Category Archives: Uncategorized

The increase in bilateral mastectomy for treating breast cancer might not be justified

Cancer, Uncategorized, , , , , , , , , , , , , , ,
September 2014
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Bilateral mastectomy has become a common procedure to treat and to prevent breast cancer. The rate of bilateral mastectomy is increasing in the United States, in the United Kingdom, and also in Singapore among women with high grade and high risk of breast cancer1–3.

An observational study published this month on The Journal of American Medical Association4 compared the use and the mortality rate of bilateral mastectomy, unilateral mastectomy, and breast conserving surgery in 189,734 women diagnosed with stage 0–III breast cancer in California between 1998 and 2011. The team from the Cancer Prevention Institute of California and Stanford University found that bilateral mastectomy had an annual increase of 14.3% (from 2.0 % in 1998 to 12.3% in 2011), and it was more common among younger, white non-Hispanic women, with bigger and  higher grade tumors, higher education, and a private insurance. On the other hand, unilateral mastectomy was more diffuse in women older than 64 years, of Asian, Hispanic, and American Indian ethnicity, with large tumor size, high grade, and no private insurance. Compared with bilateral mastectomy, unilateral mastectomy was associated with 30% increased all-cause mortality; instead, there was no difference in mortality rate between bilateral mastectomy and breast-conserving surgery. Comparing all three procedures in early stage breast cancer patients, there was no benefit on survival associated with bilateral mastectomy over breast-conserving surgery; higher mortality was only associated with unilateral mastectomy.

This is the first study presenting a comparison among the three procedures. Other studies were published in the past comparing only two procedures at a time, but never all three together. The authors of this study state that maybe the use of bilateral mastectomy could be reduced, because there are no elements to support its benefits over other, less invasive treatments, such as breast-conserving surgery. This study was performed to identify whether the rise in bilateral mastectomies could be somehow justified, or whether the procedure could be substituted with a less expensive one. Bilateral mastectomy is an expensive procedure, and in a private healthcare system clinicians need to present supportive data to justify the selection of a procedure over another one.

If there are not enough data supporting this rise, the increase might have been caused by excessive precaution or fear. Whether it was fear or something else, patients have the right to know the real risks and benefits of each treatment based on actual data, because they are going to make the last decision, not the clinicians or the health policy makers.

 

  1. Trends in the use of bilateral mastectomy in England from 2002 to 2011: retrospective analysis of hospital episode statistics. Neuburger J, Macneill F, Jeevan R, van der Meulen JH, Cromwell DA. BMJ Open. 2013 Aug 1;3(8). pii: e003179. doi: 10.1136/bmjopen-2013-003179.
  2. Contralateral prophylactic mastectomy in an Asian population: a single institution review. Sim Y, Tan VK, Ho GH, Wong CY, Madhukumar P, Tan BK, Yong WS, Ng YY, Ong KW. Breast. 2014 Feb;23(1):56-62. doi: 10.1016/j.breast.2013.10.008. Epub 2013 Nov 23.
  3. Contralateral prophylactic mastectomy in women with breast cancer: trends, predictors, and areas for future research. Tracy MS, Rosenberg SM, Dominici L, Partridge AH. Breast Cancer Res Treat. 2013 Aug;140(3):447-52. doi: 10.1007/s10549-013-2643-6. Epub 2013 Jul 28. Review.
  4. Use of and mortality after bilateral mastectomy compared with other surgical treatments for breast cancer in California, 1998-2011. Kurian AW, Lichtensztajn DY, Keegan TH, Nelson DO, Clarke CA, SL. JAMA. 2014 Sep 3, 312(9):902-14. doi: 10.1001/jama.2014.10707.

