The myeloma tap: part II

January 18, 2008 / / 4 Comments

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 12^th 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:

clonogenic myeloma stem cells do not express the characteristic CD138 antigen.
myeloma stem cells constitute less than 2% of the myeloma "population."
myeloma stem cells look like memory B cells.
myeloma stem cells display normal stem cell characteristics that protect them "from toxic injury."
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."
conventional chemotherapy doesn’t affect myeloma stem cells.

My blog finally makes its debut…inside a castle!

January 17, 2008 / / 5 Comments

This morning, due to an unexpected meeting, I had no time to reread the second part of yesterday’s post, which I won’t be posting until tomorrow or the next day. I would like instead to post about this morning’s meeting.

Background: almost exactly a month ago, I was asked by an Italian urologist (and blog reader), Dr. Roberto Benelli, to talk briefly about my experience with curcumin and my blog at the upcoming official presentation of his new book on curcumin and prostate cancer. I hesitated back then, because of fear of speaking in public. But after meeting with Dr. Benelli and one of the book presentation sponsors earlier today, I accepted. My little speech won’t last long, just ten minutes or so (that was one big thing that convinced me!).

This book presentation is actually going to be a sort of mini-conference, with brief presentations given mainly by local urologists, but also by a well-known oncologist from Florence and two molecular scientists. These scientists, one from Genoa, the other from Munich, will be talking about their work on breast cancer and curcumin. Anyway, the principal aim of this meeting is to present curcumin and suggest how it could be used in a medical setting. Dr. Benelli will present his new book, of course, and also give a separate presentation on the history of curcumin, its use in traditional Ayurvedic medicine and its potential applications in oncology today. I will definitely invite my GP and my haematologist.

It’s an open meeting, by the way. Here are the details, therefore, mainly for those blog readers who live in Tuscany: the meeting will be held in the castle of Calenzano (yes, a real castle! I am beginning to feel like a debutante !), on March 8, 2008, at 10 a.m. To be more precise, it will be held in the Auditorium del Castello di Calenzano, Calenzano Alto (Firenze). The title of the meeting is “Modulazione del fattore NF-kB e prospettive terapeutiche.” My friend Sherlock will attend the meeting and plans to tape it in mp3, which I will try to post on my blog, at least some parts of it. If possible! Of course, the meeting will be in Italian, so hey, why put off studying this beautiful language? Sign up for some Italian classes today!

Seriously, though, this should be very very interesting. If you are able to attend, please make sure you introduce yourself to me. I’d be happy to meet any blog readers! Ci vediamo l’8 marzo, spero!

The myeloma tap: part I

January 16, 2008 / / 1 Comment

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.

Guided imagery, celiac disease, wine and tooth decay

January 10, 2008 / / 2 Comments

Intriguing title, eh? I don’t have time to write a proper post today, although I am working on a couple of different, rather complicated (!) items, but I did want to post about a recent Mayo Clinic report on the benefits of guided imagery. You can read about it here: http://tinyurl.com/ythf5x An excerpt, which is practically the whole thing!: “Aristotle and Hippocrates believed in the power of images in the brain to enliven the heart and body. Today, research shows they were right. Guided imagery is helping patients use the full range of the body’s healing capacity […]. Guided imagery is more than listening to relaxing sounds. It’s a learning process to listen to someone’s voice, relax the breathing and consciously direct the ability to imagine. The effect of guided vivid imagery sends a message to the emotional control center of the brain. From there, the message is passed along to the body’s endocrine, immune and autonomic nervous systems. These systems influence a wide range of bodily functions, including heart and breathing rates and blood pressure.”

Guided imagery apparently can reduce side effects from conventional cancer treatments, reduce fear and anxiety before surgery and help manage stress and headaches. I have never heard of this technique. Has anyone tried it?

Celiac disease sufferers, have a look at this: http://tinyurl.com/ysrtex An excerpt: “Researchers have discovered a new structure for a key enzyme associated with celiac disease, a finding that could lead to the design of new medications for the common digestive disorder.” Hah!

And finally, wine-drinkers will certainly be interested in this Science Daily report: http://tinyurl.com/yqfn6s Basically, specific polyphenols found in the waste products from winemaking (fermented seeds and skins, which normally get tossed) may prevent tooth decay and, even more importantly, lessen “the ability of bacteria to cause life-threatening, systemic infections”? Hmmm. How about that?

MD Anderson Curcumin Myeloma Clinical Trial Results: Preliminary Comments

January 9, 2008 / / 6 Comments

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.

Blood Tests and A Good Story

January 8, 2008 / / 7 Comments

Sherlock and I had our blood tests done today up at the main hospital in Florence, as usual. My cocoa mass/curcumin powder, Scutellaria baicalensis and Zyflamend experiment has officially ended. Funny thing is, I just realized that I am going to miss my powder concoction at the end of the day! Oh well. I get these test results back on January 31^st, which is rather late, but that’s because I also got tested for celiac disease, a test that requires special consideration.

Today the BioCurcumax experiment officially begins. BioCurcumax is, allegedly, a more bioavailable form of curcumin manufactured by an Indian company called Arjuna (you can read a bit more about it on my Bioavailability page). It’s basically curcumin mixed with essential oil of turmeric (curcumin mixed with a fat). We shall see!

Anyway, this morning, in between dodging the coughs and sneezes of others while waiting to have our blood drawn, Sherlock and I discussed exactly HOW we would conduct this experiment. We decided the following: I will take it in two doses of 4 grams each, whereas she will take it in one big gulp. We decided it would be interesting to take it in different ways rather than the exact same way, which was our other option. We will continue to take quercetin, but I will switch to the capsule form.

Today we start with 4 grams of BioCurcumax. Tomorrow, 6 grams. On Thursday we will go up to the full 8-gram dose, which we will take until early March, then we will have blood tests repeated.

So, as things stand today, this will be my protocol for the next couple of months:

Quercetin capsules with bromelain: 1.5 grams, 10 minutes before taking curcumin.

BioCurcumax capsules: 8 grams, divided into two doses, on a empty stomach.

Vitamin D drops, cholecalciferol, oil-based preparation: 2500 IU per week.

Freshly ground flaxseeds added to my food.

A multivitamin on occasion, with mostly B vitamins.

As time goes on, I may make a few minor changes. If that happens, I will post about it here. The main difference between my intake and Sherlock’s is, as I mentioned, that she will take the daily dose all at once. She will also continue to take vitamin C, which I do not take except as part of an occasional multivitamin. That’s it, for now.

A good story. Beth told me about one her blog readers, Earl, who is treating his precancerous prostate condition with…well, go see for yourselves: http://tinyurl.com/3dfc8g My hat’s off to you, Earl!

Margaret's Corner

Month: January 2008