• Hypertension in the Oldest Old
• Melatonin Reduces Sleep Latency in Children with Neurodevelopmental Disorders
• Does Lack of Sunlight in Pregnancy Increase the Risk for Multiple Sclerosis?
• Are Organic Foods Really Better for Kids?
• Acupuncture Helps Alleviate Chronic Pain
• Early Cholecystectomy in Patients with Gallstone Pancreatitis
• Fish Consumption Is Associated with Lower Cerebrovascular Risk
• Guarding Against Holiday Weight Gain
• Obesity and the Risk for Venous Thrombosis
• Aspirin for Prostate Cancer?
MM: This is very interesting. For years we have worked under the impression that everyone needs to have blood pressure in a particular optimal range. Now we see that that optimal range could be quite different for each age and possibly gender and ethnic group. I recall my grandmother when she was in her late 80's/early 90's and that she disliked taking her blood pressure medication. She was as sharp mentally as anyone at any age. Maybe that was in part due to her periodic refusal to take her meds? Since her hypertension was considered mild to moderate that is definitely something to consider.
J Am Geriatr Soc 2012 Nov; 60:2014
Hypertension in the Oldest Old
Among 85- to 90-year-olds, high blood pressure was associated with less cognitive and physical decline.
Although a randomized trial suggested that treating hypertension is beneficial in older patients (JW Gen Med Feb 14 2012), its participants were relatively healthy. In a recent observational study, systolic hypertension was not associated with higher mortality in frail elders (JW Gen Med Aug 30 2012). Now, in a population-based study, researchers identified 572 85-year-old residents of the Netherlands and followed them until age 90. Participants were stratified at baseline into tertiles based on blood pressure (for systolic BP, 110–146, 147–161, and 162–215 mm Hg).
At baseline (age 85), higher systolic BP correlated with better scores on the Mini-Mental State Examination as well as an activities-of-daily-living scale. During 5 years of follow-up, higher baseline systolic BP was associated with less physical and cognitive decline. The apparent "protective" effect of higher BP was especially prominent in those with the most-pronounced disability at baseline. Results were similar in analyses limited to participants who were not taking antihypertensive medications.
Comment: These findings have several possible explanations: Higher BP might be protective in older people with stiffer arteries; disabling comorbidities might cause BP to fall; or people who are most vulnerable to the deleterious effects of high BP might have died already, leaving a relatively healthy cohort of hypertensive survivors. This observational study doesn't settle the question of who should receive antihypertensive treatment, but it does suggest that we should exercise caution when we consider drug therapies for the "oldest old."
— Allan S. Brett, MD Published in Journal Watch General Medicine November 29, 2012
Citation(s): Sabayan B et al. High blood pressure and resilience to physical and cognitive decline in the oldest old: The Leiden 85-Plus Study. J Am Geriatr Soc 2012 Nov; 60:2014. (http://dx.doi.org/10.1111/j.1532-5415.2012.04203.x)
http://www.ncbi.nlm.nih.gov/pubmed/23126669?dopt=Abstract
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BMJ 2012 Nov 5; 345:e6664
Melatonin Reduces Sleep Latency in Children with Neurodevelopmental Disorders
Although the treatment did not increase total sleep time, it was safe and helped children fall asleep.
Sleep disturbances are common in children with developmental disorders. In a multicenter, randomized, placebo-controlled trial, investigators examined the effectiveness of melatonin for treating severe sleep disorders (>1 hour sleep latency, <6 hours of sleep, or both for 3 of 5 nights for 
5 months) in 146 children with neurodevelopmental disorders (age range, 3–15 years) in the U.K. Immediate-release melatonin was given 45 minutes before bedtime for 12 weeks starting at a dose of 0.5 mg and increased to 12 mg based on sleep response.
After 12 weeks, melatonin significantly increased total sleep time by 22 minutes on the basis of sleep diaries (the primary outcome) compared with placebo, and reduced sleep onset latency by 38 minutes. On the basis of actigraphy, melatonin significantly reduced sleep latency only (by 45 minutes). Melatonin had the greatest effect on sleep latency in children with the longest sleep latency at baseline and was associated with earlier waking times. Melatonin was effective at doses as low as 0.5 mg and was equally effective in autistic children. Parents perceived improvements in the frequency and duration of sleep with melatonin. Adverse effects were mild and similar in the two groups; melatonin did not affect seizure control.