Light exposure at night induces resistance to therapy in breast cancer

Cancer, Uncategorized, , , , , , , , , , ,

The disruption of melatonin production during the night through light exposure reduces tumor latency and drives resistance to tamoxifen in a model of estrogen receptor positive alpha (ERa+) breast cancer.

http://commons.wikimedia.org/wiki/File:Luz_en_Movimiento.jpg
http://commons.wikimedia.org/wiki/File:Luz_en_Movimiento.jpg

Melatonin is an hormone mainly produced by the pineal gland in the brain and primarily regulates sleeping habits. Its production is light sensitive; therefore, it is produced only in complete darkness, and sleeping in synthetic lights can interfere with its production. Melatonin has also been involved in the regulation of reproduction, timing of ovulation, aging, immune function, and cancer1. In 2001 a study linked night shift rotation with a moderate increase in breast cancer risk2. Studies have shown that melatonin antagonizes the metabolism of linoleic acid, the most prevalent polyunsaturated fatty acid present in the Western diet that upregulates the expression of genes controlling ER expression, cell cycle, and growth.

A group led by Dr. Steven Hill at the Tulane University (Louisiana)3 investigated how disruption of melatonin production influences not only growth but also response to tamoxifen of ERa+ tumors implanted into rats (xenograft). They did two sets of experiments. In the first set they compared animals kept under normal conditions with animals kept under dim light exposure at night (dLEN); in the second set, they compared dLEN mice with dLEN mice supplemented with nighttime melatonin. They found that tumors implanted in the dLEN rats had a shorter latency and a 2.6-fold increase in the growth rate compared with the controls. These tumors were also totally resistant to tamoxifen, whereas the control animals responded to the therapy. The dLED tumors showed high levels of proliferative markers, increased metabolism, and low apoptosis. Strikingly, when the nighttime melatonin was supplemented in the dLEN mice, tumor growth latency was reduced and resistance to tamoxifen was reestablished, with reduction of metabolism, proliferation markers, and increase in apoptosis.

Many studies have shown that melatonin can affect tumor growth in different cancer models, but this is the first study involving melatonin in resistance to therapy. The resistance to tamoxifen is a big problem in the treatment of ER+ breast cancer; about 30% of patients show resistance, and the causes are not totally understood. Strikingly, this research indicates that melatonin disruption affects resistance to therapy, through a molecular mechanism that may involve ER phosphorylation. Several lifestyle habits can influence cancer risk, cancer development, and resistance to therapy—e.g. diet, smoking, exercise. In addition, this report indicates that even sleeping in the darkness might be more beneficial against cancer.

Sleep in the dark!

1Melatonin, sleep disturbance and cancer risk. Blask DE.Sleep Med Rev. 2009 Aug;13(4):257-64. doi: 10.1016/j.smrv.2008.07.007. Epub 2008 Dec 17. Review.

2Rotating night shifts and risk of breast cancer in women participating in the nurses’ health study.Schernhammer ES, Laden F, Speizer FE, Willett WC, Hunter DJ, Kawachi I, Colditz GA.J Natl Cancer Inst. 2001 Oct 17;93(20):1563-8.

3Circadian and melatonin disruption by exposure to light at night drives intrinsic resistance to tamoxifen therapy in breast cancer. Dauchy RT, Xiang S, Mao L, Brimer S, Wren MA, Yuan L, Anbalagan M, Hauch A, Frasch T, Rowan BG, Blask DE, Hill SM. Cancer Res. 2014 Aug 1;74(15):4099-110. doi: 10.1158/0008-5472.CAN-13-3156.

Resveratrol: just a fair-weather friend?

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JUne 2014Since its first mention in a Japansee article in 19391, over the years many beneficial effects have been attributed to the natural compound, resveratrol—anticancer, anti-inflammatory, anti-aging—which is even used in skincare cosmetic. Although a large number of studies suggest its health benefits, recently some reports have been questioning these potentials.

Resveratrol is a natural phenol and antioxidant compound found in various colored vegetables and fruit, especially in the skin of red grape. Its name comes probably from the combination if the term resorcinol (chemical compund) and Veratrum (the plant where resveratrol was first isolated). It is thought to influence inflammation, aging, neuronal degeneration, and metabolism through the serine deacetylase, sirtuin-1 (SIRT-1), the cAMP pathway, or AMP-activated protein kinase2. However the exact mechanism of action is not known. A new role for resveratrol as a partial agonist of the estrogen receptor alpha (ERalpha) has been recently described3. According to this study, resveratrol binds to the ERalpha that is recruited to the interleukin-6 (IL-6) promoter and alters the binding of coregulators, such as SIRT-1, and the activity of transcriptional activators, leading to reduced inflammation. Resveratrol was identified in a previous screening for ERalpha agonists that inhibit IL-6 transciption4; thus resveratrol may have a selective role on the ERalpha pathway, inhibiting inflammation without promoting cell proliferation.

