Breast Cancer is not a Pink Ribbon.

20 10 2010

I have always had mixed feelings in case of large happenings like marches and ribbon activities and cancer months. September is the ovarian cancer month (and also a US Prostate Cancer Month and a childhood cancer month) and  October the breast cancer month…. We have only 12 months in a year!

Please, don’t misunderstand me! Awareness is very important, also in the case of breast cancer: Awareness so to recognize breast cancer in an early stage, awareness of preventive measures of cancer,  awareness what women with breast cancer go through, awareness that breast cancer often can be cured, awareness that research is needed, and thus money.

But I also feel that the attention is overdone and often hypocritical, with fancy pink ribbons and “pink”: everywhere. This feeling is strengthened by some recent articles. For instance this article in Health.Chance.org, called Pink Ribbon Hypocrisy: Boozing It Up for Breast Cancer discussing that fast food and alcohol companies Use Breast Cancer as a Marketing Ploy (whereas these items some reputation if it comes to -certain types of- cancer). You can sign a petition here against it.

There is even a book Pink Ribbon Blues – How Breast Cancer Culture Undermines Women’s Health, written by Gayle A. Sulik, that is “thought-provoking and probing argument against the industry of awareness-raising”

From the description:

Pink ribbon paraphernalia saturate shopping malls, billboards, magazines, television, and other venues, all in the name of breast cancer awareness. (…) Gayle Sulik shows that though this “pink ribbon culture” has brought breast cancer advocacy much attention, it has not had the desired effect of improving women’s health. It may, in fact, have done the opposite. Based on eight years of research, analysis of advertisements and breast cancer awareness campaigns, and hundreds of interviews with those affected by the disease, Pink Ribbon Blues highlights the hidden costs of the pink ribbon as an industry, one in which breast cancer has become merely a brand name with a pink logo.

The following quote from a woman who had lost her mother to breast cancer illustrates the feeling of many (see comments):

As the years went by, life provided me with more reasons to hate pink. Frustration over society-defined gender roles piled on as did annoyance at the image of ultimate feminine woman. And then came the big one.

Breast cancer.

My mom passed away after a six-year long battle with breast cancer at the age of 45.

When pink later became symbolic of breast cancer awareness, I wanted to punch some pink piggies. I know that some people choose to wear pink to honor or remember or show support for a loved one. That is not what I get my panties in a bunch about–it’s the way corporate America has grabbed that pink flag and waved it to and fro for their own profit that makes me furious.

I remember once standing in the grocery store and staring at a bag of pink ribbon-adorned M&Ms, my blood boiling harder with every passing second.

She ends her post with:

Everyone has a story. Some have seen the scars of a mastectomy. Some have witnessed the toll that chemotherapy takes on a body. Some have lived the pain. We all know it’s bad.

I, for one, don’t need pink to remind me.

That same is true for me. I’ve seen my mother battling breast cancer -she is a survivor- and I have seen the scars of mastectomy and these are nowhere near pink ribbon.

“Breast Cancer is not a Pink Ribbon” tweeted Gilles Frydman yesterday and he meant a great pictures exhibition that lasted 3 days, showing portraits of young topless breast cancer survivors shot by fashion photographer David Jay.

At first I found it mainly confronting: this is the reality of breast cancer! As described elsewhere (Jezebel):

Seeing scarred and reconstructed mammary glands is not just shocking because of the way breasts are fetishized in our society, but because it speaks to how much we hide, gloss over and tidy up disease. Breasts are one of the defining physical attributes for identifying a woman. Breast cancer eats away at flesh meant to nourish. Surgery is a brutal procedure from which to recover and heal. But cute, clean, pink ribbons have come to symbolize all that.

But at a second and third look, I mainly saw the beauty of the photo’s, the fierceness of the women and their beautiful eyes.

Exactly as put into words at the website of the SCAR project:

Although Jay began shooting The SCAR Project primarily as an awareness raising campaign he was not prepared for something much more immediate . . . and beautiful: “For these young women, having their portrait taken seems to represent their personal victory over this terrifying disease.

SCAR by the way stands for ‘Surviving Cancer. Absolute Reality.”

David Jay was inspired to act when a dear friend was diagnosed with breast cancer at the age of 32.

The SCAR-project is “dedicated to the more than 10,000 women under the age of 40 who will be diagnosed this year alone The SCAR Project is an exercise in awareness, hope, reflection and healing. The mission is three-fold: Raise public consciousness of early-onset breast cancer, raise funds for breast cancer research/outreach programs and help young survivors see their scars, faces, figures and experiences through a new, honest and ultimately empowering lens.”

The exhibition was last week in New York, but you can still see the photographs at the website of the SCAR-project.

Furthermore, you can participate in the project and/or buy the (signed) SCAR project book ($55).

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Stories [9]: A Healthy Volunteer

20 09 2010

The host of Next Grand Rounds (Pallimed) asked to submit a recent blog post from another blogger in addition to your own post.
I choose “Orthostatics – one more time” from DB Medical rants and a post commenting on that from Musings of a Dinosaur.