Comment: Sleep disorders in children adversely affect quality of life for all family members. In this study, melatonin allowed children with various neurodevelopmental problems to fall asleep faster. Although the increase in total sleep time was not considered clinically significant, parents felt that sleep problems improved. Melatonin appears to be a safe and potentially helpful therapy for sleep disturbances in this highly affected population of children.
— F. Bruder Stapleton, MD Published in Journal Watch Pediatrics and Adolescent Medicine November 28, 2012
Citation(s): Gringras P et al. Melatonin for sleep problems in children with neurodevelopmental disorders: Randomised double masked placebo controlled trial. BMJ 2012 Nov 5; 345:e6664.
(http://dx.doi.org/10.1136/bmj.e6664)
http://www.ncbi.nlm.nih.gov/pubmed/23129488?dopt=Abstract
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J Neurol Neurosurg Psychiatry 2012 Nov 14
Does Lack of Sunlight in Pregnancy Increase the Risk for Multiple Sclerosis?
Two recent studies come to divergent conclusions on maternal vitamin D in pregnancy and MS in offspring.
Low serum vitamin D levels have been associated with increased risk for multiple sclerosis (MS). Because people with MS are more likely to be born in the spring, maternal winter ultraviolet light exposure and serum vitamin D levels during gestation have been suggested as contributing factors to MS risk in offspring. Two recent studies assessed this issue.
Dobson and colleagues evaluated whether month of birth affected risk for MS among a total of 172,918 participants with MS, in a meta-analysis combining 10 studies. Among 89,059 participants considered by geographic location, significantly more people with MS than expected had been born in April, May, or June (odds ratio range, 1.06–1.11) and significantly fewer than expected had been born in October or November. The seasonal birth effect did not appear in the three studies performed at a latitude of <52°N, where exposure to sufficient ultraviolet radiation for vitamin D synthesis occurs year-round.
Salzer and colleagues evaluated serum vitamin D levels in 192 individuals prior to MS diagnosis (out of 291,500 samples from 164,000 individuals) and in 37 mothers of people with MS (from 124,000 serum samples taken during pregnancy decades earlier, typically during the first trimester). Comparing the 192 MS cases with two controls each (without MS), high vitamin D levels (
75 nmol/L), in samples drawn a median of 9 years before diagnosis, were associated with a significantly decreased risk for MS (4% of cases vs. 8% of controls; OR, 0.39). For the analysis of gestational vitamin D levels, vitamin D in the mother was not associated with MS risk in the offspring.
Comment: The seasonal birth effect for MS has been attributed to an environmental exposure during gestation, whether infectious, toxic, or metabolic. The Dobson study lends circumstantial credence to the role of sunlight and vitamin D by suggesting an effect by latitude. However, few studies were conducted at latitudes <52°N, and other confounders were not available for inclusion in the models. Salzer's findings confirm the role of serum vitamin D in the individual prior to MS diagnosis, but they could not show an association with maternal vitamin D serum levels, possibly because of the relatively small number of cases or sampling too early during pregnancy (in late summer/early fall for those born in the spring). For our patients with MS, a trial of vitamin D supplementation is under way (ClinicalTrials.gov Identifier: NCT01490502) and remains highly anticipated.
— Robert T. Naismith, MD Published in Journal Watch Neurology November 27, 2012
Citation(s): Dobson R et al. The month of birth effect in multiple sclerosis: Systematic review, meta-analysis and effect of latitude. J Neurol Neurosurg Psychiatry 2012 Nov 14; [e-pub ahead of print].
(http://dx.doi.org/10.1136/jnnp-2012-303934)
Salzer J et al. Vitamin D as a protective factor in multiple sclerosis. Neurology 2012 Nov 20; 79:2140.
http://www.ncbi.nlm.nih.gov/pubmed/23170011?dopt=Abstract
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Pediatrics 2012 Nov; 130:e1406
Are Organic Foods Really Better for Kids?
The American Academy of Pediatrics Committee on Nutrition and Council on Environmental Health review the evidence and lack thereof.