The amount of resveratrol found in foods varies greatly. It is mainly found in the skin of red grapes, red wine, peanuts, berries, and in lower amount in cocoa powder and dark chocolate5. However, the amount of resveratrol in foods is thought to be not enough to justify and mediate its effects. To understand whether resveratrol levels present in the diet can influence inflammation, cancer, cardiovascular disease, and mortality in humans, a prospective cohort study has been conducted in the Chianti region in Italy (InCHIANTI—“Aging in the Chianti Region”), in a population-based sample of 783 community-dwelling men and women 65 years or older who consume a diet rich in resveratrol6. The group of researchers, who have been studying aging in this population for fifteen years, measured the concentration of resveratrol metabolites present in the urine and found that it was not associated with inflammatory markers, cardiovascular disease, or cancer. This study shows that the amount of resveratrol present in the diet is not responsible for beneficial health effects. It is possible that the health benefits that come from the diet consumed in that region are not due to resveratrol, but to other substances present in the food. On the other hand resveratrol is rapidly metabolized in sulfate and glucuronide conjugates and it has long been believed that this could limit its bioavailability. However, a study from the University of Leicester shows that resveratrol is not rendered ineffective after it is metabolized by the body: it can be generated by resveratrol sulfate and be even more effective than the un-metabolized compound7.

Supplements that contain high quantity of resveratrol are available in the market. However, people should be careful with them, because we still don’t know the repercussions of high amount of resveratrol on human health. A very recent study published on the June issue of The FASEB Journal shows that the use of resveratrol during pregnancy can have beneficial effects on the blood flow in the placenta and on the liver function (decreased placental inflammation and liver triglyceride deposition), but can increase fetal pancreatic mass and exocrine proliferation, leading to unknown consequences on the development of the fetus8.

To date, there are not definitive studies on the benefits of resveratrol. The literature is full of controversial or incomplete reports. Therefore, be careful in listening to advertisements that sell resveratrol as a health serum.

1Takaoka M, Resveratrol, a new phenolic compound, from Veratrum grandiflorum. M Takaoka, Journal of the Chemical Society of Japan, 193 (2012):1090-1100.

2Tennen RI, Michishita-Kioi E, Chua KF. “Finding a target for resveratrol”. Cell 2012,148 (3): 387–9.

3Nwachukwu J,Srinivasan S, Bruno NE, Parent AA, Hughes TS, Pollock JA, Gjyshi O, Cavett V, Nowak J, Garcia-Ordonez RD, Houtman R, Griffin PR, Kojetin DJ, Katzenellenbogen JA, Conkright MD, Nettles KW. Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network. eLife, (2014).

4Srinivasan S., Nwachukwu J.C., Parent AA, Cavett V, Nowak J, Hughes TS, Kojetin DJ, Katzenellenbogen JA, and Nettles KW. Ligand-binding dynamics rewire cellular signaling via estrogen receptor-alpha. Nat Chem Biol (2013) 9, 326-332.

5Hurst WJ, Glinski JA, Miller KB, Apgar J, Davey MH, Stuart DA. “Survey of the trans-resveratrol and trans-piceid content of cocoa-containing and chocolate products”. Journal of Agricultural and Food Chemistry (2008) 56 (18): 8374–8.

6Semba RD, Luigi Ferrucci L, Bartali B, Urpí-Sarda M, Zamora-Ros R, Sun K, Cherubini A, Bandinelli S, Andres-Lacueva C. Resveratrol Levels and All-Cause Mortality in Older Community-Dwelling Adults. JAMA Internal Medicine, (2014) May 12.