Bob Center’s (@medrants) posts was about the value of orthostatic vital sign measurements (I won’t go into any details here), and about who should be doing them, nurses or doctors. In his post, Bob Center also mentioned briefly that students were seeing this as scut work similar as drawing your own bloods and carrying them to the lab.

That reminded me of something that happened when I was working in the lab as a PhD, 20 years ago.

I was working on a chromosomal translocation between chromosome 14 and 18. (see Fig)

The t(14;18) is THE hallmark of follicular lymphoma (lymphoma is a B cell cancer of the lymph nodes).

This chromosomal translocation is caused by a faulty coupling of an immunoglobulin chain to the BCL-2 proto-oncogene during the normal rearrangement process of the immunoglobulins in the pre-B-cells.

This t(14;18) translocation can be detected by genetic techniques, such as PCR.

Using PCR, we found that the t(14:18) translocation was not only present in follicular lymphoma, but also in benign hyperplasia of tonsils and lymph nodes in otherwise healthy persons. Just one out of  1 : 100,000 cells were positive. When I finally succeeded in sequencing the PCR-amplified breakpoints, we could show that each breakpoint was unique and not due to contamination of our positive control (read my posts on XMRV to see why this is important).

So we had a paper. Together with experiments in transgenic mice, our results hinted that t(14;18) translocations is necessary but not sufficient for follicular lymphoma. Enhanced expression of BCL-2 might give make the cells with the translocation “immortal”.

All fine, but hyperplastic tonsils might still form an exception, since they are not completely normal. We reasoned that if the t(14;18) was an accidental mistake in pre B cells it might sometimes be found in normal B cells in the blood too.

But then we needed normal blood from healthy individuals.

At the blood bank we could only get pooled blood at that time. But that wasn’t suitable, because if a translocation was present in one individual it would be diluted with the blood of the others.

So, as was quite common then, we asked our colleagues to donate some blood.

The entire procedure was cumbersome: a technician first had to enrich for T and  B cells, we had to separate the cells by FACS and I would then PCR and sequence them.

The PCR and sequencing techniques had to be adopted, because the frequency of positive cells was lower than in the tonsils and approached the detection limit. ….. That is in most people. But not in all. One of our colleagues had relatively prominent bands, and several breakpoints.

It was explained to him that this meant nothing really. Because we did find similar translocations in every healthy person.

But still, I wouldn’t feel 100% sure, if so many of my blood cells (one out of 1000 or 10.000) contained t(14:18) translocations.

He was one of the first volunteers we tested, but from then on it was decided to test only anonymous persons.

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Screening Can’t Hurt, Can it?

23 11 2009

The next Grand Rounds is hosted by How To Cope With Pain and, not surprisingly, the main theme will therefore be pain. Now, I had a personal story in mind on the downside of testing, but I didn’t have a good title that fit the theme. Till, this Saturday when I a saw a perfect headline in the Los Angeles Times (Nov 21th), reading:

Cancer screening: What could it hurt? A lot, actually

It is a very thoughtful article showing the downside of screening. It was prompted by “the furor over this week’s recommendation from the U.S. Preventive Services Task Force that most women wait until age 50 to start routine mammograms, and then get them only every other year.” (also see kaleidoscope 2009- wk47).

They started their article as follows:

It seemed like a good idea at the time.

In 1984, Japan began screening the urine of 6-month-old infants for neuroblastoma, the most common type of solid tumor in young children. The test was simple and could show signs of cancer long before clinical symptoms arose.

Hundreds of infants went through the ordeal of diagnosis and treatment, but it didn’t reduce the number of tumors, including deadly ones, found later. Almost none of the tumors caught by screening turned out to be dangerous — and more of the screened children died from complications of surgery and chemotherapy than from the cancer itself.

In 2004, health officials ended the program.

The article further describes the potential downsides of current cancer screening protocols, including breast cancer screening.

  • But finding cancers that respond to early treatment is only one of the potential outcomes from a screening test. Many tests produce false positives, prompting additional tests that can be invasive, expensive, time-consuming and anxiety-inducing.(……)
  • Other screening tests produce false negatives, giving patients and their doctors the incorrect impression that they have nothing to worry about.
  • Some detect aggressive cancers whose outcomes aren’t improved by early detection.
  • And some identify small cancers that grow so slowly they’d never compromise a patient’s health. Many would even go away on their own.

All true but the problem is that people see it as their right to be screened (Will Women in Their 40s Be Denied etc). Cancer survivors are furious about the new breast cancer screening guidelines, they think decisions are made on political grounds and/or fear Medicare will no longer cover screening at younger age.

Why people are upset about the softened screening recommendations is because cancer is a frightening and deadly disease and because (as the Los Angeles Times explains so well) it’s easy to identify cancer survivors whose tumors were caught by screening, but it’s nearly impossible to put a face on the woman or man who is hurt by over-screening.

The first time I heard about the downside of screening was in 2004, when I attended a meeting for  Conn patients  to write an article for the patients association NVACP (see page 11-16, Dutch). Prof. Kievit, a surgeon and professor in decision analysis said:

“Imaging techniques (CT-scan or MRI) should only be applied if the stature test is positive and the aldosterone blood levels proven to be abnormally high. This is important because people often have benign nodules. Innocent nodules (incidentalomas) can obscure the diagnosis, worry the patient or even lead to unnecessary interventions. Furthermore it is inefficient to randomly subject people to all kind of tests. And please do not follow the current US trend to ask a CT-scan for your birthday!

