June 26, 2017

DHA improves kidney cancer therapy according to new study

DHA and kidney cancerAccording to a new study published in the journal Molecular Cancer Therapeutics, researchers demonstrate that docosahexaenoic acid (DHA) reduces renal cell carcinoma invasiveness, growth rate, and blood vessel growth when combined with the anti-cancer therapy regorafenib.

Regorafenib is one of a new generation of anti-cancer therapies that attack tyrosine kinases. Unfortunately, kidney cancers mutate to resist these therapies. However, DHA metabolites called epoxydocosapentaenoic acid (EDP) reduce the ability of cancers to invade and grow blood vessels. The study found that DHA and regorafenib have a syngergist effect with one another.

Researchers tested DHA in combination with regorafenib against cancer cell lines and human tumors in mice. As a result, kidney cancer cells were killed in both models. This combination reduced both tumor growth and angiogenesis. This is the process in which tumors recruit blood vessels to feed their expansion.

This study demonstrates the synergistic effect combining regorafenib and DHA specifically. Fish oil supplements has been shown to increase the efficacy of other medications like I shared last week with antidepressants. Previous studies have shown that omega-3 fatty acid status determines the efficacy of B vitamins.

This does not mean that DHA will have the same impact against kidney cancer on its own although there are numerous other studies that demonstrate that omega-3 fatty acids inhibit the growth and spread of other cancers.

For example, there was a study published November 2014 in the Journal of Pharmacology and Experimental Therapeutics, which supported that omega-3s reduce the risk of prostate cancer and its effectiveness in inhibiting the proliferation of cancer cells.

Researchers found working with prostate cell cultures that the fatty acids bind to a receptor called free fatty acid receptor 4 (FFA4). Instead of stimulating cancer cells, the receptor acts as a signal to inhibit growth factors that suppress the proliferation of the cancer cells.

In addition, there has been several studies have found that omega-3 consumption reduces either the risk of development of prostate cancer or the rate of mortality for those diagnosed with prostate cancer.

The research does support fish oil as a simple way patients with advanced kidney cancer could increase the effectiveness of their treatment. Most people are deficient in essential fatty acids and should be taking a fish oil supplement for their overall health.

By Michael Jurgelewicz, DC, DACBN, DCBCN, CNS
Source: J. Kim, A. Ulu, D. Wan, J. Yang, B. D. Hammock, R. H. Weiss. Addition of DHA Synergistically Enhances the Efficacy of Regorafenib for Kidney Cancer Therapy. Molecular Cancer Therapeutics, 2016; DOI:10.1158/1535-7163.MCT-15-0847

Study demonstrates nutritional supplements improve efficacy of antidepressants

depression functional medicineAccording to an evidence review published earlier this week on Tuesday in the American Journal of Psychiatry, researchers confirmed that certain nutritional supplements can increase the efficacy of antidepressants for individuals with clinical depression.

Researchers at Harvard and the University of Melbourne examined 40 clinical trials alongside a systematic review for the evidence indicating nutrient supplements used as an adjunct to treat clinical depression. As a result, fish oil, SAMe, folate, and Vitamin D all demonstrated an increased efficacy of the medication. These medications include SSRIs, SNRIs and tricyclic antidepressants.

The most significant finding from their review was seen in those taking a fish oil supplement in addition to an antidepressant. Numerous studies have demonstrated the benefits of fish oil supplements for overall brain and cognitive health, however, this review validated its use in combination with antidepressant medications.

In addition, the research team also confirmed supporting research for the use of folate, vitamin D, and SAMe for improving mood when taken with antidepressant medications. It was interesting but folic acid did not demonstrate positive results like methylfolate did. We can speculate that a large percent of this population may have an MTHFR SNP and just reinforces the importance of using natural bioactive forms of folate.

Millions of people worldwide currently take antidepressants. There is a significant amount of research supporting the use of nutritional supplements to improve mental health.

Many medical doctors are aware of the benefits of omega 3 fatty acids these days, but may be unaware of the benefits of combining them with antidepressant medication for a better outcome.

The researchers found no safety concerns in combining these nutritional supplements with antidepressant medication, however, all patients should always talk with their health care provider before taking these supplements.

