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The miscellaneous ramblings of a surgeon/scientist on medicine, quackery, science, pseudoscience, history, and pseudohistory (and anything else that interests him).
More than two-thirds of breast cancers make the estrogen receptor. What that means is that these tumors have the protein receptor that binds estrogen, which then activates the receptor and causes all the genes that are turned on or off by estrogen to be turned on and off. That's how estrogen acts on normal breast epithelial cells and on breast cancer cells. The significance of this observation is that estrogen receptor-positive (ER+) breast cancers respond to estrogen. Indeed, estrogen contributes to their growth, and blocking estrogen is an effective treatment against them. Indeed, that most breast cancers are estrogen-responsive has been understood for decades. Long ago, a standard treatment for breast cancer in reproductive age women was oophorectomy, the removal of the ovaries, in order to produce an early menopause.
Surgical approaches to decreasing the level of estrogen in a woman's body were supplanted by the use of tamoxifen, an estrogen analogue that started its life as a candidate to be a birth control pill but didn't work out for that. The simplistic view of tamoxifen is that it is an estrogen receptor blocker, and indeed it does bind to the estrogen receptor and keep estrogen from binding to it. However, we now refer to tamoxifen as a selective estrogen response modulator (SERM) because it turns out that tamoxifen blocks the action of estrogen in some tissues (for example, breast, where its estrogenic activity is much weaker than that of estrogens and why it mostly blocks estrogen activity--hence its use to treat breast cancer) and mimics it in others (for example, bone). Until recently, tamoxifen has been the mainstay of treatment for ER+ breast cancers, as it is effective (it provides at least as much benefit as chemotherapy when used in the adjuvant setting) and relatively safe. True, it has side effects, but those are related to its blockade of estrogen activity, which in essence induces a menopause-like state, complete with hot flashes that can be difficult to treat (so much that women and their physicians can be tempted by woo to treat it).
More recently, another class of drugs, the aromatase inhibitors, has become a mainstay of the treatment of breast cancer as well. Their mechanism of action is to inhibit an enzyme called aromatase, which converts androgens to estrogens in the peripheral tissues by a reaction that looks like this in the case of testosterone being converted to estradiol: Read the rest of this post... | Read the comments on this post...... Read more »
Y. H. Ju, D. R. Doerge, K. A. Woodling, J. A. Hartman, J. Kwak, & W. G. Helferich. (2008) Dietary Genistein Negates the Inhibitory Effect of Letrozole On The Growth Of Aromatase-expressing Estrogen-Dependent Human Breast Cancer Cells (MCF-7Ca) In Vivo. Carcinogenesis. DOI: 10.1093/carcin/bgn161
Ever since I started paying attention to it, acupuncture has, at least until recently, inspired ambivalence more than anything else in me. As a skeptic and science-based physician, I found it very easy to dismiss utter quackery like homeopathy or the various "energy healing" modalities, such as reiki or therapeutic touch strictly on the science alone. After all, homeopathy is based on magical thinking more than anything else, specifically the concepts of "like cures like," the concept that dilution with vigorous shaking can make a remedy stronger, and the idea that water has "memory" all are very implausible on the basis of well-established science alone. Similarly the concept that healers can manipulate living human "energy fields" (or life energy, also known as qi) for therapeutic effect is also incredibly implausible, given that no scientist has ever detected qi or shown that healers can manipulate it for therapeutic intent or any reason.
When I first became interested in "alternative medicine"--excuse me, I mean "complementary and alternative medicine" (CAM)--I viewed acupuncture somewhat differently. No, I never bought the traditional explanation that sticking thin needles into the skin somehow alters the flow of qi in order to induce a therapeutic effect. That is no more plausible than reiki or therapeutic touch. However, there are needles breaking the skin in acupuncture. It was, at least to me, not entirely implausible that that might have some sort of physiologic effect. Then I had to go and ruin that lovely kumbaya feeling towards CAM by actually going and looking at the scientific literature on acupuncture, as I've documented on this blog on multiple occasions (for example: 1, 2, 3, 4, 5). When I actually bothered to do that, I soon realized that the evidence that acupuncture is anything more than a highly elaborate placebo is shockingly thin. More like nonexistent, actually. So what do you do if you're a CAM believer but can't find studies that strongly support the efficacy of your favorite CAM modality, like acupuncture.
Why, meta-analysis, of course!
And here comes another one, this time for acupuncture to treat headaches:
WASHINGTON (Reuters) - Acupuncture works better than drugs like aspirin to reduce the severity and frequency of chronic headaches, U.S. researchers reported on Monday.
A review of studies involving nearly 4,000 patients with migraine, tension headache and other forms of chronic headache showed that that 62 percent of the acupuncture patients reported headache relief compared to 45 percent of people taking medications, the team at Duke University found.
"Acupuncture is becoming a favorable option for a variety of purposes, ranging from enhancing fertility to decreasing post-operative pain, because people experience significantly fewer side effects and it can be less expensive than other options," Dr. Tong Joo Gan, who led the study, said in a statement.
"This analysis reinforces that acupuncture also is a successful source of relief from chronic headaches."
