A MGUS and SMM patient study on the possible impact of meditation in myeloma progression

A recent Patient Power video caught my attention a few days ago, but I was caught up in my andrographolide research, so I ignored it until today. It’s titled “Can smoldering myeloma progress to full-blown myeloma?” The obvious answer is yes, it can, of course. We know that.

Here’s the link to the video, which has other interesting things, too: goo.gl/e3ksk1

At one point, Dr. Raje talks about a Harvard project, called the , during which MGUS and SMM patients used meditation and mindfulness to try to stop progressing to full-blown myeloma. The study’s main purpose is to look at the genomic profile of these patients to ascertain if meditation could actually change the genetics of myeloma progression. Isn’t that something?

Dr. Raje adds, don’t worry too much about your disease…makes common sense. And perhaps, with the data they are collecting from patients right now, we will soon have actual proof that stress can have an impact on our progression genes….Wowsie.

We know that stress plays a big role in myeloma. We’ve known that for quite a long time (remember the 2008 Ohio State study on myeloma progression and norepinephrine, = one of the stress hormones? Exactly…). Certainly at times it isn’t easy to reduce stress levels, and I myself am not always successful (life complications, you know!). But I try! And meditation really does help…It helps even to just close your eyes for a few minutes and visualize a beautiful country or place you’ve visited, an event that made you happy, whatever.

You don’t necessarily have to follow a course to learn how to meditate (I never have)…although you could, of course! I’ve found my own meditation method, mainly based on watching online videos, and it works well for me. Anyway…

But this is the first time I’ve heard a conventional myeloma doctor mention MEDITATION as a possible way of avoiding progression. And I didn’t know about this project…Something to keep an eye on, for sure…

Dr. Raje  added that their results would be presented at ASH later this year. So we have a while to wait. However, I did find this abstract, published in the Journal of Clinical Oncology in May of last year: goo.gl/68nYeq

This link informs us that the experiment has been going on for a while now, and that this meditation program REDUCED STRESS, indeed DISTRESS, “in participants with intermediate or high-risk MGUS and SMM…”

Boy, I’d love to participate in something like that. A slight, er, obstacle is that I live across the pond…! Oh well!!! I’d also love to hear from someone who might be in the program…

Time for dinner…Have to rush off…Take care, everyone! 🙂

“The bone-marrow niche in MDS and MGUS: implications for AML and MM.” Part 2.

Back to the Dana-Farber study that I wrote about a couple of days ago.

The section titled “Therapeutic opportunities” is interesting. How to prevent progression, that is. As you can imagine, the chef’s daily special consists only of conventional treatments. For example, the authors make a reference to the Spanish study (Mateos et al) that I have repeatedly condemned here on the blog. The Spanish researchers–some with strong ties to the big pharmaceutical companies (hello???)–tested lenalidomide and dexamethasone on a group of SMM patients. The study claims to have prolonged progression-free survival and even overall survival in those patients…without ever taking into consideration QUALITY OF LIFE. Sorry, but I have no patience for statistical studies that play with people’s lives…

That said, the trend toward early intervention is clearly taking off, as the Dana-Farber study points out. Very unfortunate, IMO.

And there is no way to stop it, except that we, the patients, can say just say NO. Of course, if you have CRAB symptoms, that’s another matter. But, in the absence of the CRABs, WHY TAKE THE CHANCE OF WORSENING YOUR QUALITY OF LIFE?

Makes zero sense.

And there’s another thing that bothers me: where’s the proof that the overall survival of someone with SMM was extended thanks to these conventional treatments? Do the Spanish researchers have crystal balls that give them the exact times of death for their patients, both with AND without treatment? Oh, right, no, that’s what their STATISTICS tell them. Based on the patients’ “high-risk” data (see yesterday’s post).

I’m not saying that statistics can’t be useful in certain circumstances, mind you. But in these cases, when someone with no CRABs is deciding on whether to agree to early treatment, or not!, they can be harmful. If I had agreed to begin conventional treatments in 2005, I don’t know where I would be today (according to my former hematologist, I’d be dead…would have died in 2010…didn’t happen, OBVIOUSLY!!!…I’m still here, still splendid 😉 , still no CRABs, still no conventional treatments…).

