Beth  posted (see: http://tinyurl.com/5bg9wh) about a July 31^st Science Daily article that I hadn’t read yet …Science Daily newsletters tend to pile up in my e-mail box, and I read them only when I have a snippet of extra time, which does not happen very frequently (especially of late!). Anyway, this particular article talks about the recent discovery of two processes that lead to the development of myeloma and other types of B cell malignancies. Fascinating stuff…I hope to be able to read the full study this fall. In the meantime, here are a few excerpts from the SD article (you can read the full text here: http://tinyurl.com/66kp3u).

 

Background: “We already know that the over-expression or mutation of molecules known as NIK and TRAF3 in B cells is associated with human multiple myeloma,” said Professor Mackay. “Our collaborative research uncovered two distinct processes involving these molecules that help explain why.”

 

Now, I had read about TRAF (=”TNF receptor associated factor”), but this is the first time, I think!, that I have seen any mention of this NIK thingie (NIK stands for “NF-kappaB inducing kinase,” by the way). Just goes to show how much there is to learn…!

 

Anyway, this is what happens: The first process involves NIK, an enzyme that acts closely with BAFF, the substance that regulates the number of B cells in our bodies. If we have too much of this enzyme, NIK, in our body, then we may develop a B cell malignancy. Lovely.

 

The second process, associated with the first, involves TRAF3, the molecule that negatively regulates NIK. Professor Mackay explained that in a healthy person, NIK and TRAF3 work together, helping to maintain the right number of B cells for survival. “But when there are mutations in either molecule, they become uncoupled. In other words, TRAF 3 no longer represses the action of NIK when necessary.”

 

So, under normal circumstances, the two molecules work together. But, at a certain point in time, one of them may go bonkers for some unknown reason and escape the other’s control. And this unfortunate event could lead to the development of a B cell malignancy. I am left with the question “why does this happen?” that may find an answer in the full study.

 

This discovery won’t mean much for us patients right now. But in the future perhaps we will be able to be tested for these mutations and take what the article defines as targeted medications. That would be good, so long as said medications are natural and non-toxic.

 

Speaking of non-toxic, and just for the fun of it, I just googled curcumin and NIK. Well, well. I came across something of interest that I hope to look into more carefully in the next few days: curcumin inhibits the deranged NIK oncogene…see http://tinyurl.com/6exze6 and http://tinyurl.com/64vxsl. How about that?

Oh, coincidentally, I see it’s time for me to take my daily dose of the phenomenal yellow powder! Off I go!

Now, I have heard of cats eating all sorts of odd things, from spaghetti to lettuce, the non-bitter kind. But this one is a first.

 

My second youngest cat, Priscilla, goes absolutely bonkers whenever I bring in some freshly picked arugula from our back yard. The bitterer, the better. She will sit at my feet and beg like a dog until I hand her a leaf or two, which she devours.

 

Odd, huh?

Very early this morning Sherlock and I met at the Careggi hospital where we had our blood tests done, the first tests we have had since April. I told her a couple of dumb jokes, so we had a good giggle before it was our turn. The entire process was incredibly fast, very few people in line before us (Italy is on holiday!), so we were at the hospital café having breakfast by 8 a.m. Marvellous! Thrilled at having finished so early, we looked at each other and exclaimed “from now on we will have our summer blood tests done on July 31^st!” Anyway, my test results will be ready in early September, hers in late August (I had more specific tests done, such as vitamin B12, and it takes longer to get those results).

 

Let’s see. Stefano and I are leaving for our summer holiday in about ten days, so I am busily planning our itinerary. We are driving to Bourgogne (Burgundy), France, where we will spend a couple of weeks. To break up the long (=nine hours) drive from Florence to Saulieu, we are going to stop in Mont Avic, the first natural park of the Valle d’Aosta (=Italy’s smallest region, by the way), where we will be able to enjoy a stunning mixture of mountains, lakes, forests, lakes and valleys (see for instance: http://tinyurl.com/5owxfe). We will spend a few days there, hiking and taking photos. It should be lovely. Ah, and cool!

 

This morning at the hospital Sherlock presented me with two sets of telescopic trekking poles that should help Stefano and me walk up, and down!, any steep mountain trails. That was so thoughtful of her. What a super friend! Grazie, fantastica Sherlock!!!

 

From Mont Avic we will then drive to Burgundy. We have rented a small cottage (=gîte) near the Morvan Regional Park (see: http://tinyurl.com/6kd5a4) and about an hour’s drive from the lovely city of Dijon (here is a Washington Post 2006 article titled “A little Dijon on the side”: http://tinyurl.com/zvuj5). Regrettably, there are no puffins in the Morvan Park, but we hope to see heaps of other birds and animals.

 

Anyway, there is a lot to see and do and eat in Burgundy, and it should also be cooler there than it is here, although I checked today’s temperature in Saulieu and almost fainted when I saw it was about the same as boiling Florence (yikes!)! 