Before I continue on to discuss the actual meta-analysis itself, let me test what you have learned from reading this blog on a regular basis (assuming, of course, that you've been a regular reader for a while; if you're a newbie ignore this). Can you tell me what is wrong with the above result and why it is not particularly impressive? No cheating and reading ahead yet. Think and see if you can identify what the problem is. Once you've done that, feel free to click to read below the fold to see if you found the same problem that I did. Read the rest of this post... | Read the comments on this post...... Read more »
Yanxia Sun, & Tong J. Gan. (2008) Acupuncture for the Management of Chronic Headache: A Systematic Review. Anesthesia , 107(6), 2038-2047. DOI: 10.1213/ane.0b013e318187c76a
Given that I'm the proverbial lapsed Catholic cum agnostic, religion just doesn't play that large a role in my life and hasn't since around six years ago. I don't know if I'll ever discuss or explain on this blog what the last straw resulting in that transformation was (it's too personal), but a couple of years ago I did go through a period where I became hostile to religion, perhaps spurred on by PZ and the whole anti-religion gestalt of the ScienceBlogs Collective here. That lasted maybe a year or two, during which time I did what every new disillusioned ex-religious person seems to do (reading books like Richard Dawkins' The God Delusion, for instance) but eventually my hostility abated, as regular readers may have noticed by the topics and writing tone right here on this very blog. (Don't worry, quackery and the antivaccine movement still get me as worked up as ever--perhaps even more so.) These days religion just doesn't matter that much to me one way or the other, except for when it interferes with concrete things that matter, such as patient care, the teaching of science, or civil rights. Since then, for the most part it's been live and let live.
That being said, I still maintain a healthy interest in the interface between science and religion or, more specifically, the interface between religion and medicine. That's why a study released in the Journal of the American Medical Association yesterday caught my interest. A news story in the Los Angeles Times about this study describes it thusly:
After she was diagnosed with Stage IV breast cancer that had spread to her left lung, Gloria Bailey's doctors recommended she have a mastectomy followed by hormone therapy to fight the tumors that remained. She followed their advice, but had a nagging feeling about the regimen.
"The Lord was just telling me, 'They're not being aggressive enough,' " Bailey recalled. So she sought out a new team of oncologists at the Cancer Treatment Centers of America's Midwestern Regional Medical Center in Zion, Ill., more than 300 miles away from her home in Michigan. Those doctors suggested she undergo a bone marrow transplant, a harrowing ordeal that landed her in a coma. Read the rest of this post... | Read the comments on this post...... Read more »
Andrea C. Phelps, MD, Paul K. Maciejewski, PhD, Matthew Nilsson, BS, Tracy A. Balboni, MD, Alexi A. Wright, MD, M. Elizabeth Paulk, MD, Elizabeth Trice, MD, PhD, Deborah Schrag, MD, MPH, John R. Peteet, MD, Susan D. Block, MD.... (2009) Religious Coping and Use of Intensive Life-Prolonging Care Near Death in Patients With Advanced Cancer. JAMA, 301(11), 1140-1147. DOI: http://jama.ama-assn.org/cgi/content/short/301/11/1140
From my perspective, one thing that's always been true of surgery that has bothered me is that it is prone to dogma. I alluded to this a bit earlier this week, but, although things have definitely changed in the 20 years since I first set foot, nervously and tentatively, on the wards of the Cleveland VA Medical Center for my first ever surgical rotation, some habits of surgeons die hard.
Of course, regardless of the tendency towards dogma, one thing that differentiates evidence- and science-based medicine from pseudoscientific woo is that studies do make a difference. In general and... Read more »
Kristoffer Lassen, Jorn Kjoeve, Torunn Fetveit, Gerd Trana, Helgi Kjartan, Arild Horn, & Arthur Revhaug. (2008) Allowing Normal Food at Will After Major Upper Gastrointestinal Surgery Does Not Increase Morbidity: A Randomized Multicenter Trial. Annals of Surgery, 247(5), 721-729. http://www.annalsofsurgery.com/pt/re/annos/abstract.00000658-200805000-00001.htm;jsessionid
For women undergoing menopause, hot flashes are a real problem. In my specialty, as I've pointed out before, women undergoing treatment for breast cancer are often forced into premature menopause by the treatments to which we subject them. It can be chemotherapy, although far more often it's the estrogen-blocking drugs that we use to treat breast cancers that have the estrogen receptor. Estrogen stimulates such tumors to grow, and blocking estrogen is a very effective treatment for them, be it with tamoxifen or the newer aromatase inhibors like Arimidex. The utterly predictable consequence, unfortunately, is an artificially-induced menopause.
I've written at least twice before about this topic in the context of various poorly designed studies of acupuncture for breast cancer-induced hot flashes. There's a reason for this. Despite studies demonstrating that hormone replacement therapy doesn't decrease cardiovascular disease in postmenopausal women and increased the risk of breast cancer, for severe menopausal symptoms in women without breast cancer, estrogen remains the gold standard, and it's reasonably safe to use for short periods of time. Consequently, for menopause having nothing to do with breast cancer, estrogen can be used, at least for the short term, if nonhormonal therapies don't work. Not so in the case of women rendered menopausal by breast cancer therapy. Indeed, it defeats the purpose of antiestrogen drugs to replace the estrogen they are blocking. Not only that, but even after breast cancer therapy when a woman undergos menopause naturally, estrogen replacement increases their risk of a recurrence. Consequently, if nonhormonal methods supported by science don't work, then there's nothing else, and, unfortunately, most science-based nonhormonal therapies such as antidepressants do not work very well and have significant side effects.