That the balance of harm and benefit of diagnostic tests and screening can dip the wrong way can be best understood when you experience it yourself.

from: Wikipedia

During my last pregnancy my daughter was diagnosed with a mild prenatal  hydronephrosis during routine pregnancy ultrasound. Hydronephrosis is distension and dilation of the renal pelvis, usually caused by obstruction of the free flow of urine from the kidney. Since this can lead to progressive atrophy of the kidney, my little girl also had to undergo several tests to check the function of the kidneys and the cause of this anomaly. For one of those tests she had to be injected with radioactive isotopes in the catacombs of another hospital. But everything seemed o.k.: the anatomy (no obstruction) and the kidney functions. It should also be stressed that the dilatation was near-normal and didn’t worsen. Nonetheless, because of complications often seen with children with severe dilatation my daughter had to take daily antibiotics as a preventive measure. We had to regularly visit the polyclinics for an ultrasound and urine testing (to exclude infection and resistance). After a year it was decided to discontinue the antibiotic treatment. Follow-up was not needed.  Later a pediatric urologist told us that the guidelines had been changed: preventive antibiotic treatment was no longer required in case of mild hydronephrosis with no underlying cause.

My daughter developed asthma at the age of 7. Both she and her sister had atopic eczema, a known predicting factor for asthma, when they were toddlers. In line with the hygiene-theory, that states that a lack of early childhood exposure to infectious agents, increases susceptibility to allergic diseases, I often wondered whether 1 year daily antibiotic treatment wasn’t the final trigger for my daughter’s asthma. Indeed @Allergy (Ves Dimov) recently twittered about a study in J Allergy Clin Immunol that showed an association between antibiotic use in the first year of life and current symptoms of asthma in children 6 and 7 years old. A  Systematic Review of observational studies came to the same conclusion: “Exposure to at least one course of antibiotics in the first year of life appears to be a risk factor for the development of childhood asthma.” These studies had some limitations, and don’t  prove there is a causal relationship between antibiotic treatment and asthma, but they do fuel my suspicion.

In any case, although prenatal diagnosis of hydronephrosis may help to prevent later development of serious kidney disease in children with real malformations, it only resulted in “harm” in our case. Unnecessary testing (all results negative), unnecessary polyclinic visits, worries (that stayed until she was 9, when we visited the pediatric urologist to exclude an UTI, because you never know..)), unnecessary antibiotic treatment and -perhaps- the triggering of asthma. Looking back, and knowing what I know now, I wished the somewhat dilated renal pelvis had never been observed.

Last Friday I was at a lottery offered by my Sports Club. The last 2 prices were mystery prices: A total body scan of 1000 Euros each. I heard a lot of “Aaahs” and “Oooohs”. But I whispered “not for me“. The women next to me turned their heads, looked at me perplexed with their eyes blanked. Of course it is difficult to understand why one would refuse such a price, because “if screening doesn’t help, it won’t harm either”.

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Kaleidoscope 2009 wk 47

19 11 2009

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Kaleidoscope is a new series, with a “kaleidoscope” of facts, findings, views and news gathered over the last 1-2 weeks.

Most items originate from Twitter, my Google Reader (RSS) and sometimes real articles (yeah!).

I read a lot, I bookmark a lot, but only some of those things end op in a post. Since tweets have a half-life of less than a week, I thought it would be nice to safeguard some of the tweets in a post. For me to keep, for you to read.

I don’t have the time and the discipline to post daily about health news and social media as Ves Dimov does. It looks more like the compilation at blogs of dr Shock’s (see example),  dr Bates shout-outs, Health Highlights of Highlight HEALTH and Rachel Walden’s Womens health News Round-ups, but less on one subject and less structured. It will just be a mix of old and new, Social Media and science, just a kaleidoscope. Or a potpourri  if you like.

I don’t know if this kaleidoscope will live a long live. I already wrote 2 3 4 5 6 editions, but didn’t have the time to finish them. Well, we will see, just enjoy this one.

Ooh and the beautiful kaleidoscope is made by RevBean and is called: Eyeballs divide like cells. Looks very much like the eyeball-bubblewrap of a previous post but that is thus coincidence. Here is the link (Flickr, CC)

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Medical Grand Rounds

Louise Norris at Colorado Health Insurance Insider is this week’s host of Grand Rounds.(see here). There are many interesting posts again. As a mother of two teens I especially liked the insight Nancy Brown of Teen Health 411 brings us into what teens want when it comes to their relationships with their parents and the “would you rather…?” story that Amy Tenderich of Diabetes Mine shares with us. The punch line is great. Her 9 year old melts my heart.

At InsureBlog’s Hank Stern brings us an article about a British hospital that will no longer admit expectant mothers with a BMI of more than 34, because the hospital’s labor and delivery unit is not equipped to handle complicated births. Hank concludes: “Fear not, though, portly preggies have to travel but 20 miles to the next closest facility. Assuming, of course, that they can make it that far when contractions are minutes apart.”