Also, we should consider natural alternatives to anti-depressants such as Sceletium tortuosum and Saffron flower. Sceletium tortuosum has attracted increasing attention over past few decades for promoting a sense of wellbeing and treating depression and Saffron flower has had numerous studies demonstrating positive outcomes on mild clinical depression and has gone head to head with SSRIs and tricyclic antidepressants demonstrating the same efficacy. These botanicals are used in conjunction with L-5- MTHF and vitamin B12 to improve mood, decrease anxiety, and help support individuals with depression.

By Michael Jurgelewicz, DC, DACBN, DCBCN, CNS

Source: Jerome Sarris, Jenifer Murphy, David Mischoulon, George I. Papakostas, Maurizio Fava, Michael Berk, Chee H. Ng. Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. American Journal of Psychiatry, 2016; appi.ajp.2016.1 DOI:10.1176/appi.ajp.2016.15091228

Higher vitamin D levels are associated with a decreased cancer risk

vitamin D and cancerIn a recent study published in PLOS ONE, researchers reported that higher levels of vitamin D are associated with a decreased cancer risk.

Previous studies have linked a vitamin D deficiency with colon cancer, breast, lung, and bladder. In this study researchers have quantitated amount of vitamin D to reduce cancer risk.

The researchers analyzed two previous studies. One was a randomized clinical trial of 1,169 women and a prospective cohort study of 1,135 women. In the clinical trial, the median blood serum level of 25(OH)D was 30 ng/ml and in the prospective cohort study, it was 48 ng/ml.

The researchers found that the cancer rate decreased with increased vitamin D levels. Women with a vitamin D level of 40 ng/ml or greater had a 67% lower risk of cancer than women with levels of 20 ng/ml or less.

The recommended vitamin D level as well as the recommended daily allowance have been debatable over the past several years. In 2010, the Institute of Medicine (IOM) recommended 600 IU of vitamin D daily.

It is rare that I see patient with optimal vitamin D levels (over 50 ng/ml). Most people I find need about 4000 IU to 5000 IU of vitamin D daily to maintain healthy normal levels and approximately 8000 IU to 10,000 IU daily for a few months to address a deficiency and get the vitamin D level to an optimal range.

This study confirms that reduced cancer risk is measurable at 40 ng/ml and additional benefits are seen at higher levels. These results demonstrate an inverse relationship between vitamin D OH levels and risk of cancer.

The author states that increasing vitamin D levels to at least 40 ng/ml in the population would substantially reduce cancer incidence and associated mortality and improving vitamin D status is a key to prevention.

By Michael Jurgelewicz, DC, DACBN, DCBCN

Source: Sharon L. McDonnell, Carole Baggerly, Christine B. French, Leo L. Baggerly, Cedric F. Garland, Edward D. Gorham, Joan M. Lappe, Robert P. Heaney. Serum 25-Hydroxyvitamin D Concentrations ≥40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study. PLOS ONE, 2016; 11 (4): e0152441 DOI: 10.1371/journal.pone.0152441

New study explains the pathway between diabetes and Alzheimer’s

diabetes and Alzheimer'sAccording to a new study published 3 days ago in the Journal of Alzheimer’s Disease, an NYU researcher discusses the pathway between diabetes and Alzheimer’s. It have long been known that there is a strong association between diabetes and Alzheimer’s but it was unclear. This can help guide healthcare providers and patients on how Alzheimer’s may be prevented.

The author compared decades of research on diabetes and Alzheimer’s disease. The main mechanisms that connects the two diseases are insulin and the enzymes that break it down. These same enzymes that break down insulin also break down amyloid-beta, which is the protein that forms tangles and plaques in the brains of people with Alzheimer’s disease. When people have hyperinsulinemia, they produce too much insulin due to a poor diet, pre-diabetes, metabolic syndrome, early diabetes, obesity, etc. As a result, these enzymes are too busy breaking down insulin to break down amyloid-beta, causing amyloid-beta to accumulate.

The American Diabetes Association estimates that roughly 8.1 million Americans have undiagnosed diabetes and 86 million have pre-diabetes and are unaware of this. I recently shared a study last month in the Journal of the American Board of Family Medicine where only 1/4 of patients who were prediabetic received lifestyle recommendations from their primary care physician. This is the missed opportunity for the overall health of the patient, diabetes prevention, and reducing the risks of Alzheimer’s and dementia.