That's where the temptation to turn to woo comes in. Read the rest of this post... | Read the comments on this post...... Read more »
G. Elkins, J. Marcus, V. Stearns, M. Perfect, M. H. Rajab, C. Ruud, L. Palamara, & T. Keith. (2008) Randomized Trial of a Hypnosis Intervention for Treatment of Hot Flashes Among Breast Cancer Survivors. Journal of Clinical Oncology. DOI: 10.1200/JCO.2008.16.6389
I have to say, this is getting monotonous.
Let me back up a minute. One of the most common beliefs among users and advocates of "complementary and alternative" medicine (CAM) is that supplementation with vitamins will have all sorts of beneficial health effects. True, this belief is also pervasive among people who wouldn't go to an acupuncturist if you held a gun to their head, but it has become most associated with CAM. That this is so can actually be viewed as evidence of just how successful CAM activists have been in completely yoking all manner of lifestyle interventions to prevent or treat disease as somehow being "alternative" rather than, as they really are, science- and evidence-based. Of course, diet and exercise are the Trojan horse that CAM advocates hope to get the guardians of scientific medicine to bring into the fortress. When that happens (actually it is happening), diet and supplement warriors will leap out and open the gate of the castle to let in all the woo whose practitioners have coopted potentially science-based lifestyle interventions. One thing that should be noted is that in CAM world, diet and exercise are often not considered enough. No, it's not considered adequate to eat enough fruit and vegetables and to avoid fatty foods. Oh, no. You also have to swallow all manner of vitamin supplements, because, or so we are told, they will prevent all manner of disease.
The concept that vitamin supplementation might prevent cancer is not in and of itself an unlikely idea. Diet has a powerful effect on health, and it is not unreasonable to hypothesize that supplementation with certain vitamins might have beneficial health effects. For example, although I used to be very skeptical about it, I'm starting to think that there might just be something to the hypothesis that vitamin D supplementation can decrease the risk of colon and breast cancer if the appropriate amount is taken to raise the blood level to a certain range. (Perhaps that will be the topic for another post, but in the meantime Dr. Len and Ed Yong have written good primers on the suggestive but muddled state of the evidence with regard to whether vitamin D prevents breast cancer.) While I haven't gone whole hog and started advocating that my patients take vitamin D supplementation, given that it's pretty clear that a certain target blood level must be not only reached, but verified, or started taking it myself, I certainly will if more evidence clarifies the picture better. In fact, from my perspective, the case for vitamin D is actually harmed by idiots like Mike Adams routinely bringing home the crazy by painting it as some sort of miracle vitamin that prevents and cures all manner of cancer, because his infectious idiocy is tainting what may well be a science-based preventative measure.
Other studies of vitamins and cancer have been a lot more disappointing. One recent study examining the effects of selenium and vitamin E on preventing prostate cancer had to be stopped early because there was no benefit and a hint that there were more cancers in those taking vitamin E and more diabetes in those taking selenium. And just this week, a new study has been published that has also found no benefit in preventing cancer or heart disease due to routine vitamin supplementation. The study, using data from the Women's Health Initiative and entitled Multivitamin Use and Risk of Cancer and Cardiovascular Disease also found no benefit from multivitamin supplementation in overall survival. Read the rest of this post... | Read the comments on this post...... Read more »
Marian L. Neuhouser, Sylvia Wassertheil-Smoller, Cynthia Thomson, Aaron Aragaki, Garnet L. Anderson, JoAnn E. Manson, Ruth E. Patterson, Thomas E. Rohan, Linda van Horn, James M. Shikany.... (2009) Multivitamin Use and Risk of Cancer and Cardiovascular Disease in the Women's Health Initiative Cohorts. Arch Intern Med, 169(3), 294-304. DOI: http://archinte.ama-assn.org/cgi/content/full/169/3/294
NOTE: Orac is on semi-vacation this week, trying very hard to recharge his Tarial cells. Actually, although he is at home, he is spending much of his time in his Sanctum Sanctorum (i.e., his home office) working on an R01 for the February submission cycle. Given that the week between Christmas and New Years Day tends to be pretty boring, both from a blogging and blog traffic standpoint, he's scaling back the new, original stuff and mixing in some "best of" reruns, as well as some more recent stuff that appeared in a different form elsewhere, modified a bit to be more appropriate to this blog. Why? Because he likes them enough that he wants to make sure that as many people as possible see them.
Fear not, though. If something sufficiently interesting happens, Orac will welcome a break from the drudgery of grant writing to apply some appropriate not-so-Respectful Insolence to it. Oh, wait. He already did break his "vacation" to post two or three times....
Science-based medicine consists of a balancing of risks and benefits for various interventions. This is sometimes a difficult topic for the lay public to understand, and sometimes physicians even forget it. My anecdotal experience suggests to me that surgeons are probably more aware of this basic fact. Of course, that isn't because we're better than other doctors or anything like that; rather, it's because our interventions generally involve taking sharp objects to people's bodies and using steel to remove or rearrange parts of people's anatomy for (hopefully) therapeutic effect. Ditto oncologists, who prescribe highly toxic substances to treat cancer, the idea being that these substances are more toxic to the cancer than they are to the patient. Often they are only marginally more toxic to the cancer than to the patient. However, if there's one area where even physicians tend to forget that there is potential risk involved, it's the area of diagnostic tests, in particular radiological diagnostic tests, such as X-rays, fluoroscopy, computed tomography (CT) scans, and the variety of ever more powerful diagnostic studies that have proliferated over since CT scans first entered medical practice in the 1970s. Since then, the crude images that the first CT scans produced have evolved, thanks to technology and ever greater computing power, to breathtaking three dimensional-views of the internal organs. Indeed, just since I finished medical school back in the late 1980s, I'm continually amazed at what these new imaging modalities can accomplish.