Dr Charles of the The Examining Room wrote an in depth article about a cheerleader who was supposedly stricken with dystonia following a seasonal flu vaccine in August. Dr Charles not only highlights why (specialists) think it is not dystonia, but gives also background information about the efficacy of vaccins.

Recent editions of the Grand Rounds were at CREGRL, flight nurse (link), NonClinicalJobs (link) and Codeblog, tales of a nurse (link). You can always find previous and upcoming hosts at the Grand Rounds Archive at Blogborygmi.

3621322354_4bc3bb115e Breast cancer screening

The update of the 2002 USPSTF recommendation statement on screening for breast cancer in the general population, published in the November issue of The Annals of Internal Medicine has led to heated discussions in the mainstream media (i.e. New York Times and MedPage Today). Based on current evidence, partly based on 2 other articles in the same journal (comparison screening schedules and an systematic review) the guidelines advise scaling back of the screening. The USPSTF recommends:

  • against routine screening mammography in women aged 40 to 49 years
  • against routine screening mammography of women 75 years or older.
  • biennial (instead of annual) screening mammography for women between the ages of 50 and 74 years.
  • against teaching breast self-examination (BSE).
  • against either digital mammography or magnetic resonance imaging (MRI) instead of film mammography as screening modalities.

The two articles published in Ann Intern Med add to the evidence that the propagation of breast cancer self exam doesn’t save lives (see Cochrane review discussed in a previous post) and that the benefits of routine mammography in the young (<50) or old (>75) do not outweigh the harm (also covered by a  Cochrane review before). Indeed, as put forward by Gary Schwitzer at Schwitzer health news blog this is NOT a new debate. He refers to Slate who republishes a five-year old piece of Amanda Schaffer that does a good job of explaining the potential harms of screening. However it is difficult for women (and some doctors) to understand that “When it comes to cancer screening, more isn’t always better.” Indeed -as Kevin Pho at Kevin MD states, the question is whether “patients will accept the new, evidence-based, breast cancer screening guidelines”.

In the Netherlands it is already practice to start biannual routine mammography at the age of 50. The official breast cancer screening site of the RIVM even states that the US is now going to follow the Dutch guidelines 😉 (one of assessed guidelines in one the Ann Intern Med papers is Dutch). But people still find the  long established guidelines difficult to accept: coincidentally I saw tweets today asking to sign a petition to advance the age of screening ‘because breast cancer is more and more frequently observed at young age…(??)’ Young, well educated, women are very willing to sign…

No time to read the full articles, but interested to know more, then listen to the podcast of this Ann Intern Med edition:

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Systematic Reviews, pharma sponsored trials and other publishing news

Cochrane reviews are regarded as scientifically rigorous, yet a review’s time to publication can be affected by factors such as the statistical significance of the findings. A study published in Open Medicine examined the factors associated with the time to publication of Cochrane reviews. A change in authors and updated reviews were predictive factors, but the favorability of the results was not.

Roy Poses of the Health Care Renewal Blog starts this blogpost as follows: “Woe to those of us who have been advocates for evidence-based medicine”. He mainly refers to a study published in the NEJM, that identified selective outcome reporting for trials of off-label use of gabapentin: for 8 of the 12 published trials, there was a disagreement between the definition of the primary outcome in the protocol and that in the published report. This seriously threatens the validity of evidence for the effectiveness of off-label interventions. Roy was surprised that the article didn’t generate much media attention. The reason may be that we have been overwhelmed by manipulation of data, ghostwriting and by the fact that pharma-sponsored trials rarely produce results that are unfavorable to the companies’ product (see previous posts about Ghostwriting (Merck/Elsevier, Conflict of Interest in Cancer Studies and David Tovey about Cochrane Reviews). At least two authors of the NEJM review (Bero and Dickersin) have repeatedly this to be the case [e.g. see here for an overview, and papers of Lisa Bero]. It is some relief that at least 3 of the 4 NEJM authors are also members of the Cochrane Collaboration. Indirectly better control of reporting, i.e. by clinical trials registries, can improve the reliability of pharma sponsored trials and thus systematic reviews summarizing them. As a matter of fact Cochrane authors always have to check these registries.

At Highlight Health Walter Jessen writes about Medical Journal Conflict of Interest Disclosure and Other Issues, which also discusses how money can taint objectivity in scientific publishing. Half of the post discusses the book The Trouble with Medical Journals, written in 2007 by Richard Smith, the former editor of the BMJ.
By the way, Walter just hosted MedLibs Round with the theme “Finding Credible Health Information Online”.

Good news in the Netherlands: right after international Open Access week and the launching of the Dutch Open Access website (www.openaccess.nl), the Netherlands Organization for Scientific Research (NWO) has announced that it is in favor of Open Access. (via PLOS-facebook).

The open access nature of PLOS itself gets out of hand: they even peer-review T-shirts (according to Bora Zivkovic of a Blog around the Clock, see here)

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Other Health & Science News:

Medline Plus summarizes an article in the Journal of Nutrition, that states that Selenium supplements, may pose a heart risk.