Sorry for the rant. Okay, let’s calm down and try to understand the rationale of early intervention from the Dana-Farber study perspective. The researchers say that if the number of osteoblasts (bone-forming cells) can be increased in the early stages of myeloma, myeloma cells cannot proliferate. That’s good to know. There are non-toxic ways to do that, btw, but let’s keep to the study…

Mice that were injected with nanoparticles loaded with bortezomib before being contaminated with MM cells lived longer than non-injected mice. The researchers give another example in which early treatment of an antiangiogenic antibody was used on mice. Okay, but we’re talking about mouse models here. The reality, as the researchers themselves admit at the end of this paragraph, is that “…the use of antiangiogenic agents other than thalidomide and other immunomodulatory agents has not been shown to be successful in patients with MM.”

Not successful in patients.

So much for that.

Then there’s immunotherapy, which we have heard and read a lot about in the last few years. You may have heard about the anti-CD38 antibody known as daratumumab, which activates the immune system.

Anyway, it’s in this paragraph that I found a remarkable admission.

But first, let me say that ever since I joined online myeloma support groups, one of the key issues we discussed was what how to deal with our immune system. Should we stimulate it, thereby possibly stimulating our myeloma cells, too? Or should we avoid anything that stimulates the immune system? The consensus usually drifted toward the former approach. I wrote a post about this in 2013: http://margaret.healthblogs.org/2013/10/20/long-term-survival-in-myeloma-is-finally-linked-to-a-robust-immune-system-and-my-new-discovery/

I’ve had mixed feelings about it throughout the years, but my gut has always told me that it makes no sense to keep our immune system weak.

And here, in this paragraph, I finally have my answer (vindication!!!): “Indeed, trials involving these antibodies provide the first proof of concept that activation of the immune system has therapeutic benefits in patients with MM.”

After years of not knowing what to do, we finally know that having a strong immune system is GOOD.

Quelle surprise…not.

“The bone-marrow niche in MDS and MGUS: implications for AML and MM.”

Remember the post I wrote back in December 2014 about myeloma subpopulations and the bone marrow microenvironment? Probably not…so here’s the link: http://margaret.healthblogs.org/good-or-bad-for-myeloma/first-do-no-harm-myeloma-subpopulations/

The main point is that not much is known about the interactions between the myeloma subpopulations living in our bone marrow, how they compete for survival and so on…

Therefore, the only conclusion, in my opinion, is that going in with conventional bombs and blasting the heck out of this microenvironment doesn’t seem to be the best strategy for those of us with MGUS and SMM…certainly not until we know a LOT more about what goes on inside this complex and, I would add, delicate setting.

Luckily, there have been more studies on this topic since my 2014 post, including this recent Dana Farber one, titled “The bone-marrow niche in MDS and MGUS: implications for AML and MM.” A blog reader sent me the link (thanks!): goo.gl/Ew3K4A

The full study isn’t available for free online, but I was able to read it thanks to a good friend. Okay, let’s have a look at it…

We know that MM is preceded by MGUS and by an intermediate stage called SMM.

Progression, that is, the “clonal evolution” of myeloma, takes place between MGUS and MM. But, the researchers add, some of the characteristics of myeloma can be found, “at lower frequencies,” at the MGUS and SMM stages. For example, the gene deletions.

Therefore, they say, it is the development of neoplastic “subclones” in the earlier stages that probably leads to the progression to myeloma.

This development wouldn’t be able to take place without the help of the bone marrow microenvironment, which therefore must be targeted in order to prevent progression as well as increase the effectiveness of conventional treatments once the stage of MM has been reached.

As I was reading this study, full of technical jargon that I could barely grasp, I began imagining the bone marrow microenvironment as a marketplace where strong nasty myeloma hooligans live and operate in coexistence with other, not-so-harmful, silly myeloma characters, as well as a bunch of normal folks, our normal cells.

Problem: myeloma clones have the ability of turning the marketplace into a toxic environment that helps them grow and proliferate.

A lot depends on how the marketplace reacts to these attempted changes. If it is weak and yields to the MM hooligans, it will become full of “weeds.” If it resists, it will be full (well, perhaps not entirely!) of crowds of happy customers, what the researchers call a “physiologically useful crop of mature blood cells,” that is, normal blood cells.

Now, a NORMAL marketplace contains all sorts of custome…I mean, all sorts of cells, including osteoclasts, macrophages, endothelial cells and, don’t you love this one?, sympathetic neurons. Lots of different cells that live happily ever after in this lovely area of the body.