The downside of these imaging modalities is that most of them require the use of X-rays to produce their images. True, over the last 15 years or so MRI, which uses very strong magnetic fields and radiofrequency radiation rather than ionizing radiation to produce its images, has become increasingly prevalent. MRI is great because it produces more contrast between different kinds of soft tissue than CT scans do. However, CT tends to be superior for examining calcified organs, such as bone. (The breast surgeon in me notes that breast MRI is pretty much useless for detecting microcalcifications, an important possible indicator for cancer.) Also, MRI scans require a prolonged period of laying still in a very tight tube, which is a problem for patients with any degree of claustrophobia, although "open" MRIs are becoming increasingly available. More importantly for the quality of images, because they require a patient to lie more still than a CT, MRIs tend to be prone to more motion artifacts, which is perhaps why CT is more frequently used to image the abdomen other than large solid organs such as the liver. The point is that, although MRI is becoming more prevalent, CT scans aren't going away any time soon. They have different strengths and weaknesses as imaging modalities and are therefore best suited for different, albeit overlapping, sets of indications. Read the rest of this post... | Read the comments on this post...... Read more »
Berrington de Gonzalez, A., Mahesh, M., Kim, K., Bhargavan, M., Lewis, R., Mettler, F., & Land, C. (2009) Projected Cancer Risks From Computed Tomographic Scans Performed in the United States in 2007. Archives of Internal Medicine_id, 169(22), 2071-2077. http://archinte.ama-assn.org/cgi/doi/10.1001/archinternmed.2009.440
Smith-Bindman, R., Lipson, J., Marcus, R., Kim, K., Mahesh, M., Gould, R., Berrington de Gonzalez, A., & Miglioretti, D. (2009) Radiation Dose Associated With Common Computed Tomography Examinations and the Associated Lifetime Attributable Risk of Cancer. Archives of Internal Medicine, 169(22), 2078-2086. DOI: 10.1001/archinternmed.2009.427
Redberg RF. (2009) Cancer risks and radiation exposure from computed tomographic scans: how can we be sure that the benefits outweigh the risks?. Archives of internal medicine, 169(22), 2049-50. PMID: 20008685
Brenner DJ, & Hall EJ. (2007) Computed tomography--an increasing source of radiation exposure. The New England journal of medicine, 357(22), 2277-84. PMID: 18046031
Sometimes I have to look for blog ideas, trolling through various alternative medicine sites, medical news sites, or science news feeds or my medical and science journals. Sometimes ideas fall on me seemingly out of the blue. This is one of the latter situations. This time around, as I do twice a month I was perusing the very latest issue of Cancer Research, hot off the presses October 1. As I did so, it didn't take me long to come across an article from the Memorial-Sloan Kettering Cancer Center and the Herbert Irving Comprehensive Cancer Center at Columbia entitled Vitamin C Antagonizes the Cytotoxic Effects of Antineoplastic Drugs, whose first author is Dr. Mark Heaney.
I didn't think I'd be revisiting this topic again so soon. After all, I wrote one of my characteristic magnum opuses (opi?) less than two months ago, when I asked whether a recent animal study had vindicated Linus Pauling's belief that high dose vitamin C is a highly effective cancer treatment. That was more than two years after my last magnum opus about this topic. But this latest study examined an aspect of the vitamin C phenomenon that I hadn't considered before. In fact, it found results that I had not seen reported before.
Given that, how could I resist throwing myself once more into the fray? Read the rest of this post... | Read the comments on this post...... Read more »
M. L. Heaney, J. R. Gardner, N. Karasavvas, D. W. Golde, D. A. Scheinberg, E. A. Smith, & O. A. O'Connor. (2008) Vitamin C Antagonizes the Cytotoxic Effects of Antineoplastic Drugs. Cancer Research, 68(19), 8031-8038. DOI: 10.1158/0008-5472.CAN-08-1490
A few days ago, I came across an article on Engadget that mentioned almost in passing some studies that seemed to indicate health problems or no health problems, depending on the specific study, due to the ubiquitous and maligned cellular telephone. Not having dealt with this issue much on my blog, I decided to take a look, mostly out of curiosity. The claims that cell phones somehow cause cancer have been circulating for many years, and the studies marshaled to show such a link have in general been not that impressive. However, even though radiofrequency radiation of the sort used in cell ... Read more »
Anu Karinen, Sirpa Heinavaara, Reetta Nylund, & Dariusz Leszczynski. (2008) Mobile phone radiation might alter protein expression in human skin. BMC Genomics, 9(1), 77. DOI: 10.1186/1471-2164-9-77
A AGARWAL. (2008) Effect of cell phone usage on semen analysis in men attending infertility clinic: an observational study. Fertility and Sterility, 89(1), 124-128. DOI: 10.1016/j.fertnstert.2007.01.166
Here we go again.