The market for organic foods has increased greatly in recent years, but what is known about actual health and environmental benefits of organic products (JW Pediatr Adolesc Med Sep 26 2012)? In a clinical report, the American Academy of Pediatrics (AAP) reviews regulations, labeling standards, nutritional quality, and safety of organic versus conventional foods. Highlights of the report include the following:
- Organic labeling: For the past 10 years, the U.S. Department of Agriculture has required that products labeled "organic" must consist of at least 95% organically produced ingredients. Some other labeling terms are not as closely regulated.
- Produce: Some studies show lower nitrates and higher vitamin C, phosphorus, and antioxidant levels in organic produce, but nutrient content is affected by many farming variables. No convincing or consistent evidence demonstrates substantial differences in nutritional value between organic and conventional produce.
- Milk: Organic milk has been found to have higher antioxidant and polyunsaturated fat levels, but these levels depend on the diets of organic and conventional cows. No evidence exists that bovine growth hormone alters the macronutrient or vitamin/mineral composition of cow's milk. Certified organic milk is pasteurized. Raw milk is unpasteurized and not recommended.
- Sex steroids: Despite the use of sex steroids to increase meat and milk yield, studies have shown that sex steroid levels in meat, fish, poultry, milk, and eggs are clinically insignificant. Organic and estrogen-fed cows produce milk with similar estrogen concentrations. No studies support concerns that ingested estrogen from treated animals causes precocious puberty or breast cancer. Even small sex steroid concentrations must be evaluated in the context of the current environment, in which endocrine disruptors such as bisphenol A and phthalates are ubiquitous.
- Nontherapeutic antibiotic use: Evidence is clear that this conventional practice increases the risk for disease caused by antibiotic-resistant organisms.
- Pesticides: An organic diet reduces children's exposure to harmful pesticides, but no experimental studies show that pesticide exposure from conventional foods causes adverse neurodevelopmental or other health outcomes.
- Environmental impact: Organic farms use less energy and produce less waste. A large prospective farming study showed productivity was comparable on organic and conventional farms.
- Cost: Organic products cost 10% to 40% more than conventional products; a family on a fixed budget cannot purchase as much healthy food (e.g., fruits and vegetables) if they choose to buy organic products.
Comment: No direct evidence demonstrates that children receive meaningful nutritional or overall health benefits from consuming organic foods rather than conventional foods. The AAP recommends that clinicians focus on promoting diets rich in fresh fruits and vegetables, whole grains, and low-fat dairy products. The information in this report provides clinicians with details about nutritional and environmental differences between organic and conventional foods to share with parents.
— Cornelius W. Van Niel, MD Published in Journal Watch Pediatrics and Adolescent Medicine November 28, 2012
Citation(s): Forman J and Silverstein J. Organic foods: Health and environmental advantages and disadvantages. Pediatrics 2012 Nov; 130:e1406.
(http://dx.doi.org/10.1542/peds.2012-2579
http://www.ncbi.nlm.nih.gov/pubmed/23090335?dopt=Abstract
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Arch Intern Med 2012 Oct 22; 172:1454
Acupuncture Helps Alleviate Chronic Pain
A systematic review shows modest benefit that is explained partly by the placebo effect.
Many people believe that acupuncture can relieve chronic pain (particularly headache and musculoskeletal pain), but most studies are small and of low quality; thus, considerable skepticism persists. This systematic review included only high-quality, randomized, controlled trials (patient-level data from 29 studies; 17,922 patients with headache; osteoarthritis; or shoulder, back, or neck pain) conducted with sham acupuncture, no acupuncture, or both as controls. Patients were followed for 1 to 6 months in most studies.
Significant, albeit modest, improvements in pain control were seen in acupuncture groups versus sham or no-acupuncture groups. The clinical benefit of acupuncture compared with no acupuncture translated to a difference of roughly 50% versus 30% of patients achieving at least a 50% reduction in pain. The relative benefit of acupuncture compared with sham acupuncture was much smaller.
Comment: Although these results support the belief that acupuncture can help alleviate chronic pain, the strong response to sham acupuncture suggests that much of the benefit of acupuncture results from a strong placebo effect. However, acupuncture's efficacy in patients with debilitating chronic pain still has potential value. As exploration of the biological pathways responsible for the placebo effect continues, acupuncture is worth considering for such patients.
— Thomas L. Schwenk, MD Published in Journal Watch General Medicine November 29, 2012
Citation(s): Vickers AJ et al. Acupuncture for chronic pain: Individual patient data meta-analysis. Arch Intern Med 2012 Oct 22; 172:1444. (http://dx.doi.org/10.1001/archinternmed.2012.3654)
Avins AL. Needling the status quo. Arch Intern Med 2012 Oct 22; 172:1454.