Too many details here…okay, we don’t need to know this stuff…skip skip skip.

Certain cells (the above-mentioned stromal cells, e.g., after they have gone over to the dark side) become responsible for helping myeloma develop. Furthermore, whenever myeloma cells initiate a disruption, things that should be sleeping (in technical terms: in a quiescent state) wake up (remember EBV?). Not good.

Disruptions also cause tumor suppressor genes, such as Rb1, to be…suppressed. Also not good!

The end result of all the disrupting and suppressing, without any reaction from the immune system, is that the BM microenvironment becomes myeloma-friendly, and MM stem cells can begin proliferating, helped along by processes such as angiogenesis (remember all my posts on VEGF?).

As you can imagine, the study doesn’t mention anything remotely non-conventional. But some of its findings are interesting, so let’s keep reading.

Ah, another thing occurs: immunosuppressive cells arrive in the marketplace and make such a ruckus that T cells and B cells are completely overwhelmed and can’t function properly. This means, of course, that myeloma cells are no longer being sought and destroyed by our immune system.

The study therefore gives us a lesson in progression. First and foremost, as we’ve just seen, myeloma cells learn how to avoid being annihilated by the immune system. They then create what the researchers call an “immunosuppressive environment” where the immune system defenders are no longer able to function normally. Other types of important cells present in this now-toxic environment are also affected, such as stromal cells.

When MGUS progresses to SMM and then MM, immunosuppression is one of the main culprits. In fact, I recently read a study that discussed this problem, concluding that patients with SMM whose other immunoglobulins—in my case, e.g., IgA and IgM—are suppressed are more at risk of developing myeloma. *

The questions are: can we stop this process? How? And…when?

In 2014 (and before), my opinion was to “watch and wait” for as long as possible. Until CRAB symptoms appear. My opinion hasn’t changed in all these years. Indeed, it hasn’t changed today.

“Watch and wait” doesn’t mean sitting around and moping and doing nothing but watch TV series all day long. It means being proactive, doing research, enjoying life, taking something that doesn’t have any toxic side effects and that has been shown at least in vitro to be anti-myeloma, such as curcumin. And so on. There’s lots of stuff we can do in this stage…

Okay, I think this is enough for one day. After almost falling asleepzzz myself, I decided to divide this post into three parts…or perhaps only two.

So…more on this topic tomorrow! Ciao!

P.S. The study also discusses the evolution from MDS to AML, but I didn’t really look at that part, of course, since it’s not my main focus…

* P.P.S.S. While it’s true that my IgA and IgM are suppressed (barely “alive,” in fact!), it’s also true that they’ve been pretty much at the same tiny level for years now. So yes, I am in the high risk category BUT I am still here, leading a normal life, no CRAB symptoms…

Living proof that being at “high risk” doesn’t have to be as scary as it sounds…right?  🙂 

“Long-term follow-up of curcumin treated MGUS/SMM patients – an updated single centre experience”

In an email I received yesterday, Dr. Terry Golombick notified me that her team’s most recent article has been  published in the Journal of Hematology and Medical Oncology. It is available for free online…just click here: goo.gl/cEP93h

keep calm and turmeric onAhhhh. Wonderful…absolutely wonderful.

Wonderful, because finally…FINALLY (!!!)…we have a long-term look at a GROUP of MGUS and SMM patients taking curcumin. These are those who participated in the Australian MGUS/SMM study and who “continued to take curcumin over a number of years, of their own volition, even though the studies in which they were participating are complete.”

So this is a “long-term follow-up of 13 MGUS/SMM patients who have been taking curcumin (at a dose of 4 -8 grams daily) for a period of 3-9 years.”

Only one patient, who had cardiac amyloidosis (!), went on to full-blown myeloma and is currently undergoing conventional treatments. The rest of the patients are doing quite well, some better than others…anyway, you can read all the details in the report…

I really hope that this report will encourage more and more centers to start giving curcumin to their MGUS and SMM patients and, why not?, to their MM patients as well. At this point, I could go into a tirade about the short-sightedness of conventional medicine, but, at least for now, I’d rather look at the positive side, which is the publication of some CASE STUDIES, like the one concerning my blog reader D., and this Australian one.