The good news is that hyperinsulinemia is preventable and reversible through dietary changes, lifestyle changes, exercise, and proper nutrient support. If we address the epidemic of metabolic syndrome, pre-diabetes, and obesity, we could significantly reduce the risk of Alzheimer’s disease and dementia, as well as the many complications that come along with diabetes.

It is important to test every patient’s A1C levels are on regular basis. Hyperinsulinemia is linked to insulin resistance and obesity. Weight loss and exercise are considered the best treatments.
It is important to watch carbohydrate intake. Consume a diet that is high in fiber and low in sugars and flour with a low glycemic load. A healthy diet turns on the right gene messages, promotes a healthy metabolism, and prevents insulin resistance and diabetes.

In addition, there are several nutrients that can play a role in such as chromium, zinc, carnosine, benfotiamine, alpha lipoic acid, and inositol. For those individuals that may need some further support to reduce insulin resistance when the essential nutrients are not enough, consider berberine. It has very similar metabolic effects to metformin but also has a significant effect on body composition (waist circumference and waist to hip ratio) and dyslipidemia, which is not seen with metformin. Furthermore, berberine has long been known for its antimicrobial properties. This is another antidiabetic mechanism of berberine through modulating the gut microbiota.

By Michael Jurgelewicz, DC, DACBN, DCBCN, CNS

Source: Unraveling Alzheimer’s: Making Sense of the Relationship between Diabetes and Alzheimer’s Disease, Schilling, Melissa A., Journal of Alzheimer’s Disease, doi: 10.3233/JAD-150980, published 12 April 2016.

New study finds vitamin D improves heart function

vitamin D and heart diseaseAccording to a new study published Monday in the Journal of the American College of Cardiology, researchers demonstrated that vitamin D improves heart function in patients with chronic heart failure.

Heart failure affects more than 23 million people worldwide. This is significant because this is the first evidence that vitamin D supplementation can improve heart function of people with heart failure. These findings could make a significant difference in the care of heart failure patients.

These patients are often deficient in vitamin D because older people make less vitamin D in response to sunlight than younger people. In addition, many people avoid the sun due to the dangers of overexposure and those using sunscreen with reduce their production of vitamin D.

This study included over 160 patients who were already being treated for their heart failure using proven treatments including beta-blockers, ACE-inhibitors and pacemakers. The participants took a vitamin D supplement or placebo for one year. The patients who took vitamin D had an improvement in heart function which was not demonstrated in those who took the placebo.

These changes in heart function were measured by cardiac ultrasound. Researchers measured heart function by performing an echocardiogram and measuring the ejection fraction. The ejection fraction in healthy individuals is typically between 60% and 70%. In heart failure patients, the ejection fraction is significantly decreased. The patients in this study had an average ejection fraction of 26%.

The results demonstrated that those patients who took Vitamin D saw an improvement in heart function from 26% to 34%. In those who received the placebo saw no change in cardiac function. This confirms that vitamin D supplementation may decrease the risk for implantable cardioverter defibrillators (ICD). These are expensive and also involve an operation. This is a benefit to the patient’s overall health and the healthcare system.

I would also consider using a vitamin D supplement containing vitamin K or taking a vitamin K supplement in addition to vitamin D to optimize the level of each vitamin and prevent against arterial calcification. I find that most of individuals need anywhere from 4,000-10,000 IUs/day of vitamin D and then about 1-2 mg of vitamin K1 since most people do not eat enough vegetables to get enough vitamin K. This is also the amount that completely carboxylates osteocalcin and the amount most may need to convert to K2.

By Michael Jurgelewicz, DC, DACBN, DCBCN, CNS

Source: “Effects of Vitamin D on Cardiac Function in Patients With Chronic HF: The VINDICATE Study” Klaus K. Witte, MD, FACC, FESC; Rowena Byrom, RN; John Gierula, BSc; Maria F. Paton,MSc, BSc; Haqeel A. Jamil, PhD; Judith E. Lowry, BSc, MSc; Richard G. Gillott, BSc; Sally A. Barnes, BSc, MSc; Hemant Chumun, RN; Lorraine C. Kearney, LC, RN; John P. Greenwood, PhD; Sven Plein, PhD; Graham R. Law, PhD; Sue Pavitt, PhD; Julian H. Barth, MD; Richard M. Cubbon, PhD; Mark T. Kearney, MD. Journal of the American College of Cardiology, doi:10.1016/j.jacc.2016.03.508. April 4, 2016.