(http://dx.doi.org/10.1001/archinternmed.2012.4198)
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Arch Surg 2012 Nov; 147:1031
Early Cholecystectomy in Patients with Gallstone Pancreatitis
Early surgery shortened length of hospital stay, with no downside.
Traditionally, surgeons have waited several days before performing cholecystectomy in patients who experience mild gallstone pancreatitis. However, in a 50-patient randomized trial, UCLA researchers demonstrated that such patients can undergo cholecystectomy safely during the first 48 hours of hospitalization (JW Gen Med Apr 16 2010). Now, the same research group has performed a retrospective study of surgery timing in 303 patients with mild gallstone pancreatitis at two medical centers. Patients with suspected cholangitis, marked dehydration, or evidence of persistent common bile duct stones were excluded.
Thirty-nine percent of patients underwent early laparoscopic cholecystectomy (within 48 hours of admission); their characteristics were similar to those of patients who underwent procedures after 48 hours. Median length of hospital stay was significantly shorter in the early group than in the delayed group (3 vs. 6 days). Complication rates and readmission rates were similar between the two groups. No deaths occurred.
Comment: This study provides further evidence that early surgery is safe for patients with mild gallstone pancreatitis. When these patients are admitted to nonsurgical services, surgeons should be consulted promptly.
— Allan S. Brett, MD Published in Journal Watch General Medicine November 29, 2012
Citation(s): Falor AE et al. Early laparoscopic cholecystectomy for mild gallstone pancreatitis: Time for a paradigm shift. Arch Surg 2012 Nov; 147:1031. (http://dx.doi.org/10.1001/archsurg.2012.1473)
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MM: Here is an example of an article that can lead to" throwing the baby out with the bath water". Fish oil supplements may not be adequate to make a significant difference relative to cerebrovascular risk but we have seen benefits in patients with arthritis, cognitive thinking and ADD. Don't give up on this nutritional supplement yet! And, don't forget Krill Oil. It may show marked benefits as additional studies are performed. Remember though, always refrigerate any of these products once they have been opened. After all, they are from FISH!
BMJ 2012 Oct 30; 345:e6698
Fish Consumption Is Associated with Lower Cerebrovascular Risk
But supplementation with long-chain 
-3 fatty acids was not.
Fish consumption and long-chain 
-3 fatty acid intake are associated with lower coronary heart disease risk. In a systematic review and meta-analysis, investigators assessed whether such an association also exists for cerebrovascular disease (defined as ischemic or hemorrhagic stroke, or transient ischemic attack).
In 21 prospective cohort studies that involved 675,000 participants, researchers assessed fish consumption and cerebrovascular risk. Compared with weekly consumption of 
1 servings of fish, consumption of 2 to 4 servings was associated with 6% lower risk for cerebrovascular disease, and consumption of 
5 servings was associated with 12% lower risk; both differences were significant. In contrast, analysis of 14 prospective cohort studies that involved 305,000 participants revealed no association between dietary intake of long-chain 
-3 fatty acids (or circulating 
-3 biomarkers) and cerebrovascular risk. Likewise, analysis of 12 randomized trials that involved 62,000 participants showed that 
-3 supplementation (typically oil capsules at an average daily intake of 1.8 g; average follow-up, 3 years) was not associated with lower cerebrovascular risk.
Comment: In this large analysis, fish consumption, but not supplementation with long-chain 
-3 fatty acids, was associated with lower cerebrovascular risk. The authors speculate that the benefits of fish consumption likely are "mediated through a complex interplay among a wide range of nutrients commonly found in fish," which cannot be captured in a supplement. However, given the observational design of the fish-consumption studies, residual confounding is possible (e.g., higher fish consumption might be associated with other healthy behaviors, such as consuming less red meat).
— Paul S. Mueller, MD, MPH, FACP Published in Journal Watch General Medicine November 27, 2012
Citation(s): Chowdhury R et al. Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: Systematic review and meta-analysis. BMJ 2012 Oct 30; 345:e6698.