I would like to end this post by stating that we all owe a large debt of gratitude to dedicated researchers like Dr. Golombick who have overcome all sorts of obstacles (I’m sure of that!!!) to help patients like us have the best quality of life possible, for as long as possible…

To all the Golombicks of the world: thank you, thank YOU, THANK YOU!!!  🙂 keep calm and watch and wait

By the way, let me remind you that Dr. Golombick and her team have set up a useful website for all of us who have a type of blood cancer. I’ve talked about it here on the blog, but just in case you missed that post, here is the link: https://www.watchandwaitbloodcancers.com/

KEEP CALM AND…

WATCH AND WAIT!!!!!! 

Metabolic changes in the bone marrow could be an important key in the development of myeloma

The fact that multiple myeloma develops from the pre-existing condition known as MGUS is nothing new. I mean, I wrote about this very topic back in 2009 (remember that cancer screening trial that allowed researchers from the Mayo Clinic and the National Cancer Institute to examine blood samples taken from patients several years before they were diagnosed with MM? If not, have a look at the post I wrote back then: “Does MGUS always precede MM?”).

IMG_5327But today I read something that adds a new piece to the puzzle of myeloma–a recent discovery made by a team of researchers at the University of Birmingham: http://goo.gl/vE6PWU

It’s an easy read, but I did want to highlight a few points, such as this one: “Surprisingly, the researchers found that the metabolic activity of the bone marrow of patients with MGUS was significantly different to plasma from healthy volunteers, but there were very few differences at all between the MGUS and myeloma samples.” Ouch. See Priscilla’s expression? That was pretty much how I must have looked after reading that sentence…

Here’s an excerpt providing more details: “The research team found over 200 products of metabolism differed between the healthy volunteers and patients with MGUS or myeloma, compared to just 26 differences between MGUS patients and myeloma patients. The researchers believe that these small changes could drive the key shifts in the bone marrow required to support myeloma growth.”

IMG_5315Things get a bit, er, alarming, though, when Dr. Tennant, the head researcher, says that “very few changes are required for a MGUS patient to progress to myeloma.” VERY FEW changes? I had to let that sink in for a second or two before reading on. And at this point I probably looked like Prezzemolo (photo on the right)…

But then Dr. Tennant adds that a “drug that interferes with these specific initial metabolic changes could make a very effective treatment for myeloma, so this is a very exciting discovery.”

Okay, so first he TOTALLY freaks us out with the news that only a few metabolic changes in the bone marrow are required to jump from MGUS to MM. Then he reassures us that a “metabolic” drug might be able to stop said progression. Bad news followed by potentially good news…

Well, this is the most interesting study I’ve read about in a while…a study that has given my brain some real food to chew on…

Need to do some research now.

Any thoughts, dear readers and friends?

MGUS may be linked “only” to some serious diseases…

I am slowly going through my still unopened Science Daily updates…the August 27 issue (see: http://tinyurl.com/mmg7j5) contained a title that caught my interest: “Common blood disorder may not be linked to as many serious diseases.” The common blood disorder turns out to be MGUS.

In a nutshell, doctors have long been linking MGUS to more diseases than “just” multiple myeloma, amyloidosis and Waldenström macroglobulinemia. To my surprise, I discovered that there is a list of 75 other MGUS-associated diseases out there. 75! This list will almost certainly undergo some changes now…after the publication of the August 2009 Mayo Clinic Proceedings, which contain an interesting patient screening study declaring that the above-mentioned association is likely coincidental, in most cases, at least.

After reading the Science Daily summary, I went to have a look at the study (full study: http://tinyurl.com/lr55lc). Do you know that one of the MGUS-linked diseases is urticaria?! Eeek, just writing that word makes me itch all over!

Well, even though the full study is available online (above link), I thought I would take the time to go over a few points. Let’s see. The researchers confirmed that disorders of the bone, such as hip and vertebral fractures, osteoporosis, and hypercalcemia, are all significantly increased with MGUS, even in the absence of progression to multiple myeloma. We also confirmed known associations of MGUS with chronic inflammatory demyelinating neuropathy […] and autonomic neuropathy.