Even Folic Acid and vitamin B12, when taken in large doses, have been reported to Increase Cancer Risk (WebMD)

Luckily WebMD also reports that dark chocolate seems to help against stress, that is it reduced stress hormones in the blood. However @evidencematters and @NHSChoices cast doubt on that“Chocolate cuts stress, says newspaper. Does the study really say that? And who paid for the study?…”

Scientists made the unexpected discovery (published in Molecular Cell) that BRAF, which is linked to around 70 per cent of melanomas and seven per cent of all cancers, is in fact controlled by a gene from the same RAF family called CRAF – which has also been linked to the disease. For the first time it is shown “how two genes from the same ‘family’ can interact with each other to stop cancer in its tracks” (Source: Info Cancer Research UK)

For the first time, scientists have successfully used exome sequencing to quickly discover a previously unknown gene responsible for Miller syndrome, a rare disorder. The finding demonstrates the usefulness of exome sequencing in studying rare genetic disorders. The exome is enriched for coding (thus functional) DNA, it is only 1% of the total DNA, but contains 85% of the mutations (Published in , source: PhysOrg.com)

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Web 2.0
For information regarding the FDA hearings on internet and social media see #FDASM: http://www.fdasm.com.

Read Write Web summarizes the new numbers released by analytics firm Postrank that indicate that reader engagement with blogs has changed dramatically over the last three years, primarily because of the rise of online social networks.

Twitter has began to relaunch the new retweet feature, although not without controversy. What do you think about the newest feature?

The Next Web gives an overview of which Twitter application is hot and which is not.

And Finally: Top 100 tools for learning, compiled by Jane Hart from the contributions of 278 learning professionals worldwide. You can see the lists here (HT: http://blogs.netedu.info/?p=1005)

The web 2.0 part is relatively short, but it is time to conclude this edition. Till next time!

  • MEDLIB’s ROUND 1.6 (laikaspoetnik.wordpress.com)
  • Tool Talk: quick links re Facebook, GReader and GWave (socialfish.org)
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    Hot News: Curry, Curcumin, Cancer & Cure

    3 11 2009

    347513745_54fd37f269 curcuma curry

    *Hot* News via Twitter and various news media a few days ago. Big headlines tell the following in respectively The Sun, Herald, Ireland, BBC News / NHS Health and Reuters:

    Curry is a ‘cure for cancer

    Spices in curry may help cure cancer

    Curry spicekills cancer cells

    Scientists say curry compound kills cancer cells

    The message of these headlines is quite different and so are the articles themselves (covered more in depth by @jdc325 at the BadScience Blog “Stuff and Nonsense” (see here)). They vary from “curry being a cure for cancer” to “a possible effect of one of its compounds on cancer cells”.

    So what was (not) done?

    1. Cancer was not cured.
    2. It was not a human trial.
    3. The study didn’t test effects on living laboratory animals, like mice, either.
    4. The study was done in the test tube, using individual cancer cell lines.
    5. The cells tested were (only) esophageal cancer cell lines.
    6. Testing the drugs efficacy was not the main aim of the study.
    7. Curry (a complex spicy mixture) wasn’t used.
    8. Curcumin was tested, which makes up 3% of “turmeric”, that is one of the spices in curry.
    9. That curcumin has some anti-carcinogenic effects is not new (see my tweet linking to 1120 hits in PubMed with a  simple PubMed search for curcumin and cancer: http://bit.ly/3Qydc6)

    So why the fuss? This doesn’t seem to be a terribly shocking study. Why the media picked this one up is unclear. It must have been, because they were sleeping (missed all the previous studies on curcumin) and/or because they are fond of these kind of studies: except from the experimental details- these studies translate so well to the general public: food – cure – cancer.

    And the headlines do it much better than the actual title of the article:

    Curcumin induces apoptosis-independent death in oesophageal cancer cells

    I experienced the same when my study was picked up at a cancer conference by BBC-health, whereas other far more pioneering studies were not: these were harder to grasp and to explain ‘to the public’ and without any possible direct health benefit.

    What was already known about curcumin and cancer? What was done in the present study? What is new? And is curcumin really a promising agent?

    Already known.

    Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. It gives the curry it bright yellow color. Curcumin has a plethora of beneficial effects in vitro (in the test tube) and in animal studies, including anti-microbial,  anti-arthritic and  anti-inflammatory effects, but most interesting is its anti-carcinogenic effect. It has potential for both prevention and therapy of cancer, but the evidence for preventive effects is most convincing. The mechanisms playing a role in the anticarcinogenic effect are also multifold and complex. Possible mechanisms include: Inhibition/protection from DNA damage/alterations, Inhibition of angiogenesis, Inhibition of invasion/metastasis, Induction of apoptosis, Antioxidant activity, Induction of GST, Inhibition of cytochromes P450, I NF-jB, AP-1, MMPs, COX-2, TNF-a, IL-6, iNOS, IL-1b, the oncogens ras/fos/jun/myc, MAPK, ornithine decarboxylase, Activation of Nrf2, Induction of HO-1, Activation of PPAR-c  and Immunostimulant/immunorestorer effect……….[2]

    New Findings

    This is to put in perspective that the researchers found yet another possible mechanism (although others have found evidence before, see introduction [1]). Using a small panel of esophagus cancer cells, they first showed that the cells were selectively killed by curcumin. Next they showed that the major mechanism wasn’t apoptosis, cell death by suicide, but cell death by a mechanism called “Mitotic catastrophe”, a type of cell death that occurs during mitosis (cell division) (see free review in Oncogene [3]). As with apoptosis many steps have to go wrong before the cell will undergo mitotic catastrophe. The researchers show that curcumin-responsive cells were found to accumulate poly-ubiquitinated proteins and cyclin B, consistent with a disturbance of the ubiquitin–proteasome system: ubiquitin labels proteins for degradation by proteasomes, thereby controlling the stability, function, and intracellular localization of a wide variety of proteins.