It seems just yesterday that I was casting a skeptical eye on yet another dubious acupuncture study. OK, it wasn't just yesterday, but it was less than two weeks ago when I discussed why a study that purported to show that acupuncture worked as well as drug therapy for hot flashes due to breast cancer therapy-induced menopause. Unfortunately, these days these sorts of dubious studies seem to be popping up fast and furious like Whac-A-Mole, so much so that I can't always keep up with them. So it is again, although this time it's acupressure, not acupuncture. Unfortunately, this time it's an experiment on children as well. Why woo-meisters insist on subjecting children to their woo, I don't know, but they do:
An adhesive bead placed at a pressure point between the eyebrows reduced anxiety by 9% during the preoperative waiting period whereas anxiety continued to rise 2% for children who got sham acupressure (P=0.012), reported Shu-Ming Wang, M.D., of Yale, and colleagues in the September issue of Anesthesia & Analgesia.
However, the randomized trial showed acupressure had no effect on the need for intraprocedural propofol (Diprivan) or the depth of sedation.
Steve Novella's not going to be happy about this. The lead author of the study is Shu-Ming Wang, MD in the Department of Anesthesiology at Yale School of Medicine. I feel his pain. I'm lucky in that I have not seen much woo in my particular institution thus far. I can only imagine how irritating it would be to be at an institution that not only produces studies like this one but has earned a prominent place in my Academic Woo Aggregator, largely thanks to its most famous woo-meister, Dr. David Katz. I don't see him on this article, but I see his influence permeating even departments that should know better.
But my sympathy has lead me to digress. Read the rest of this post... | Read the comments on this post...... Read more »
Shu-Ming Wang, Sandra Escalera, Eric C. Lin, Inna Maranets, & Zeev N. Kain. (2008) Extra-1 Acupressure for Children Undergoing Anesthesia. Anesthesia , 107(3), 811-816. DOI: 10.1213/ane.0b013e3181804441
Why, oh, why do I keep perusing NaturalNews.com?
Why do I subject myself to wave after wave of neuron-apoptosing stupidity of a magnitude that even activation of NF-kappaB, Akt, and neuronal cell survival signaling pathways can barely keep the killing stupidity at bay? I guess it's because it provides such good blog fodder for a skeptical blog dedicated to science- and evidence-based medicine. On the other hand, it often gives me a headache to read its contents. Really, it does. I mean, looking at how Mike Adams, the Woo-meister Supreme and Chief Tin Foil Hat responsible for the lunacy there, regularly serves up fare that alternates between the simply over-the-top hilarious (unintentionally, of course) and the truly vile (although leaning more towards the vile) that the alternating current of fun woo and dumb woo seriously stresses the electrical impulses flowing through my brain.
Perhaps I could use some acupuncture for that headache.
But not just any acupuncture. Oh, no. That would be too mundane, too boring, too...pedestrian. Needles? Stuck into the skin? Physically? How primitive! There might even be a tiny drop of blood! We can't have that! No, I'm a 21st century kind of guy, and I need a 21st century form of woo. It needs to be high tech woo of the finest caliber. Just like Dr. Evil, I want my frikkin' sharks to have frikkin' laser beams.
That's right: Laser acupuncture! Fellow woo-traveler of Mike Adams Dave Gabriele shows me the way right there on NaturalNews.com: Read the rest of this post... | Read the comments on this post...... Read more »
S GOTTSCHLING, S MEYER, I GRIBOVA, L DISTLER, J BERRANG, L GORTNER, N GRAF, & M SHAMDEEN. (2008) Laser acupuncture in children with headache: A double-blind, randomized, bicenter, placebo-controlled trial. Pain, 137(2), 405-412. DOI: 10.1016/j.pain.2007.10.004
You can tell I'm really busy when I fall behind my reading of the scientific literature to the point where I miss an article highly relevant to topics I'm interested in, be they my laboratory research, clinical interests, or just general interests, such as translational research. As you know, I like to think of myself as a translational researcher. Translational research is research that (or so we try to do) spans both basic science and clinical science; i.e., bridges the gap between basic and clinical science. Now don't get me wrong; I don't devalue basic science, and I've said so many times before. Without a robust pipeline of basic science developments to try to translate, translational research grinds to a halt. On the other hand, the NIH emphasizes translational research these days. In any grant, if the applicant can't articulate a reasonable (or at least reasonable-sounding) rationale by which the results could lead to a treatment or greater understanding of disease that could lead to a treatment, that grant's chances of being funded drop like a rock.
Even though I believe translational research is extremely important, sometimes I think that it's a bit oversold. For one thing, it's not easy, and it's not always obvious what basic science findings can be translated. For another thing, it takes a long time. The problem is that the hype about how much we as a nation invest in translational research leads to an expectation that is not unreasonable that there will be a return on that investment. Such an expectation is often not realized, at least not as fast and frequent as we would like, and the reason has little to do with the quality of the science being funded. It has arguably more to do with how long it takes for a basic science observation to follow the long and winding road to producing a viable therapy. But how long is that long and winding road?
A lot longer than many, even many scientists, realize. At least, that's the case if the latest paper by John Ioannidis in Science is any indication. The article appeared in the Policy Forum in the September 5 issue and is entitled Life Cycle of Translational Research for Medical Interventions. As you may recall, Dr. Ioannidis made a name for himself a couple of years ago by publishing a pair of articles provocatively entitled Contradicted and Initially Stronger Effects in Highly Cited Clinical Research and Why Most Published Research Findings Are False. I've blogged about both before.