But they also found no significant association with MGUS in the 61 remaining disease diagnoses, an indication that most of these previously reported associations are either coincidental or clinically insignificant. So, in this patient population, 61 out of 75 diseases cannot be linked to MGUS. Interesting. Incidentally, see Table 2 (http://tinyurl.com/md35fy) for a complete list of diseases…you might be surprised by some of ’em…I was!

Also, have a look at Table 3 (http://tinyurl.com/mdzoqk) for a list of 20 new MGUS-associated diseases, including acute depression (!!!)…

In the Discussion part, we are also told that the frequency of osteoporosis and bone fractures is increased in patients with MGUS, independent of progression to myeloma. Eh.

Further on: The fact that we did not demonstrate a significant disease association with MGUS in such a large sample size is of major importance because it implies that these associations are likely not true associations, but rather coincidental ones. This has important therapeutic implications, because in some settings therapy has been administered to eradicate the monoclonal protein in the hopes that the associated disorder would be alleviated. Our study suggests that caution is needed.

Caution…indeed, I couldn’t agree more!

Blood tests, more on cyclopamine and…Cancer Vixen

Blood tests. Last night I decided that a silly little fever wasn’t going to stop me from taking these tests. So this morning I got up at the crack of dawn, made sure I had no fever (the little coward vanished overnight, hah!), and set off for the hospital, where I met up with Sherlock. We were tested together and were out by 8 a.m. She had work to do so she headed home, while I went to another part of the hospital to have a breath test…ah, no, not what YOU are thinking, no siree! This test will determine if I am infected with Helicobacter pylori. In case you don’t know what I am babbling about, check out my page on Helicobacter pylori and MGUS. In a nutshell: it’s a bacterium that infects the stomach and can cause us a lot of grief, A LOT!, ranging from peptic ulcers to cancer.

A slight aside. Wikipedia provides a fascinating account about how H. pylori was discovered, or rather, rediscovered in the early 1980s more or less, by two Australian scientists, Warren and Marshall, who were the first to successfully culture it. They believed that most stomach ulcers and gastritis were the result of an infection caused by this bacterium and not by stress or spicy foods as had been previously assumed. To prove their point, Marshall drank a Petri dish of H. pylori and developed gastritis. A man after my own heart!  Gutsy! You can read the full story on Wikipedia.

Anyway, this was an interesting test. First, using a plastic straw, I had to blow some air into two vials, enough to steam them up. Then I had to drink something that tasted like very bitter lemonade (urea) and wait for a half hour. I then blew into two different vials. That was it. For details on how the H. pylori breath test works, see http://tinyurl.com/33nvay

I will have all my test results back in about three weeks. Probably a few of my values will be altered due to the cold I have been fighting (successfully, so far!!!), but I am hoping they won’t be TOO off. No worries.

A few words on cyclopamine. Yesterday I wrote to CT, asking the question posed by one of my blog readers (see my recent cyclopamine post) concerning water solubility. CT replied: I took cyclopamine tartarate which Logan labs claims is somewhat water soluble. Mice at UTMS took the regular cyclopamine orally for basal cell CA and it worked, so it must be getting absorbed. I note that is does mix well in water. In any event, my M-marker did go down. I will know more when I retest.

Cancer Vixen. While I was waiting to have my breath re-tested this morning, I began reading a book that Sherlock gave to me (grazie!), titled "Cancer Vixen," by Marisa Acocella Marchetto, a cartoonist for the New Yorker (etc.). At one point I almost laughed out loud. I wonder what the other patients sitting in the waiting room thought of me: a grown woman reading and chuckling over what looks like a…comic book!  (Not that I cared one whit, mind you!). Hehe.

Anyway, since you already know (if you have been reading my blog for a while) that I have a wacky sense of humour, you won’t be surprised to read that the part that thus far has amused me the most, and I am only on page 20!, is when she is told that she has an "abnormality" (referring to a breast tumour). Oh yeah, that’s a bit of really hilarious news, ujú ja ja ja ja ja jaaaaaa…ñaca-ñaca (that’s an "evil laugh" in Spanish, no kidding; you can find the most peculiar items in Wikipedia…), but I assure you that the cartoons are quite amusing, IF you have a warped sense of humour, that is!  

Well, I haven’t read any cartoons since I was in my teens, so this is fun, even though the subject itself (cancer!) isn’t that much…fun, admittedly! Oh, wait, another funny cartoon is the one depicting "possible cancer cells" in a petri dish, "magnified 3 gazillion times." Marisa makes them look like evil little green buggers sticking out their tongues and giving us the…finger. Good job, Marisa, so far. I will keep reading.