High doses of EPA for depression according to new study

Omega 3 and DepressionDepression is a major cause of disease burden worldwide which affects approximately 350 million people. Fish oil supplementation has been a recommended adjunct for treating major depressive disorder (MDD).

According to a new meta-analysis published two weeks ago in Translational Psychiatry researchers further confirm the link between intake of omega-3 fatty acids and the reduction in major depressive disorder. This meta-analysis included 13 studies with 1233 participants which included only random placebo-controlled trials assessing the effects of EFA supplementation on depressive symptoms in MDD. In addition, whether the supplementation effects depended upon EPA or DHA dose or their ratio.

Among the participants, those who supplemented with EPA and DHA had similar effects as compared to meta-analyses of those taking antidepressants. In addition, this effect was greater in studies where participants were supplementing with higher doses of EPA. Furthermore, the present meta-analysis demonstrated that EPA/DHA ratio had no significant effect nor did the DHA dose. The DHA did not have an effect on the MDD systems. In conclusion, this suggests that it is not the ratio of EPA vs DHA that is important, but the higher EPA dose. It is interesting that EPA seems to be responsible for the beneficial effects of omega fatty acid supplementation while DHA concentrations appear to vary more between patients and controls. We must consider that the beneficial effects of EFA supplementation are not because the supplementation corrects a membrane DHA insufficiency, but due to the anti-inflammatory properties of EPA.

This new meta-analysis supports earlier research on the importance and beneficial effects of omega-3 fatty acids in MDD and this effect seemed more significant in studies including those who supplemented with higher doses of EPA and included patients taking antidepressants.

Also, we should consider natural alternatives to anti-depressants such as Sceletium tortuosum and Saffron flower. Sceletium tortuosum has attracted increasing attention over past few decades for promoting a sense of wellbeing and treating depression and Saffron flower has had numerous studies demonstrating positive outcomes on MDD and has gone head to head with SSRIs demonstrating the same efficacy.

By Michael Jurgelewicz, DC, DACBN, DCBCN

Source: R J T Mocking, I Harmsen, J Assies, M W J Koeter, H G Ruhe, A H Schene. Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. Translational Psychiatry (2016) 6, e756; doi:10.1038/tp.2016.29 Published online 15 March 2016

Antibiotic use before age 2 increases risk of childhood obesity

functional medicine infants gut healthAccording to new research published last Friday in Gastroenterology, researchers found that administration of three or more courses of antibiotics before children reach an age of 2 years is associated with an increased risk of early childhood obesity.

Antibiotics have been used to promote weight gain in livestock for several decades and this research confirms that antibiotics have this same effect in humans. This does not mean antibiotics should not be used when necessary. However, healthcare providers as well as parents must think about their usage in infants in the absence of confirmed indications.

In this study, researchers conducted a large cohort study in the UK to assess the association between antibiotic exposure before the age of 2 and obesity at age 4 years. Children who had antibiotic exposure had a 25% increase in the risk of early childhood obesity. This risk was strongest with repeated exposures to antibiotics.

This is another study that confirms how antibiotics alter the composition the gut microbiome and its function predisposing children to obesity just as seen in livestock and animal models.

There was a previously study published back in November which demonstrated how a single course of antibiotics could alter the gastrointestinal microbiome for up to one year.

Antibiotics are prescribed in approximately 49 million pediatric outpatient visits per year in the United States. Many of these antibiotics are prescribed without clear indication although there is a stronger awareness of antibiotic resistance and other risks such as dermatologic and allergic concerns as well as increased risks of inflammatory bowel disease and autoimmune conditions.

If a patient is prescribed a course of antibiotics, it is crucial they concurrently take a probiotic
such as Saccharomyces boulardii. This non-pathogenic yeast that protects the microbiome during antibiotic therapy. S. boulardii is protective to the intestinal epithelial cells and maintaining intestinal barrier function. It also increases SIgA secretion, directly inhibits colonization of harmful bacteria, and restores normal intestinal function in patients with diarrhea.