Dr. Ioannidis lays it out right in the first paragraph: Read the rest of this post... | Read the comments on this post...... Read more »
D. G. Contopoulos-Ioannidis, G. A. Alexiou, T. C. Gouvias, & J. P. A. Ioannidis. (2008) Life Cycle of Translational Research for Medical Interventions. Science, 321(5894), 1298-1299. DOI: 10.1126/science.1160622
If there's one thing I've learned over the last four years of examining the various forms of woo out there, it's to be very, very skeptical whenever an advocate of a highly dubious-sounding "therapy" points to a study as "proof" that the therapy, whatever it is, works. Usually, what I find is a small pilot study with inadequate controls or even a poorly designed study. For example, the acupuncture literature is rife with these sorts of studies. It's also rife with larger studies for which the control was inadequate--or for which there was no real control at all. This phenomenon is generalizable to many, if not most, studies of so-called "complementary and alternative medicine" (CAM), as is another feature, namely that the larger and better designed the study, the less likely it is to find a treatment effect greater than placebo due to the treatment. Another principle is that at a statistical significance level of 95%, at least 5% of studies will appear to find a treatment effect through random chance alone. Guess which studies will be cherry picked and held up as "proof" while the preponderance of studies showing no effect are ignored?
There is at least one other form of studies pointed to by CAM advocates to "prove" that their woo "works." Indeed, this form is perhaps their favorite crutch to fall back on. It's what I like to call the "non sequitur" study. In other words, it's a study that is, at best, only tangentially related to the question at hand, or, as I like to put it, a study that is related to the therapy being argued for only by coincidence. This sort of study is a favorite of homeopathy. Just think of studies about the molecular bonds of water homeopaths like to point to as "evidence" for the "memory of water." It is this latter form of study that I'm going to deal with here.
Remember about three weeks ago, when I had a bit of fun with one of the most hilariously ludicrous bits of woo that I've ever seen, Tong Ren? If you're really new to the blog and didn't happen to read my post, I encourage you to go back and do so now. If you do, you'll see, besides my own inimitably insolent prose, YouTube videos of a man named Tom Tam leading a bunch of people tapping on acupuncture dolls with small hammers and concentrating their "intent" to "heal" a person. I've seen a lot of woo before. A lot of woo. But Tong Ren was about the most ridiculous things I've ever seen. These people really believe that by taking what looks in essence to be a voodoo doll and tapping on it at the correct acupuncture points, they can direct some vague "energy" undetectable by science to cure cancer and all manner of other diseases. One thing you'll also see is a news report that mentions a study of Tong Ren being done at the Dana Farber Cancer Institute, a very prestigious institution indeed. Naturally, at every opportunity, the connection to Harvard University is played up, so desperate is Tom Tam to wrap himself in the mantle of seeming legitimacy that the attention of Harvard University suggests. When I poked around various Tong Ren websites, I couldn't find out anything about the study other than that it appeared to be some sort of survey and that the manuscript had been submitted.
It appears that the manuscript has been accepted and was published recently in a journal I've never heard of, namely Complementary Health Practice Review. The article, entitled The Tong Ren Healing Method: A Survey Study, by Amy M Sullivan, EdD (Virginia Commonwealth University School of Medicine), Susan Bauer-Wu, PhD, RN (Emory University), and Michael Miovic, MD (Dana Farber Cancer Institute). Of course, that this study appeared in a journal called Complementary Health Practice Review does not bode well for the quality of the study, and this is no exception. More importantly, the question studied by this study is related to the question of whether Tong Ren "heals" anything only by coincidence. Check out the abstract:
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I think my title says it all: Can we finally just say that acupuncture is nothing more than an elaborate placebo? Can we?
The reason I ask this question is because yet another large meta-analysis has been released that is entirely consistent with the hypothesis that acupuncture is a placebo. Because I've written about so many of these sorts of studies over the last year or two that I really had a hard time mustering up the will to write about one more. But I got in pretty late last night and therefore knew I could handle this in a reasonably expeditious fashion. Besides, it is a fairly interesting study as far as methodology. Also, I've been on a roll writing about antivaccine nonsense, but it's taken a toll. My foray into the Mothering.com discussion forums resulted in a real assault on my neurons, so much so that, while I had considered taking on the not-so-dynamic duo, two crappy tastes that taste crappy together, otherwise known as David Kirby and Robert F. Kennedy, Jr. in the pages of The Huffington Post. Truly, just when I think HuffPo can't go any lower, damn if it doesn't prove me wrong. In any case, I thought it ill advisable to subject myself to more of Kirby and RFK, Jr. so soon on the heels of Mothering.com waves of burning mommy stupid. Better to take on this study, because it's yet another piece of evidence that backs up what I've come to accept after having actually read that acupuncture literature: That acupuncture is nothing more than a placebo.