    In other words, this study is mainly about the mechanisms behind the anti-cancer effects of curcumin.

    Cure?

    Of course this paper itself has no direct relevance to the management of human esophagus cancer. The sentence that may have triggered the media is:

    “Curcumin can induce cell death by a mechanism that is not reliant on apoptosis induction, and thus represents a promising anticancer agent for prevention and treatment of esophageal cancer.”

    Which is of course to far-fetched. The authors refer to the fact that esophageal cancers are often resistant to cell death induction with chemotherapeutic drugs, but this only indirectly points at a possible role for curcumin.

    It has to be stressed that no human study has convincingly shown an anti-tumor effects of curcumin. Studies that have been done are observational, i.e. show that people taking higher concentrations of curcumin in their diet have a lower incidence of several common cancer types. However, such studies are prone to bias: several other factors (alone or in together) can be responsible for a anti-cancer effect (see previous post [5] explaining this for other nutrients).

    The Current grade of evidence for a preventive or therapeutic effect is C, which means “unclear scientific evidence” (see MedlinePlus).

    Although there are several trials under way there is reason to be skeptical about the potential of curcumin as cancertherapeutic agent.

    • The limited bioavailability and extensive metabolism of curcumin suggest that many of its anticancer effects observed in vitro may not be attainable in vivo. On the other the gastro-intestinal system is he most likely place for an effect of curcimin taken by the oral route. [2]
    • Although relatively high concentrations of curcumin have not shown significant toxicity in short-term studies, these concentrations may lead to toxic and carcinogenic effects in the long term.[2]
    • The therapeutic effects are dose-dependent. As often seen with these bioactive compounds, toxic effects can occur at supra-optimal amounts. Indeed curcumin has shown to be toxic and carcinogenic under specific conditions. At low and high doses curcumin behaves as an anti-oxidant and a pro-oxidant (toxic) respectively. [2, 6 ]
    • Often more ingredients add to the therapeutic effect, or more foods/habits [5].
    • The FDA has a shortlist of “187 Fake Cancer “Cures” Consumers Should Avoid”, compounds containing curcumin are on that list [7].

    Conclusion

    So, concluding, a study that unraveled one of the mechanisms whereby curcumin can kill cancer cells, led to an exaggerated and sometimes completely wrong coverage in the media. Why this was done is unclear, but the ultimate result of such misplaced drumroll will only lead to disbelief or carelessness.

    Shame on you, media!!ResearchBlogging.org

    Photo credits

    http://www.flickr.com/photos/trentstrohm/347513745/

    References

    1. O’Sullivan-Coyne, G., O’Sullivan, G., O’Donovan, T., Piwocka, K., & McKenna, S. (2009). Curcumin induces apoptosis-independent death in oesophageal cancer cells British Journal of Cancer, 101 (9), 1585-1595 DOI: 10.1038/sj.bjc.6605308
    2. López-Lázaro, M. (2008). Anticancer and carcinogenic properties of curcumin: Considerations for its clinical development as a cancer chemopreventive and chemotherapeutic agent Molecular Nutrition & Food Research DOI: 10.1002/mnfr.200700238
    3. Castedo, M., Perfettini, J., Roumier, T., Andreau, K., Medema, R., & Kroemer, G. (2004). Cell death by mitotic catastrophe: a molecular definition Oncogene, 23 (16), 2825-2837 DOI: 10.1038/sj.onc.1207528
    4. Stuff and Nonsense – Curry can cure cancer, say scientists (2009/10/28)
    5. The best study design for dummies (2008/08/25)
    6. Huge disappointment: Selenium and Vitamin E fail to Prevent Prostate Cancer.(post on this blog about the SELECT trial – 2008/11/16)
    7. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/ucm171057.htm

    You may also want to read:

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    Evolution and Medicine. Cancer and adaptive immune responses as evolutions ‘within’.

    29 12 2008

    I had almost finished my submission for the Grand Round when I took a look at the site of the host, Moneduloides*, to find that this edition had “the interface of evolution and medicine” as a theme.

    What should I write about, considering I only had a few hours to write about this difficult theme?

    Quite coincidentally (or not, considering the forthcoming bicentenary of Darwin’s birth (1809) and the 150th anniversary of the publication of ‘On the Origin of Species’) the December 2008 Lancet is a Special Issue: Darwin’s Gifts. But it would be to easy to just summarize one or two articles from this Lancet issue…

    Evolution and Medicine can be interpreted differently. One can just see it as the evolution of medicine. Enough to write about this theme….