With the growing levels of antibiotic resistance and exit of major pharmaceutical companies from antibiotic development really makes phage therapy another great treatment option for the growing number of untreatable infections. They have a 80 to 90 percent success rate against bacteria likely to show antibiotic resistance, such as Escherichia coli.

In addition, there are many botanical extracts, essential oils, and silver that have a long history of antimicrobial properties while being relatively sparing to the beneficial bacteria that should be considered.

Source: Frank I. Scott, Daniel B. Horton, Ronac Mamtani, Kevin Haynes, David S. Goldberg, Dale Y. Lee, James D. Lewis. Administration of Antibiotics to Children Before Age 2 Years Increases Risk for Childhood Obesity. Gastroenterology, 2016; DOI: 10.1053/j.gastro.2016.03.006

New study shows how anxiety disrupts our decision making

anxiety functional medicineAccording to a study published four months ago in The Journal of Neuroscience, researchers discovered a mechanism for how anxiety may impact decision making. They noted that anxiety disengages a region of the brain called the prefrontal cortex (PFC), which is critical for flexible decision making. Think of the PFC as the CEO of our brain. This is the area that helps us get tasks done.

In this study researchers monitored the activity of neurons in the PFC in an animal model. As a result, the scientists made two observations. First, anxiety leads to bad decisions when there were distractors present. Second, bad decisions from anxiety involve numbing of PFC neurons.

The evidence indicates that anxiety has a selective effect on neuronal activity that supports decision making. Anxiety can be very overwhelming not only from how the person feels, but how it interferes with virtually all aspects of daily life including decision making.

The current approach to studying and treating anxiety is simplistic. It is associated with fear and it has been mostly assumed that it over-engages entire brain circuits. However, this study demonstrates that anxiety disengages brain cells in a specific manner.

Many people experience anxiety in their daily lives. For some individuals it is just a bad, passing feeling, but for many, anxiety controls their daily life to the point of affecting the decisions they make.

Patients with anxiety are commonly treated with selective serotonin reuptake inhibitors (SSRIs). Some individuals try to avoid these because they don’t want to take a medication. In addition, long term SSRI use can upregulate phosphodiesterase-4 (PDE4), which can reduce the sensitivity of SSRIs in response to long term treatment.

An alternative botanical to consider is Sceletium tortuosum. This is a South African plant that has been used for hundreds of years for stress and relaxation. It does act as natural SSRI and PDE4 inhibitor and therefore, has a synergistic effect on the central nervous system and broader therapeutic effect than an SSRI alone. Another advantage is this botanical is not contraindicated with other nutrients like St. John’s wort, 5-HTP, and SAMe.

Sceletium tortuosum reduces anxiety related amygdala reactivity. This is the area of the brain responsible for arousal, the regulation of emotion, and plays an important role in mediating anxiety and depression. This botanical dampens the response from the amygdala, which decreases the feeling of fear.

Saffron flower is another botanical that has been shown to decrease anxiety. There have been several research reviews comparing saffron head to head with SSRIs demonstrating the same efficacy.

Source: Park J., Wood J., Bondi C., Del Arco A., Moghaddam B. Anxiety Evokes Hypofrontality and Disrupts Rule-Relevant Encoding by Dorsomedial Prefrontal Cortex Neurons. The Journal of Neuroscience, 16 March 2016, 36(11): 3322-3335; doi: 10.1523/JNEUROSCI.4250- 15.2016

New study shows prediabetes is ignored by primary care physicians

diabetes functional medicineAccording to a study published 3 days ago in the Journal of the American Board of Family Medicine, less than 25% of patients who met the criteria for prediabetes received lifestyle recommendations from their primary care physician. This is a huge missed opportunity for the overall health of the patient, diabetes prevention, and decreasing future health care costs.
Metabolic syndrome and insulin resistance are a significant health care problem in the United States. Over one-third of the population has prediabetes. This is the most important time to take action and educate these individuals on diet, lifestyle, and exercise. Prediabetes is considered one of the biggest risk factors for the development of diabetes. Approximately 30% of people with prediabetes will develop diabetes within five years we play the wait and see game and do not make dietary and lifestyle interventions.