(http://dx.doi.org/10.1136/bmj.e6698)
http://www.ncbi.nlm.nih.gov/pubmed/23112118?dopt=Abstract
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Guarding Against Holiday Weight Gain
Simple tips for minimizing weight gain during the food-focused holiday season
By Craig Weatherby
On average, Americans gain from 0.5 to 1.75 pounds a year – and about half of that gain occurs during the winter holidays.
People tend to lose a little of that weight in January, but the net holiday-related gain really adds up.
According to the U.S. Centers for Disease Control (CDC), average body weight in adults aged 25 to 44 years rises by 3.4 percent in men and by 5.2 percent in women (Williamson DF et al. 1990).
The same CDC study found that people who gain five pounds or more during the holiday season are more likely to already be obese or overweight, compared with those who gain less.
It’s also well known that weight-loss programs are less effective over the holidays than at other times of year.
With those sobering facts in mind, we offer a few simple tips on avoiding weight gain during the winter holidays.
Stick to healthful whole foods
We’re faced with an abundance of alluring, fatty and starchy foods during the holidays.
There’s nothing wrong with fat per se … omega-3s in particular are metabolic allies. But don’t add much oil or butter to otherwise healthful, filling, high-fiber whole foods such as colorful vegetables.
Skip the gravy and don’t put butter on your mashed potatoes. And don’t over-stimulate your appetite by adding salt or seasoning to your food.
Some foods may actually help limit appetite and overeating … a topic we covered in “Food Allies in the Weight War: Spices, Tea, and Fish” and in other articles in the Foods & Metabolic Health, General Weight & Fitness, and Omega-3s & Metabolic Health sections of our news archive.
Favor filling foods
Focus on foods low in “energy density” and high in “nutrient density”.
Energy density means the number of calories per ounce or gram, and nutrient density is the amount of protein, fiber, healthy fats, vitamins, minerals, and antioxidants.
Nutrient-dense foods are relatively low in calories. These include seafood, lean meats, beans and legumes, whole grains, whole soy foods (tofu, tempeh, miso), and colorful vegetables.
Energy-dense foods that are typically high in starches, sugars, and fats.
Slow the pace of meals
Relax during meals. Chew your food slowly and thoroughly so that you can start feeling full before you’ve wolfed down a lot of calories.
Keep moving
Studies consistently show that exercise prevents weight gain and maintains higher levels of appetite-suppressing hormones (e.g., leptin) and brain chemicals.
Take walks after meals, add extra workouts, and whenever possible, stand instead of sitting.
Manage stress
Stress promotes weight gain in several ways, and the holidays are an inherently stressful time for many people. Make time for rest, relaxation, and leisure.
“Emotional eating” is common over the holidays. People tend to spend more time with their families over the holidays and – depending on the relationships in question – that can be stressful.
Remain aware of why you are eating, and if you are not actually hungry, take a walk to ease anxiety.
Stay well-rested
Poor sleep is proven to increase eating. Even a single night of poor sleep can increase appetite the following day.
Sources : Berman SM, Paz-Filho G, Wong ML, Kohno M, Licinio J, London ED. Effects of Leptin Deficiency and Replacement on Cerebellar Response to Food-Related Cues. Cerebellum. 2012 May 11. [Epub ahead of print]; Cornier MA, Melanson EL, Salzberg AK, Bechtell JL, Tregellas JR. The effects of exercise on the neuronal response to food cues. Physiol Behav. 2012 Feb 28;105(4):1028-34. Epub 2011 Dec 3.; Flores MB, Fernandes MF, Ropelle ER, Faria MC, Ueno M, Velloso LA, Saad MJ, Carvalheira JB. Exercise improves insulin and leptin sensitivity in hypothalamus of Wistar rats. Diabetes. 2006 Sep;55(9):2554-61.; Loria-Kohen V, Fernández-Fernández C, Bermejo LM, Morencos E, Romero-Moraleda B, Gómez-Candela C. Effect of different exercise modalities plus a hypocaloric diet on inflammation markers in overweight patients: A randomised trial. Clin Nutr. 2012 Nov 6. doi:pii: S0261-5614(12)00230-0. 10.1016/j.clnu.2012.10.015. [Epub ahead of print]; Williamson DF, Kahn HS, Remington PL, Anda RF. The 10-year incidence of overweight and major weight gain in US adults. Arch Intern Med. 1990 Mar;150(3):665-72.; Zhao J, Tian Y, Xu J, Liu D, Wang X, Zhao B. Endurance exercise is a leptin signaling mimetic in hypothalamus of Wistar rats. Lipids Health Dis. 2011 Dec 2;10:225.
