growing tumor can be another cause of immune disruptions. Recently, several observations indicate that a chronic inflammatory condition develops in patients with advanced cancer, causing oxidative stress that can shut off immune functions, including those of T and NK cells. Oh, this is not good at all.

Before proceeding, let me just mention that I was confused enough about all these different types of cells that today I looked everything up, from A to Z. I am now in the midst of putting together a brief (!) explanation (?) of a very complex topic. For now, let it suffice that B, T and NK (natural killer) cells are three types of lymphocytes (white blood cells) that originate from hematopoietic stem cells (HSCs), located in the bone marrow. They have different functions, but we don’t need to get into the nitty gritty, yet. If you can’t wait for my explanation, then click on the fabulous link I provide below. Back to the study, now.

A tumour has a negative influence on the production of T cells in the thymus, which is a small organ, located behind the sternum, that produces T cells (the “T” stands for “thymus,” in fact). A tumour causes a massive depletion of both thymic and circulatory T cell populations. Massive depletion of T cells? Yikes. But there is GOOD news. The administration of curcumin brought back thymic CD4+8+, CD4+, and CD8+ cells as well as circulatory effecter CD4+ and CD8+ cells to control level. (CD4 and CD8 are the two main T cell subsets, by the way.) Curcumin brought these cells back to CONTROL level? Well, knock me down with a feather!

Ah, but it gets better. Curcumin protected T cells from being killed by the tumour. When preincubated with curcumin, these cells turned into Superduperfantastic cells, resistant to any tumour attack (sort of like Harry Potter versus Voldemort). In other words, they survived. Oh, sure, this is all happening in vitro. But the researchers experimented with mice, i.e., in vivo, too. Exact same results. They conclude that from aforementioned in vitro and in vivo results, it may be envisaged that curcumin might also protect T cells from a tumor-induced demise in humans. Hey, it’s not every day that I get excited about something called thymic CD4 plus! 😉

My next topic stumped me for hours, it seems, until I came across an absolutely brilliant website that opened up a whole new world for me: the world of relatively easy biology. Itsy bitsy thingies no longer have any secrets for me thanks to John Kimball, a retired biology professor who taught at Tufts and Harvard (I must remember to write him a glowing fan letter). The updated sixth edition of his biology textbook is online (free, too): http://tinyurl.com/57ygj So from now on, if you ever have a doubt about, say, the JAK-STAT pathway, this is the place to go. 😉 Seriously, though, thank you from the bottom of my heart, Prof. Kimball! Everything is crystal clear now. Well…more or less!

Here’s what stumped me: in the curcumin T cell study, I read that tumours downregulate the anti-apoptotic Bcl-2 protein (take my word for it, this is NOT a good thing). But that’s precisely what curcumin does: it downregulates Bcl-2 in myeloma cells. Wait, how could this be? Why is the downregulation of Bcl-2 bad for T cells, good for myeloma cells? Ah, you see, perhaps, had I written out the question, I wouldn’t have spent hours trying to figure it out!

It’s very simple, really. In the case of T cells, in fact, we WANT to have a high level of Bcl-2. In the case of myeloma cells, we don’t. Prof. Kimball’s page on Bcl-2 explains that B cells, like all activated lymphocytes, die a few days after they have had a chance to do their job. This ensures that they do not linger around after the threat has been dealt with and turn their attack against self components. Aging B cells kill themselves by apoptosis. But high levels of the Bcl-2 protein protect the cells from early death by apoptosis. After reading these four sentences, a light went on in my brain: we want T cells to LIVE, but myeloma cells to DIE. Therein lies the difference. Okay, so it took me hours, not minutes, to figure this out, but I am not a biologist, and I didn’t have this wonderful reference text at my fingertips until the latter part of the afternoon.

Well, we have yet another (!) good reason to take curcumin. I can feel my T cells getting more powerful by the second…!

My brain is fried, now, and I need to get off the computer, but will certainly take a second look at this study at some point over the weekend. I would like to end by pointing out that Mary has some good advice for us (see her most recent comment to my December 3rd post). Please go have a look!