Researchers from the University of Florida analyzed data from the 2012 National Ambulatory Medical Care Survey. About 34% of the patients had a HA1c level between 5.7 and 6.4. Of these patients, only a few were told they even had prediabetes, and only 23% received treatment for their issue (lifestyle modification counseling or medication).
Low rates of prediabetes diagnosis and treatment would be expected if doctors don’t have lab results available, but those in this study all had recent lab tests. Even with the results in front of them, doctors were not acknowledging prediabetes in their patients or providing any type of management or treatment.

Insulin resistance is preventable and reversible through lifestyle changes, proper nutrition, supplements, exercise and stress management. Weight loss and exercise are considered the best treatments for restoring the body’s ability to respond to insulin. Losing even a few pounds can reduce the risk for health problems and help control glucose levels.

Exercise can help prevent diabetes by lowering your blood sugar and reducing weight. It also helps the cells become more sensitive to insulin.

In addition, it is important to watch carbohydrate intake. Consume a diet that is high in fiber and low in sugars and flour with a low glycemic load. Previous research has indicated that insulin resistance has a microbial component that alters the caloric extraction from ingested food. This ties together the importance of dietary fiber and insulin resistance. We also see this with short chain fatty acids (SCFA) on patient stool profiles. Low levels of SCFAs tend to be associated with low levels of beneficial bacteria. When patients introduce pre-biotics or increase their dietary fiber intake by consuming fruits and vegetables, the beneficial bacteria and SCFAs both increase.

Healthy, whole foods help prevent and reverse diabetes and insulin resistance. A healthy diet turns on the right gene messages, promotes a healthy metabolism, and prevents insulin resistance and diabetes.

In addition, there are several nutrients that can play a role in improving insulin signaling such as chromium, zinc, carnosine, benfotiamine, alpha lipoic acid, and inositol.

The key to diabetes prevention is properly educating these individual with prediabetes on the proper diet and lifestyle modifications. We don’t want to manage half the population with diabetes but prevent them from getting diabetes.

Source: Arch G. Mainous III, PhD, Rebecca J. Tanner, MA and Richard Baker, MD. Journal of the American Board of Family Medicine. March 8, 2016. DOI.10.3122/jabfm.2016.02.150252

New study demonstrates link between low vitamin D and prostate cancer

vitamin D and prostate cancerIn a new study published February 22nd in the Journal of Clinical Oncology, researchers find a major link between low levels of vitamin D and aggressive prostate cancer. This study showed that low serum vitamin D blood levels in men can predict aggressive prostate cancer identified at the time of surgery.
This finding is significant because it can offer guidance to men and their doctors who may be monitoring the cancer rather than removing the prostate.

The research team stated that “vitamin D deficiency may predict aggressive prostate cancer as a biomarker and that a deficiency should be corrected with supplements.”

Previous studies that showed this association were based on labs performed well before treatment. The study provides a more direct correlation because it measured D levels within a few months before the tumor was visually identified as aggressive during surgery.

Since vitamin D is a biomarker for both bone health and severity of many other chronic diseases, everyone should have their levels routinely checked.

The researchers further went on to say that all men should be assessing and supplementing according to optimize their vitamin D levels. This is smart preventive health care.

This study was part of a larger ongoing study of 1,760 men in the Chicago area investigating the association between vitamin D and prostate cancer. The current study consisted of 190 men with an average age of 64 who had a radical prostatectomy to remove their prostate from 2009 to 2014.
Eighty seven men of this group had aggressive prostate cancer. Those with aggressive cancer had an average vitamin D level of 22.7 ng/ml. Most people should taking vitamin D supplements, specifically during winter months, however, I found this is really required all year round.

It is rare to have normal vitamin D levels when you work in an office every day. Most people I find need about 4000 IU daily to maintain healthy normal levels whereas 8000 IU to 10,000 IU daily is usually required to get low vitamin D levels to an optimal range.

By Michael Jurgelewicz, DC, DACBN, DCBCN

Source: Y. A. Nyame, A. B. Murphy, D. K. Bowen, G. Jordan, K. Batai, M. Dixon, C. M. P. Hollowell, S. Kielb, J. J. Meeks, P. H. Gann, V. Macias, A. Kajdacsy-Balla, W. J. Catalona, R. Kittles. Associations Between Serum Vitamin D and Adverse Pathology in Men Undergoing Radical Prostatectomy.Journal of Clinical Oncology, 2016; DOI: 10.1200/JCO.2015.65.1463