    One can also see the theme in the light of consequences of evolution on medicine or illnesses. Indeed there are ample examples of the consequences of men’s evolution on the susceptibility to certain illnesses, e.g. see moneduloides’ blog about the consequence of human bipedalism.

    Yesterday @carlosrizo (twitter) pointed out a link to Darwinian Medicine 2.0″. Since this would be of special interest to this web 2.0 audience, I took a look to see if I could ‘use’ this blogpost. However the post appeared to be based on a rather distorted interpretation of natural selection. Darwinian Medicine 1.0. is considered synonymous with eugenics (!), whereas Darwinian Medicine 2.0 is “gentler, interested in finding “evolutionary causes and remedies for diseases.” while leaving out the genocide”. The counterpart blog being intelligentdesign.org. it is easy to position their view.

    Although this blog merits no further discussion, it highlights the often wrong interpretations of the natural selection theories. Eugenics is “just” a political interpretation by some of Darwin’s theorie (see Wikipedia). Darwin himself thought it “absurd to talk of one animal being higher than another” and saw evolution as having no goal.

    As a biologist I grew up with the following definition of natural selection.

    Natural selection is the process by which favorable heritable traits become more common in successive generations of a population of reproducing organisms, and unfavorable heritable traits become less common, due to differential reproduction of genotypes.

    In other words natural selection genetic alterations are mostly random and chance (environment, conditions) will determine whether the genotype exhibiting a new phenotype will continue to exist or even will be more likely to survive (natural selection).

    Antibiotic resistance
    During my biology study we did all kind of mini-evolution experiments. For instance, we treated bacteria that were deficient for a specific amino-acid (AA) with mutagens and plated them on solid agar plates with or without that particular AA. Only bacteria with a mutation making them independent of that AA would survive on AA-less plates.

    Although this is not an experiment of nature, a very similar example of natural selection in action is the development of antibiotic resistance in microorganisms (see wikipedia).

    natural-selection-90

    Enhancement of antibiotic resistance by natural selection - modified from wikipedia

    Natural populations of bacteria contain considerable variation in their genetic material, primarily as the result of mutations. When exposed to antibiotics, most bacteria die quickly, but some (red in Figure) may have mutations that make them less susceptible. If the exposure to antibiotics is short, these individuals will survive the treatment. This selective elimination of maladapted individuals (lighter colors) from a population is natural selection.

    Evolutions within
    It is not difficult to see how infectious diseases were driven by natural selection (of the organisms causing these diseases). Because all rules that apply to eukaryotic organisms apply to prokaryotic organisms as well. But I would make a point that evolution and natural selection also takes place at a lower level: that of viruses (non-living organisms, see post about sputnik-virus here) and of “individual cells” within an organism. That is to say: the same mechanisms apply.

    Clonal selection and B-cell adaptive immune response.
    One example of a cellular evolution is the development of the B cell (and T cell) immune repertoire. B and T cells are cells of
    the adaptive immune response. In contrast to the innate immune response, which is always ready to respond to whatever intruder, the adaptive immune response matures throughout life, is antigen-specific and long-living. The specificity of B cells lies in the variable region of their immunoglobulins or antibodies, Y-like molecules, anchored in the B cells’ plasma membrane. There are endless antibody variants and each B cell (and its progeny) produces antibodies with one particular specificity.
    How is this diversity established?
    In the Pre-B cell phase, when B cells do not produce any immunoglobulins individual gene segments coding for the V, (D) and J regions of the heavy and light chain of the immunoglobulin molecule are randomly assembled to one molecule. The random assembly of 51 V, 27 D and 6 J gene segments provides a minimum of 8.300 different possible combinations for the heavy chain alone, but since the recombination process is not precise and extra nucleotides are inserted the number of possibilities of antibody V region diversity turn out to be greater than that.[2]
    (The following excellent animation is recommended: www.blink.biz/immunoanimations/ (be sure to choose Open > Antigen Recognition > Recombination)

    vdj-recombination-2

    When an organism encounters a foreign microorganism or other antigen, only those B cells that recognize the antigen are stimulated to divide and to become plasma cells which produce many antibodies specific for the particular antigen. This process is called clonal selection. It results in a B cell repertoire skewed towards the antigens encountered in life. The advantage is that those B cells are selected that have been proved useful. The next time the same antigen is encountered the response is quicker, stronger and more specific, a process called memory.This is also the principle behind vaccination and boostering.

    The principle of clonal B cell selection is very similar to the development of antibiotic resistance, discussed above.

    clonal-selection-users-path

    Carcinogenesis: Follicular Lymphoma
    However, sometimes clones are selected that erroneously react with ‘self’ which results in ‘autoimmunity‘.

    Cancer can also be considered as another faulty ‘evolution’, be it within the organism. Cancer cells are better at surviving and reproducing than other cells, because they have escaped the body’s controls. This allows them to increase their population much faster than other cells.