Fabulous news!

A MMA and Beating Myeloma list friend sent me a fabulous bit of news yesterday morning via e-mail, as follows:

I was diagnosed with MGUS. Feb.06, m-spike 0.03, went up to 0.07, and then I took control, took all your advice and listened to my body. I worked my way to 5 grams of curcumin among other things. Reduced stress, soaked in 104 degree water twice a day. Last test before Dr’s appointment: 0.02. The day of appointment I had another test, just got it back: "NO monoclonal protein detected by the current electrophoresis study.

HURRAY!!! 

I asked her for permission to post her story here. She very kindly (thank you!) consented, also providing me with the details of her protocol.

She takes the following: Andrew Weil’s Daily Multivitamin, Daily Antioxidant, Immune System Builders that include ashwaganda, cordyceps, astragalus, Siberian ginseng – the quantities are prepackaged in an AM and PM dose.

She also takes: Life Extension Super Curcumin with Bioperine 800 mg, 3 pills in the morning and 3 in the afternoon. Lysine: 1000 mg, 1/day. Resvera Wine Complex 500 mg, which contains: grapeseed extract, ellagic acid, & resveratrol, 1/day. Guggul Plex 340 mg, 1/day. Zyflamend softgels by New Chapter, 1/day. Yaeyama Chlorella 400 mg., by Yarrow Formulas, 1/day.

She writes: I am anemic if I am not careful and I take Slow FE- 47.5 mg. slow release iron- doesn’t upset my stomach.

Every morning and afternoon, she soaks in a 104 degree hot tub for 35 to 45 minutes and, she adds, there I do nothing but soak- it was hard to learn.

She adds: “I eat lots of veggies, some fruit and meat 2 or 3 times weekly (salmon, or whatever I’m craving, meatloaf last week, buy organic whenever I can). If I crave an old evil food, I eat it- it’s usually not as satisfying as I remember, and it takes care of the craving, although I recently made a German chocolate cake.

Lots of nuts, focusing on walnuts- make my own chocolate bars by roasting walnuts and pouring Ghirardelli’s chocolate (bought at Trader Joe’s) over top, keep it in my freezer for a quick fix.

No coffee, diet anything, fast food. Use real butter (organic) and olive oil- did notice a difference for the better when I gave up Smart Balance. Try to keep all food real—very little pre-prepared. In spring and summer frequent my local farmer’s market. Juice carrots every other day, and buy Green food juice at Trader Joe’s. Drink tons of water.

I have early retired, and I now do projects that used to take 1 day. I now spread them out over 3 or 4 days. If I’m fatigued, I do nothing.

I’m careful to avoid stress, I have started saying no to volunteer situations.

I’m 58, I have neuropathy from the waist down -large areas of no temperature feeling- reflexes not strong below the waist- My doctors are now saying fibromyalgia just because they don’t know. But if I listen to my body I can do anything I want, just slower with planning- I used to be a construction worker and have worn out my spine.

Hope this helps.

Upon rereading this post, I must admit that the list of things that she takes is quite daunting. I don’t take anything except for curcumin, quercetin, flaxseed oil, black cumin oil and an occasional multivitamin (heavy on the B vitamins). That’s my current intake. My list pales in comparison with hers. Hmmm.

At any rate, she will continue to monitor her blood situation every four months for the next year, then will go to every six months. She believes that getting rid of stress has really helped her, as well as ignoring the reports that we shouldn’t build our immune systems. Well, this approach clearly worked in her case! In her own words: I do believe our society demands multi-tasking, major stress, the need to buy more, have more. I think my efforts at doing nothing helped reset my immune system and yes, I ignored those reports that you don’t want to build your immune system.

Speaking of immune systems. Incredible but true: yesterday I began feeling a bit ill. And it just so happens that tomorrow Sherlock and I are supposed to go to the hospital lab to have our Biocurcumax tests done. But this morning I am having chills and, can you believe it?, a low-grade fever. Needless to say, I am quite annoyed! But not too surprised, since all of my students have been ill, with fevers and colds and terrible coughs…SIGH! Che pazienza che ci vuole…Well, unless I get worse, I will go have my tests done anyway. Oh, bother!