So let's take a bit more of a look at the study. Entitled Acupuncture treatment for pain: systematic review of randomised clinical trials with acupuncture, placebo acupuncture, and no acupuncture groups appeared in the BMJ two days ago and was performed by Madsen et al at the Nordic Cochrane Center, meaning it's a Cochrane review. Read the rest of this post... | Read the comments on this post...... Read more »
M. V. Madsen, P. C Gotzsche, & A. Hrobjartsson. (2009) Acupuncture treatment for pain: systematic review of randomised clinical trials with acupuncture, placebo acupuncture, and no acupuncture groups. BMJ, 338(jan27 2). DOI: 10.1136/bmj.a3115
Two of the major themes on this blog since the very beginning has been the application of science- and evidence-based medicine to the care of patients and why so much of so-called "complementary and alternative" medicine, as well as fringe movements like the anti-vaccine movement, have little or--more commonly--virtually no science to support their claims and recommendations. One major shortcoming of the more commonly used evidence-based medicine paradigm (EBM) that has been in ascendance as the preferred method of evaluating clinical evidence. Specifically, as Dr. Kimball Atwood IV (1, 2, 3, 4, 5, 6, 7, 8) has pointed out extensively before, EBM values clinical studies above all other forms of evidence. On the surface, this sounds quite reasonable (after all, what we as physicians really want to know is whether a treatment works better than a placebo or not). Unfortunately, it ignores one very important problem with clinical trials, namely that prior scientific probability really does matter. Indeed, four years ago, John Ioannidis made a bit of a splash with a paper published in JAMA entitled Contradicted and Initially Stronger Effects in Highly Cited Clinical Research and, more provocatively in PLoS Medicine, Why Most Published Research Findings Are Wrong. In his study, he examined a panel of highly cited clinical trials and determined that the results of many of them were not replicated and validated in subsequent studies. His conclusion was that a significant proportion, perhaps most, of the results of clinical trials turn out not to be true after further replication and that the likelihood of such incorrect results increases with increasing improbability of the hypothesis being tested.
Not surprisingly, CAM advocates piled onto these studies as "evidence" that clinical research is hopelessly flawed and biased, but that is not the correct interpretation. Basically, as Steve Novella, Alex Tabarrok, and I pointed out, prior probability is critical. What Ioannidis' research shows is that clinical trials examining highly improbable hypotheses are far more likely to produce false positive results than clinical trials examining hypotheses with a stronger basis in science. Of course, estimating prior probability can be tricky based on science. After all, if we could tell beforehand which modalities would work and which didn't we wouldn't need to do clinical trials, but there are modalities for which we can estimate the prior probability as being very close to zero. Not surprisingly (at least to readers of this blog), these modalities tend to be "alternative medicine" modalities. Indeed, the purest test of this phenomenon is homeopathy, which is nothing more than pure placebo, mainly because it is water. Of course, another principle that applies to clinical trials is that smaller, more preliminary studies often yield seemingly positive results that fail to hold up with repetition in larger, more rigorously designed randomized, double-blind clinical trials.
Last week, a paper was published in PLoS ONE Thomas by Thomas Pfeiffer at Harvard University and Robert Hoffmann at MIT that brings up another factor that may affect the reliability of research. Oddly enough, it is somewhat counterintuitive. Specifically, Pfeiffer and Hoffmann's study was entitled Large-Scale Assessment of the Effect of Popularity on the Reliability of Research. In other words, the hypothesis being tested is whether the reliability of findings published in the scientific literature decreases with the popularity of a research field. Although this phenomenon is hypothesized based on theoretical reasoning, Pfeiffer and Hoffmann claim to present the first empirical evidence to support this hypothesis. Read the rest of this post... | Read the comments on this post...... Read more »
Pfeiffer, T., & Hoffmann, R. (2009) Large-Scale Assessment of the Effect of Popularity on the Reliability of Research. PLoS ONE, 4(6). DOI: 10.1371/journal.pone.0005996
The anti-vaccine movement is a frequent topic on this blog, sometimes to the point where it seems to take over the blog for days (or even weeks) at a time and I cry for respite. There are a number of reasons for this, not the least of which being that the anti-vaccine movement is one of the most dangerous forms of pseudoscience, a form of quackery that, unlike most forms of quackery, endangers those who do not partake of it by breaking down herd immunity and paving the way for the resurgence of previously vanquished diseases. However, anti-vaccine beliefs share many other aspects with other forms of quackery, including the reliance on testimonials rather than data. Even so, although the intelligentsia (and I do use the term loosely) of the anti-vaccine movement realizes and exploits the power of anecdotes and testimonials and how human beings tend to value such stories over dry scientific data, leaders of the anti-vaccine movement realize that science is overwhelmingly against them and that testimonials alone are not adequate to counter that science in the realm of public policy and relations.
That's why, over the years, various anti-vaccine "scientists" (and I use that term very loosely as well) have produced poor quality, sometimes even fraudulent studies, which are then touted as evidence that vaccines cause autism or at least as evidence that there is actually still a scientific controversy when in fact from a scientific standpoint the vaccine-autism hypothesis is pining for the fjords. Examples abound, including the work of Mark and David Geier, whose studies led the to use chemical castration to treat autistic children; Andrew Wakefield, whose small case series almost certainly included fraudulent data; a truly incompetent "phone survey" commissioned by Generation Rescue designed to compare "vaxed versus unvaxed" children; and an even more incompetent "study" in which Generation Rescue used a cherry picked group of nations to try to argue that nations that require more vaccines have higher rates of infant mortality. These efforts continue. For example, last year Generation Rescue requested $809,721 from the Airborne settlement to set up a "vaxed versus unvaxed" study, despite the known difficulties with such a study and the low likelihood of finding anything without huge numbers of children.
Earlier this month, they were at it again. Read the rest of this post... | Read the comments on this post...... Read more »
Miller, N., & Goldman, G. (2011) Infant mortality rates regressed against number of vaccine doses routinely given: Is there a biochemical or synergistic toxicity?. Human . DOI: 10.1177/0960327111407644
I hate science press releases.