    In an interesting editorial, J Breivik comments on the work of Vineis and Berwick[4,5]:

    Vineis and Berwick argue that ‘Carcinogenesis, at least for some types of cancer, can be interpreted as the consequence of selection of mutated cells similar to what, in the theory of evolution, occurs at the population level’. Taking a more conclusive stand, I will ague that carcinogenesis is an evolutionary process within the multicellular organism. Evolution by means of natural selection is a scientific principle that reaches far beyond the origin of the species and is applicable to all systems of inheritance, including somatic development.

    One example is follicular lymphoma (FL). Follicular lymphoma is characterized by a chromosomal translocation between chromosome 14 and 18, t(14;18), caused by a faulty coupling of the immunoglobulin heavy J chain to the BCL-2 proto-oncogene on chromosome 14 during the normal VDJ-rearrangement process, described above. This mistake leads to a constitutive overexpression of BCL-2, which makes the cell less vulnerable to apoptosis (programmed cell death). Mice bearing a transgene mimicking the BCL-2 translocation have an increased incidence of spontaneous B lymphoid tumors. The lymphomas take many months to develop, however, and the penetrance of disease is low, arguing that BCL-2 overexpression on its own is not highly oncogenic (reviewed in[6]). Indeed our group has shown many years ago that t(14;18) translocations, that were considered specific for follicular lymphoma generally occur in follicular hyperplasias [7] and even in B-cells of healthy individuals [8]. Apparently B cells with the t(14;18) translocation are regularly generated in normal individuals, but only very few cells with the translocation will acquire the additional oncogenic hits necessary to establish the malignant phenotype. Overexpression of BCL-2 only gives the cells a survival advantage. Indeed, according to recent insights [9]:

    “Accumulation of genomic alterations and clonal selection account for subsequent progression and transformation. Recently, the role of the immunologic microenvironment of FL in determining clinical behavior and prognosis has been substantiated. Combined genetic and immunologic data may now support a model for the development of FL as a disease of functional B cells in which specific molecular alterations infer intrinsic growth properties of the tumor cells as well as dictate a specific functional cross talk with the immunologic regulatory network resulting in extrinsic growth support.”

    The theme of this week inspired me to philosophize about immunity and cancer being examples of evolutionary process. While reading I found that this idea is by no means new; a lot has been written about this concept. For instance in “Understanding Evolution” the writer(s) quite nicely explain the process of evolution within a cell lineage. They first explain that the key elements of the evolutionary process – variation, inheritance, and selective advantage – characterize not just populations of organisms in a particular environment, but also populations of cells within our own bodies.
    Furthermore they make the interesting statement that

    cancer – even within one person – isn’t a single entity. It’s a diverse and evolving population of cell lineages. A single tumor, for example, is made up of a variety of cell types, produced as the cells proliferated and incurred different mutations. All of this diversity means that the population of cells could easily include a mutant variety that happens to be resistant to any individual chemotherapy drug we might administer. To make matters even more difficult, treating the patient with that drug creates an environment in which the few resistant cancer cells have a strong selective advantage in comparison to other cells. Over time, those resistant cells will increase in frequency and continue to evolve. It’s not surprising then that a simple cure for cancer has yet to be developed: treating even a single type of cancer is a bit like trying to take aim at a whole set of moving targets all at once”

    Thus, this challenge helps explain why research has not yet provided us with a cure, but also points the way toward new solutions that take that evolution into account ….

    Sources:

    1. Wikipedia (several pages, as indicated)
    2. Kimball Biology Pages: [A] AgReceptorDiversity (very good background information in dictionary-format)
    3. Evolving Immunity – A Response to Chapter 6 of Darwin’s Black Box. Matt Inlay. [blog] Talkdesign: interesting discussion on whether or not clonal selection system could have evolved in the context of irreducible complexity.
    4. Cancer the evolution-within, by Dan [blogpost] on Migrations (2007/04/18) referring to:
    5. Cancer – evolution within. Breivik, J. Int. J. Epidemiol. (2006) 35, 1161-1162.
    6. The Bcl-2 family: roles in cell survival and oncogenesis. Suzanne Cory1, David C S Huang1 and Jerry M Adam. Oncogene (2003) 22, 8590-8607.
    7. Bcl-2/JH rearrangements in benign lymphoid tissues with follicular hyperplasia. Limpens J, de Jong D, van Krieken JH, Price CG, Young BD, van Ommen GJ, Kluin PM. Oncogene. 1991 Dec;6(12):2271-6.(PubMed-link)(
    8. Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Limpens J, Stad R, Vos C, de Vlaam C, de Jong D, van Ommen GJ, Schuuring E, Kluin PM. Blood. 1995 May 1;85(9):2528-36.(PubMed-link)(Google Scholar)
    9. Molecular pathogenesis of follicular lymphoma: a cross talk of genetic and immunologic factors. de Jong D. J Clin Oncol. 2005 Sep 10;23(26):6358-63.(PubMed-link)
    10. Another perspective on cancer: Evolution within. [blog] Understanding Evolution with a detailed description on natural selection within, and the evolution of cancer cells plus possible solutions.

    Figures:

    1. Antibiotic Resistance: wikipedia
    2. Clonal Selection: http://users.path.ox.ac.uk/~scobbold/tig/clons.gif
    3. Recombination: Evolving Immunity – A Response to Chapter 6 of Darwin’s Black Box, adapted from janeway