Well, I am not in the proper holiday mode yet…I have classes to prepare for tomorrow and confess to feeling a bit worn-out after having all that blood drawn from my arm this morning…so this is it for today. Take care, everyone!

Teacher: “Nick, what is the past participle of the verb to ring?”

Nick: “What do you think it is?”

Teacher: “I don’t think, I KNOW!”

Nick: “I don’t think I know, either!”

 

Teacher: Tell me a sentence that starts with an “I”.

Student: I is the…

Teacher: Stop! Never put ‘is’ after an “I”. Always put ‘am’ after an “I”.

Student: OK. I am the ninth letter of the alphabet.

 

Two cows are standing in a field.

One says to the other “Are you worried about Mad Cow Disease?”

The other one says “No, it doesn’t worry me in the least, I’m a horse…”

 

Last but not least, try this one on your friends and family (I got a few guffaws out of this one..both my parents fell for it…hehe):

 

“Spell SPOT three times.”

“S P O T , S P O T , S P O T”

“What do you do when you come to a green light?”

(answer is invariably=) “Stop!”

“What, at a GREEN light?”

 

Stefano and I got back yesterday evening from a very pleasant long weekend spent in the Apennine mountains, near the Corno alle Scale, where my in-laws have a house.

 

Even though I had fun and played lots of card games this weekend, I didn’t sleep too well. In recent years, I have discovered that I have vivid nightmares if I have dinner after 9 p.m. And since southern Italians (Stefano was born in Florence, but his family is from a town near Naples) tend to eat rather late in the evening, we never finished dinner before 10 or even 10:30 p.m. this weekend. And, as expected, I had nightmares. Normally, I wouldn’t mind too much. But this time…

 

On Friday night I had a particularly bad nightmare that startled me awake. In my dream, I was having some sort of heated discussion with someone (I don’t remember a lot of details, but I was not arguing with Stefano) when all of a sudden I burst into tears and began shrieking, in Italian: “What do I care about that? That’s not important! Don’t you understand that myeloma is killing me??? Myeloma is killing me!!!” Il mieloma mi sta uccidendo!!! I remember those words very clearly.

 

That sentence and my desperate dream sobs still echo in my mind. So much so that I decided to write about it today. I have reached the conclusion that a part of me is really scared. It’s a deep down, hidden part that has already surfaced on a few occasions…so I knew of its existence. But now, for the first time, I have begun to acknowledge that I may be split into two selves: the cheerful, confident, optimistic me & the frightened, anxious, “what if…!” me. Luckily, the former is dominant. Very much so!

 

I am strong, I am positive, I am determined. But, it would seem, on some level I am also frightened of what may lie ahead.

 

I guess I’m human, after all…

A few days ago Prof. Aggarwal’s senior administrative assistant sent me a message with an unexpected and very welcome attachment: the full report (yippee!) on the pancreatic cancer-curcumin clinical trial that has been taking place at MD Anderson in Texas. The report was published in the July 15 issue of “Clinical Cancer Research” (see abstract: http://tinyurl.com/6fjk59).

 

This was a Phase II study to determine whether oral curcumin has biological activity in patients with pancreatic cancer. Let’s skip all the introductory parts describing pancreatic cancer and then curcumin and go have a look at the “Results.”

 

The average age of the 25 patients enrolled in the study was 65. No treatment-related toxic effects were observed. To date, one patient remains stable for >18 months and another patient had a dramatic but brief tumor response. The former patient had previously undergone a failed Whipple’s surgery followed by gemcitabine and radiation for locally advanced disease. Curcumin decreased this particular patient’s CA125 level (CA125 is the abbreviation for Cancer Antigen 125, which is elevated in many types of cancer, but apparently and surprisingly not that common in myeloma), the size of his lesions remained stable, and indeed there has been a decrease in the standardized uptake value in those lesions from a baseline level of 10.6 to a level of 5.7 after 12 months of therapy.

 

The report continues: One patient had a brief but marked response (73% reduction in tumor size by Response Evaluation Criteria in Solid Tumors) that lasted 1 month […]. Interestingly, at the time of progression, the lesions that had regressed remained small, but other lesions grew larger. This patient also had a rapid and dramatic increase in cytokine levels (IL-6, IL-8, IL-1RA, and IL-10). When I read this last sentence, I confess to having felt slightly alarmed…Then I read the following: Conceivably, this occurred because of release of cytokines from the tumor associated with shrinkage. Oh, phew! Relief!

  

The discussion regarding this particular patient continues later on: Also, of potential importance in this patient is the observation that the tumors that originally regressed continued to show regression during the follow-up period on curcumin, whereas the tumors that grew were the ones that had been small originally. This observation suggests that there was a malignant clone responsive to curcumin, whereas another resistant clone emerged.

 

In contrast, the patient who has appeared to have benefited most from treatment with curcumin (patient 14) has had slow improvement over 1 year and a gradual decrease in cytokine levels […]. Of interest, patient 14 had the highest baseline levels of IL-1RA of any of the study patients. IL-1RA stands for “Interleukin 1 receptor antagonist” and is the natural antagonist of the pro-inflammatory cytokines interleukin-1alpha and interleukin-1beta (from Wikipedia).