Well, not exactly. I hate science press releases that hype a study beyond its importance. I hate it even more when the investigators who published the study make statements not justified by the study and use the study as a jumping off point to speculate wildly. True, it's not always the fault of the investigators, particularly if they don't have much experience dealing with the press, but all too often scientists fall prey to the tendency to gab glibly and give the reporter what he or she wants: Pithy, juicy quotes that relate the results to what the reporter wants them related to. It's irritating as hell, not so much because it's pure self-promotion. (After all, self-promotion is not in and of itself a bad thing) but rather because it's almost inevitably an excuse for the investigators to say what they want without peer pesky peer reviewers telling them that they should keep their remarks focused on what the evidence will support. Often these press releases lead to credulous news stories that make conclusions that aren't justified from the actual study. Sometimes an investigators' comments are taken out of context. Sometimes the investigator says something dumb. Sometimes it's all three.
There's a certain Reuters story entitled Cancer cells slurp up fructose, U.S. study finds making the rounds, and it's being represented as yet more evidence about the evils of high fructose corn syrup. That it might be viewed as a few years in the future, after followup studies have been done, but for right now all it is is an intriguing study being used to serve an agenda that it doesn't serve well: Read the rest of this post... | Read the comments on this post...... Read more »
Liu, H., Huang, D., McArthur, D., Boros, L., Nissen, N., & Heaney, A. (2010) Fructose Induces Transketolase Flux to Promote Pancreatic Cancer Growth. Cancer Research, 70(15), 6368-6376. DOI: 10.1158/0008-5472.CAN-09-4615
I tell ya, I'm on the light blogging schedule for a mere four days, thanks to the Thanksgiving holiday weekend, the happy invasion of family on Thursday and Friday, and a significant amount of grant writing I've had to deal with on Saturday and Sunday, and somehow I missed not only a study relevant to my field of interest, but the reaction of antiscientific quackery apologists to said study. First, let's look at the reaction, then the study, which reports that as many as 22% of mammographically detected breast cancer may spontaneously regress.
First off the block is Dr. Joel Fuhrman:
It's easy to understand why this study was so hard to get published and the stranglehold the drug companies and the medical profession has on the status quo in disease-care. It should not even be called health care!
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Per-Henrik Zahl, MD, PhD, Jan Mæhlen, MD, PhD, & H. Gilbert Welch, MD, MPH. (2008) The Natural History of Invasive Breast Cancers Detected by Screening Mammography. Archives of Internal Medicine, 168(21), 2311-2316. DOI: http://archinte.ama-assn.org/cgi/content/abstract/168/21/2311
About a year ago, I discussed an article by Dr. Atul Gawande describing a quality improvement initiative that appeared to have been stalled by the Office for Human Research Protections and its apparent tendency to apply human subjects research protection rules to initiatives that are not exactly research using human subjects. The problem appeared to be an excessively legalistic and a "CYA" attitude more than a genuine concern for protecting human subjects. At the time, I was more concerned with the ethical and policy implications of the story rather than the actual research itself. After all, what was being examined was not something new or experimental. It was nothing more than a checklist designed to remind doctors placing central venous catheters to use rigorous sterile technique, and, not surprisingly, its use was associated with a dramatic decrease in catheter infections. Given that the checklist contained nothing more than tried-and-true infection control measures, it was not surprising that catheter infections dropped. What was somewhat surprising is how much they dropped.
One question that arises from these results is: Do these lists have a more general utility? In last week's issue of the New England Journal of Medicine, a study published by Gawande and numerous collaborators takes the use of checklists to a whole other level. Read the rest of this post... | Read the comments on this post...... Read more »
A. B. Haynes, T. G. Weiser, W. R. Berry, S. R. Lipsitz, A.-H. S. Breizat, E. P. Dellinger, T. Herbosa, S. Joseph, P. L. Kibatala, M. C. M. Lapitan.... (2009) A Surgical Safety Checklist to Reduce Morbidity and Mortality in a Global Population. New England Journal of Medicine. DOI: 10.1056/NEJMsa0810119
Hot on the heels of yesterday's paper in Pediatrics showing that vaccine refusal elevates the risk of pertussis in a child by nearly 23-fold, a commentary in PLoS Biology asks what can be done to combat anti-vaccine misinformation. Entitled A Broken Trust: Lessons from the Vaccine-Autism Wars, it's an interview with a professor of medical anthropology at UCSF named Sharon Kaufman, who took a 26 month hiatus from her usual work on aging and longevity to study the anti-vaccine movement from an anthropological perspective. Her observations in some way echo observations I've been making as a commentator and blogger, but she also makes at least one suggestion that strikes me as rather implausible, if not wildly so.
The article treads on ground that I've covered many times on this blog before in that it gives a good, concise history of the latest incarnation of the anti-vaccine movement since the late 1990s, when a confluence of two events, one in the U.K. and one in the U.S., worked to plant the seeds of antivaccine lunacy that continue to germinate now, over a decade later. The U.K. incident was, of course, the publication of the infamous Lancet paper by scientific fraudster Andrew Wakefield, who was also in the pocket of trial lawyers who were suing vaccine manufacturers. That was 1998. The second, which occurred in the U.S. in 1999, was the sudden decision, bulldozed through merican Academy of Pediatrics' vaccine advisory committee and the CDC mostly due to Dr. Neal Halsey, to recommend the removal of mercury from all childhood vaccines by the end of 2001. As described in the PLoS Biology article: Read the rest of this post... | Read the comments on this post...... Read more »
Gross, L. (2009) A Broken Trust: Lessons from the Vaccine–Autism Wars. PLoS Biology, 7(5). DOI: 10.1371/journal.pbio.1000114
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