Herbs Against Myeloma: Ursolic Acid

December 4, 2007 / / 4 Comments

The September 2007 issue of Molecular Cancer Research has a fascinating study, co-authored by Prof. Aggarwal, titled: “Ursolic Acid Inhibits STAT3 Activation Pathway Leading to Suppression of Proliferation and Chemosensitization of Human Multiple Myeloma Cells.” The abstract can be viewed here: http://tinyurl.com/2fkrxl As usual, thanks to my friends, I have read the full study. Ursolic acid can be found in rosemary, apples, bilberries, cranberries, pears, peppermint, lavender, oregano, holy basil, thyme and prunes. There are a ton of studies on the anti-cancer effects of this plant extract, but today I want to focus on this one in particular.

First, a word or two on STAT3. According to one of the main studies on myeloma and curcumin, published in 2003 in the Journal of Immunology (full text: http://tinyurl.com/397tow), STAT3, which stands for Signal Transducer and Activator of Transcription 3,” is a cell signalling protein and a prime anticancer target because it can protect cancer cells from apoptosis. Curcumin inhibits the activation of STAT3, quelle surprise. Another inhibitor of STAT3 is capsaicin (see my capsaicin Page on the right): Capsaicin down-regulated the expression of the STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, and vascular endothelial growth factor. I used to shun spicy hot foods, but since reading the studies on capsaicin, I have begun sprinkling spicy red pepper on my food. And now I really like it. Yesterday I made an organic vegetable and free-range chicken soup (Stefano has a cold, poor dear) with the usual ingredients (garlic, onions and vegetables of all sorts), to which I added a Southern Italian hot red pepper mamma mia!, together with a bit of every single herb we have in the garden and in the house (oh yes, turmeric, too!) and a big piece of ginger. Delicious!

Back to us. The ursolic acid study tells us that STAT family proteins have been shown to play an important role in tumor cell survival and proliferation, and in particular STAT3 is often constitutively active in many human cancer cells including multiple myeloma, leukemia, lymphoma, and solid tumors. It can be activated by IL-6 (interleukin-6), by the way. Without going into too much detail, what we want to do, clearly, is inhibit STAT3. One way is through DIET, that is, eating foods that contain ursolic acid. So much for my being told, back in 2005, that there was nothing I could do to stop the obvious (by then) progression from MGUS to MM. Drat. I wish I had known back then a fraction of what I know now. But, as the saying goes, better late than never/meglio tardi che mai! 🙂

The study tells us that Ursolic acid is a pentacyclic triterpenoid that has been shown to suppress the growth of various hematopoietic tumors, inhibit tumor promotion, and inhibit tumor angiogenesis. We have recently shown that ursolic acid is a potent inhibitor of nuclear factor-kB (NF-kB) activation pathway, which is activated by inflammatory agents, carcinogens, and tumor promoters. In this study, the researchers wanted to test their theory that ursolic acid suppresses the STAT3 pathway in myeloma cells. They were successful.

The following will be of interest in particular to those taking Velcade and Thalidomide: In our experiments, ursolic acid indeed suppressed both constitutive and inducible STAT3 activation. This inhibition decreased cell survival and down-regulated expression of proliferative and angiogenic gene products, leading to suppression of proliferation, induction of apoptosis, and enhancement ofthe response to the cytotoxic effects of thalidomide (an inhibitor of tumor necrosis factor expression) and bortezomib (a proteasome inhibitor; also called PS341) in multiple myeloma cells. Further on, we read that ursolic acid significantly enhanced the apoptotic effects of thalidomide from 20% to 70% and of bortezomib from 25% to 80%. Now, those are significant numbers, I’d say!

I cannot examine every single bit of information provided by the study, but for instance ursolic acid increased the expression of Bax and Bak proteins, which cause apoptosis in myeloma cells. Yeah! Also, similarly to capsaicin, ursolic acid suppresses the expression of several STAT3-regulated genes, including proliferative (cyclin D1) and antiapoptotic gene products (survivin, Bcl-2, Bcl-xL, and Mcl-1) and angiogenic gene product (VEGF). Super. At the end of the study we find a reference also to other cancers, including head and neck cancers, hepatocellular carcinoma, lymphomas, and leukemia. They, too, also have constitutively active STAT3. The suppression of constitutively active STAT3 in multiple myeloma cells raises the possibility that this novel STAT3 inhibitor might also inhibit constitutively activated STAT3 in other types of cancer cells.