7Patel KR, Andreadi C, Britton RG, Horner-Glister E, Karmokar A, Sale S, Brown VA, Brenner DE, Singh R, Steward WP, Gescher AJ and Brown K. Sulfate Metabolites Provide an Intracellular Pool for Resveratrol Generation and Induce Autophagy with Senescence. Science Translational Medicine, (2013) Oct 2;5(205).

8Roberts VHJ, Pound LD, Thorn SR, Gillingham MB, Thornburg KL, Friedman JE, Frias AE, and Grove KL. Beneficial and cautionary outcomes of resveratrol supplementation in pregnant nonhuman primates. FASEB J. (2014) June 28:2466-2477.

On the road of science: reproducibility, fraud, and authorship for sale

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Argentina 015 
Happy 2014!

This is my first post of the year and I would like to start this New Year reflecting on some concerning habits in science. I will just focus on only three recent articles that undermine the trustfulness of science, but there are many others out there in the jungle of scientific journals.

In a Comment published in Nature last November, Mina Bissell justifies the non-reproducibility of some in vitro experiments1`. Nowadays, “the techniques and reagents are sophisticated, time-consuming and difficult to master”, challenging the ability to reproduce complicated experiments in different laboratories. The solution, for Dr Bissell, “is to consult the original authors thoughtfully […] ask either to go to the original lab to reproduce the data together, or invite someone from their lab to come to yours.” However, this can be true for in vitro assays that are already an artifact, but I hope that it isn’t for in vivo studies used for preclinical studies. This article has opened an intense discussion on scientific reproducibility, as you can read in the comments published this month by Nature2. You can either agree or disagree with her statements, but we are spending words and time on a topic, experimental reproducibility, that shouldn’t be an issue.

Last December, Nature has reported the news regarding duplicated images used on different journals from the same group3.  Professor Fusco at the University of Naples (Italy) and an associate professor from the Academia of Lincei (Italy) are now under investigation by the police and the university. The misconduct has been revealed by Enrico Bucci, a molecular biologist founder of a small startup (BioDigitalValley) aimed at creating a database of all images from Italian papers published since 2000. Running all images on his gel-checking software, he found that out of 300 papers published from Fusco, 53 contained duplicated or cut and paste images, even one from 1985.  Some of the papers have already been retracted; one of them was published on Journal of Clinical Investigation in 2007.  It is highly possible that Fusco is only the first target of this operation that is going to reveal other misconducts. This is quite concerning not only because it is not a right practice, but also because it comes from a country, Italy, where scientific research is well behind and the funding situation is not good; this circumstance is not going to help Italian science. However, fortunately, this fraud has been unmasked.

An article published last November on Science describes a concerning practice in the Chinese scientific community4. Some intermediary agencies sell authorships on papers that have already been accepted for publication, sometimes without the consent or the knowledge of the actual authors. The price for this service varies based on the position in the author’s list. Thus someone can publish a paper not only without doing anything, but also without even knowing the authors. These practices worry the same Chinese scientific community because “hinder China’s growth in original science, damage the reputation of Chinese academics, and dampen the impact of science developed in China”, as asserted by the president of the National Natural Science Foundation of China, Wei Yang in the Editorial published on the same number of Science5.

These are just three examples of the present scientific world. Every month there is at least one retraction, at every meeting there is someone who mistrusts other’s experiments.  Unfortunately we are in a system that gives rewards and funding to sexy science and high Impact Factors publications at the expenses of the truth, the real science, made by simple and reproducible experiments and not artifactual and sexy assays.

Where is science going?

1 Bissell M. Reproducibility: The risks of the replication drive. Nature. 2013 Nov 21;503(7476):333-4.

2 NATURE ’S READERS COMMENT ONLINE.Nature. 2014 Jan 2;505:27.

3 Abbott A. Image search triggers Italian police probe. Nature. 2013 Dec 5;504(7478):18.

4 Hvistendahl M. China’s publication bazaar. Science. 2013 Nov 29;342(6162):1035-9.

5 Yang W. Research Integrity in China. Science. 2013 Nov 29;342(6162):