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J Thromb Haemost 2012 Sep; 10:1761
Obesity and the Risk for Venous Thrombosis
The risk for VT is magnified when factor VIII and activated protein C resistance are combined with non-O blood type or factor V Leiden.
Obesity is associated with a two- to threefold increased risk for venous thrombosis (VT), but how obesity influences this risk is unclear. In particular, the hemostatic factors that contribute to thrombosis have not been previously identified.
To examine the relationship between obesity, hemostasis, and risk for VT, investigators from the Netherlands and Norway studied two large cohorts of VT patients and healthy controls. Body-mass index (BMI), factor VIII (FVIII), activated protein C resistance (aPCR), factor V Leiden (FVL), and blood group were examined in a Dutch cohort of 474 patients and 474 controls, and BMI, FVL, and blood group were examined in a Norwegian cohort of 515 patients and 1476 controls.
In the Dutch cohort, BMI was directly related to FVIII and inversely related to aPCR; the associations were stronger for men than women. Risk for VT was significantly higher for individuals with BMIs in the middle and upper tertiles (1.9 and 2.2 times higher, respectively) than for those in the lowest tertile; the differences remained significant after adjustments for FVIII and aPCR.
In the combined Dutch and Norwegian cohorts, the odds ratio for VT rose significantly with increasing BMI in those with blood group O and negative FVL (from 1.0 to 1.9) and in those with blood group O and FVL (from 3.0 to 9.7). The OR for VT also rose significantly with increasing BMI in those with non-O blood type and negative FVL (from 1.5 to 3.4); ORs were >25 at all BMI tertiles in those with non-O blood group and FVL.
Comment: Increased FVIII and aPCR have previously been associated with an increased risk for VT and also appear to be raised in persons with obesity. When these risk factors are combined with non-O blood group or FVL, the risk for VT is magnified. Whether weight reduction will result in a decline in FVIII, improved sensitivity to aPC, and a decrease in VT should be evaluated in future clinical trials.
— David Green, MD, PhD Published in Journal Watch Oncology and Hematology November 27, 2012
Citation(s): Christiansen SC et al. The relationship between body mass index, activated protein C resistance and risk of venous thrombosis. J Thromb Haemost 2012 Sep; 10:1761. (http://dx.doi.org/10.1111/j.1538-7836.2012.04828.x)
http://www.ncbi.nlm.nih.gov/pubmed/22726452?dopt=Abstract
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J Clin Oncol 2012 Oct 1; 30:3540
Aspirin for Prostate Cancer?
In an observational study of men with localized prostate cancer, aspirin use was associated with lower cancer-specific mortality.
Recently published data suggest that daily aspirin use can lower cancer incidence and mortality (JW Gen Med Apr 24 2012). In the present study, researchers examined whether aspirin improved outcomes in 6000 patients with localized prostate cancer who underwent radical prostatectomy or radiotherapy. The data came from the multicenter CaPSURE study, an observational investigation of men with prostate cancer, about a third of whom used aspirin.
During median follow-up of 6 years, 3.2% of participants died of prostate cancer. Unadjusted 10-year estimated prostate cancer–specific mortality was significantly lower among aspirin users than nonusers (2% vs. 8%). In multivariable analysis (with adjustment for clinical stage, Gleason score, and treatment modality), cancer-specific mortality remained significantly lower among aspirin users than among nonusers (hazard ratio, 0.43).
Comment: This report has numerous limitations, including a lack of information on duration of aspirin use, comorbidities, and overall mortality in aspirin users versus nonusers. Still, the results are sufficiently provocative and plausible that it seems reasonable to offer aspirin therapy to men with prostate cancer who have no strong contraindications.
— Allan S. Brett, MD Published in Journal Watch General Medicine October 18, 2012
Citation(s): Choe KS et al. Aspirin use and the risk of prostate cancer mortality in men treated with prostatectomy or radiotherapy. J Clin Oncol 2012 Oct 1; 30:3540.
(http://dx.doi.org/10.1200/JCO.2011.41.0308)
http://www.ncbi.nlm.nih.gov/pubmed/22927523?dopt=Abstract
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