This is excellent news. Stefano and I grow quite a variety of herbs in our garden, including at least four or five different types of thyme and two of rosemary. We even have an oregano plant. Herbs add taste to any dish, as we know…but using herbs in our cooking goes way beyond taste enhancement, now that we have discovered that ursolic acid inhibits a crucial myeloma survival pathway, inhibits the proliferation of myeloma cells AND induces apoptosis in the same…why, I believe it’s time for a little dance of joy…! And before it gets dark, I really must go outside to gather some rosemary for dinner tonight. 🙂 Ciao!

Lunching With Baicalein

December 3, 2007 / / 13 Comments

Hah, and you thought that perhaps I was DONE with baicalein, eh? Nope. Not by a long shot. I still have a few baicalein studies to read…Besides, at lunchtime TODAY I will start taking Scutellaria baicalensis, which contains a high percentage of baicalein and also a bit of wogonin. I will also start taking Zyflamend, which is a blend of various herbal extracts (see my page on Polyherbal Zyflamend). Of course, I will keep taking my curcumin-quercetin-cocoa mass-honey mixture at night, since I didn’t give it enough time to work before having blood tests done a couple of weeks ago (I should have my results by next week, by the way). We shall see what happens. Of course, my next set of tests may be influenced by the flu vaccine (which apparently can increase IgG levels for up to six months after administration!), so they may need a bit of interpretation.

Thanks to a friend (thanks you! 😉 ), I got my hands on a very interesting study that I looked at more carefully this morning, even though I really SHOULD BE preparing my English classes for tomorrow, sigh. Published in the November 2007 issue of Clinical and Molecular Allergy, the study is titled: Baicalein inhibits IL-1b- and TNF-a-induced inflammatory cytokine production from human mast cells via regulation of the NF-kB pathway. Let’s quickly examine the title. IL-1beta is an inflammatory cytokine that is a potent inducer of the important myeloma growth factor, IL-6. (see these two Mayo Clinic study abstracts from 2006 and 2007, respectively: http://tinyurl.com/2hu4am and http://tinyurl.com/27ffa4). Anything that induces IL-6 is no friend of mine! I am almost certain that I have already written about TNF-alpha, or tumour necrosis factor-alpha, but just in case I haven’t, here goes: it is a growth and SURVIVAL factor for myeloma cells, albeit not as powerful as IL-6. So, also not good news for us.

A few remarks on human mast cells. As the abstract (see: http://tinyurl.com/24f2ge) informs us, these are multifunctional cells capable of a wide variety of inflammatory responses. According to the full study, these cells accumulate wherever there is an inflammatory process going on and even mediate the production of inflammatory cytokines. Now, that’s really no good, no good at all, especially since Inflammatory cytokines are important factors in chronic inflammation, allergy, asthma, atherogenesis, and autoimmune diseases. Reading on, we are told that mast cells have been implicated in acute and chronic inflammatory responses and in many diseases characterized by inflammation. Oh, and read this: activated mast cells secrete IL-6! Tsk, tsk. Bad BAD mast cells!

Another interesting bit: The activation of NF-kB requires phosphorylation and proteolytic degradation of the inhibitory protein IkBa. This sentence takes us back to the discussion section of the 2005 Blood study on baicalein and myeloma (full text: http://tinyurl.com/2jnlej). I quote: NF-kB regulates the expression of many genes (IkB-a, Bcl-xL, IL-6, and cyclin D1) important for the proliferation and survival of myeloma cells.

Well, on page 16, the November 2007 study states: The results suggest BAI inhibits the NF-kB activation via inhibition of IkBa phosphorylation and degradation. BAI, by the way, stands for baicalein.

Hmmm, how about THAT? So, is it lunchtime yet? 😉

Margaret's Corner

Month: December 2007