  

Okay, in sum, this means that two patients appeared to have biological activity of curcumin after treatment. That sounds even less encouraging than the myeloma-curcumin study at first glance…BUT, after treatment with curcumin, a decline in NF-kB, STAT3 and COX-2 was observed, and that is important, methinks.

 

I was particularly interested in the test results of the patients taking 8 grams of curcumin/day: Although we found little, if any, free or unconjugated curcumin in these patients’ plasma, we easily detected levels of curcumin following digestion of plasma with combined glucuronidase and sulfatase enzymes. This is consistent with data suggesting that curcumin is present in plasma in conjugated (glucuronide and sulfate) forms. […] Plasma levels of drug released from conjugated derivatives of curcumin on day 1 of dosing decreased on average to 22 to 41 ng/mL from 2 to 6 h after the first dose of curcumin […]. This simply means that the curcumin that enters our body is transformed into conjugate forms, whose levels continue to decrease as time passes.

 

There is a lot of detail in this 9-page study. I couldn’t possibly summarize it or quote it all. But I think many of us are chiefly interested in the issue of bioavailability, which is dealt with on pages 7-8: only low levels of curcumin are detectable in plasma (steady-state level at day 3 is ~22-41 ng/mL). Nevertheless, some of the patients had biological activity of curcumin as evidenced by the antitumor effects noted above in two patients and by effects on cytokine levels and on NF-kB, COX-2, and pSTAT3 […]. Conceivably, the limited bioavailability of curcumin attenuated the response rate, because exposure to microgram amounts of curcumin is required to show antiproliferative effects in vitro. It is also possible that circulating curcumin levels do not reflect tumor tissue curcumin levels.

 

Ah, now this is what I have suspected (or hoped!) for quite some time: curcumin may be barely detectable in the bloodstream, but that doesn’t mean that it isn’t working on some different level…This thought seems to be confirmed by the following: It has been suggested previously that systemic levels of drug may not reflect drug levels actually present in tissues of interest. Although at least one study has examined curcumin levels in colon tissue of mice after oral administration, few, if any, studies have analyzed curcumin or curcumin metabolites in malignant human tissues. This is important: few, if any, studies have analyzed curcumin or curcumin metabolites in malignant human tissues.

 

The study continues with an unwelcome bit of news: However, the researchers add that even though the levels of NF-kB and COX-2 were decreased by curcumin, this did not translate into a clinical response. Bummer…

 

Conclusion: as we know, oral curcumin is well tolerated at doses for of 8 grams for up to 18 months (in my case, much longer than that!). And, even though our body doesn’t absorb it very well, biological activity is evident. This is an important statement.

 

The problem as far as pancreatic cancer is concerned is that higher levels of exposure need to be achieved. Curcumin is hydrophobic and therefore cannot be given i.v. However, because it is lypophilic, it can be encapsulated in a liposome, and such a preparation would allow i.v. administration, leading presumably to higher circulating levels of curcumin. Lipophilic…meaning that it dissolves in fats and oils. Okay, we already knew that, but read the following:

 

The researchers suggest that liposomal curcumin or other better formulations of curcumin may provide more consistent blood levels with better pharmacologic effect. And, (drum roll) they are developing liposomal curcumin for clinical trials.

 

Well, until liposomal curcumin is available, I will probably go back to my kitchen this fall and try to come up with another palatable fat-based concoction containing curcumin C3 Complex powder.

 

Blog-related “business”: I appreciate all the comments I have received recently. Thank you! I have been super busy these past few days, working hard and whatnot, and that is the reason why I haven’t gotten in touch with everyone privately, as I try to do (when I have more time). Sorry!

 

Personal note: I wrote this post in a bit of a hurry because Stefano and I are getting ready to leave for a brief holiday in the Apennine mountains. We will be back in Florence on Sunday. Have a great weekend, everyone!

A July 14 Science Daily article (see: http://tinyurl.com/5dy7xo) tells us that honokiol, extracted from the magnolia tree and used in Eastern traditional medicine for a variety of ailments, has recently (?) been found to target tumors with activated Ras. And Ras refers to a family of genes whose mutation stimulates the growth of several types of cancers. Although the Ras family is mutated in around a third of human cancers, medicinal chemists have considered it an intractable target.

 

Is Ras active in myeloma, too? I will give you one guess. Then you can go read this 2004 abstract: http://tinyurl.com/5sz6z7. Or this 2006 “Blood” study where we find that Oncogenic RAS expression occurs in up to 40% of multiple myeloma (MM) cases and correlates with aggressive disease: http://tinyurl.com/6otz4y. I rest my case.

 

Toward the end of the Science Daily article we read that Emory University is in the process of licensing honokiol and related compounds so that they can be tested in people in cooperation with industry partners. Let’s hope that this will happen soon. In the meantime, I am going to enjoy the view of my magnolia tree from my study window…