Omega 3 fatty acid for the prevention of cognitive decline and dementia.

Evidence from observational studies suggests that diets high in omega-3 long-chain polyunsaturated fatty acids (PUFA) may protect people from cognitive decline and dementia. The strength of this potential protective effect has recently been tested in randomised controlled trials.


To assess the effects of omega-3 PUFA supplementation for the prevention of dementia and cognitive decline in cognitively healthy older people.

Search methods

We searched ALOIS – the Cochrane Dementia and Cognitive Improvement Group’s Specialized Register on 6 April 2012 using the terms: “omega 3”, PUFA, “fatty acids”, “fatty acid”, fish, linseed, eicosapentaenoic, docosahexaenoic.

Selection criteria

Randomised controlled trials of an omega-3 PUFA intervention which was provided for a minimum of six months to participants aged 60 years and over who were free from dementia or cognitive impairment at the beginning of the study. Two review authors independently assessed all trials.

Data collection and analysis

The review authors sought and extracted data on incident dementia, cognitive function, safety and adherence, either from published reports or by contacting the investigators for original data. Data were extracted by two review authors. We calculated mean difference (MD) or standardised mean differences (SMD) and 95% confidence intervals (CI) on an intention-to-treat basis, and summarised narratively information on safety and adherence.

Main results

Information on cognitive function at the start of a study was available on 4080 participants randomised in three trials. Cognitive function data were available on 3536 participants at final follow-up.

In two studies participants received gel capsules containing either omega-3 PUFA (the intervention) or olive or sunflower oil (placebo) for six or 24 months. In one study, participants received margarine spread for 40 months; the margarine for the intervention group contained omega-3 PUFA. Two studies had cognitive health as their primary outcome; one study of cardiovascular disease included cognitive health as an additional outcome.

None of the studies examined the effect of omega-3 PUFA on incident dementia. In two studies involving 3221 participants there was no difference between the omega-3 and placebo group in mini-mental state examination score at final follow-up (following 24 or 40 months of intervention); MD -0.07 (95% CI -0.25 to 0.10). In two studies involving 1043 participants, other tests of cognitive function such as word learning, digit span and verbal fluency showed no beneficial effect of omega-3 PUFA supplementation. Participants in both the intervention and control groups experienced either small or no cognitive declines during the studies.

The main reported side-effect of omega-3 PUFA supplementation was mild gastrointestinal problems. Overall, minor adverse events were reported by fewer than 15% of participants, and reports were balanced between intervention groups. Adherence to the intervention was on average over 90% among people who completed the trials. All three studies included in this review are of high methodological quality.

Authors’ conclusions

Direct evidence on the effect of omega-3 PUFA on incident dementia is lacking. The available trials showed no benefit of omega-3 PUFA supplementation on cognitive function in cognitively healthy older people. Omega-3 PUFA supplementation is generally well tolerated with the most commonly reported side-effect being mild gastrointestinal problems.

Further studies of longer duration are required. Longer-term studies may identify greater change in cognitive function in study participants which may enhance the ability to detect the possible effects of omega-3 PUFA supplementation in preventing cognitive decline in older people.


Plain language summary

Fish oils for the prevention of dementia in older people

Dementia is a progressive illness which mainly affects older people. Previous research from observational studies has suggested that increased consumption of fish oils rich in omega-3 long-chain polyunsaturated fatty acids (omega-3 PUFA) may reduce the chance of developing dementia, while other studies show no effect. Oily fish, such as salmon, mackerel, herring and sardines are a rich source of omega-3 PUFA which are essential for brain development.

The authors of this review included studies where healthy participants over the age of 60 years who were cognitively healthy at the start of the study were randomly assigned to receive extra omega-3 PUFA in their diet or a placebo (such as olive oil). The main outcomes of interest were new cases of dementia diagnosed during the study period, cognitive decline, side-effects, and adherence to the intervention.

The authors included three randomised controlled trials involving 3536 participants. In two studies participants were randomly assigned to receive gel capsules containing omega-3 PUFA or olive or sunflower oil for six or 24 months. In the third study, participants were randomly assigned to receive tubs of margarine spread for 40 months (regular margarine versus margarine fortified with omega-3 PUFA).

None of the studies examined the effect of omega-3 PUFA on new dementia cases over the study period. In two studies involving 3221 participants there was no difference between the omega-3 PUFA and placebo group in mini-mental state examination score at final follow-up. In two studies (1043 participants), other tests of cognitive function such as word learning, digit span and verbal fluency showed no beneficial effect of omega-3 PUFA supplementation. Participants in both the intervention and control groups experienced little or no cognitive decline during the studies.

The main reported side-effect of omega-3 PUFA supplementation was mild gastrointestinal problems, but overall minor symptoms were reported by fewer than 15% of participants, and people in the control group were just as likely to report symptoms as those receiving an omega-3 PUFA supplement. Adherence to the supplementation protocol was high in all trials with on average over 90% of supplements being apparently consumed by trial participants. All three studies included in this review were of high methodological quality, and so the findings are unlikely to be due to chance or bias.

The results of the available studies show no benefit for cognitive function with omega-3 PUFA supplementation among cognitively healthy older people. Omega-3 PUFA supplements may have other health benefits, and the authors comment that consumption of fish is recommended as part of a healthy diet.

Longer studies are required, during which greater changes in cognitive function may occur, to enable researchers to identify possible benefits of omega-3 PUFA in preventing cognitive decline.

Source: Cochrane Library.

First Statewide Ban of Plastic Bags.

In a first-of-its-kind move in the United States, the residents of Hawaii have collectively said “No!” to plastic bags.

Honolulu Mayor Peter Carlisle penned the crowning achievement when he signed a bill banning the bags beginning July 1, 2015.

While Honolulu’s new law does have some exceptions, like plastic bags for newspaper delivery, frozen foods and flowers, within three years Hawaii will be the first state in the union to have banned the vast majority of the bags everywhere in the state.

Is It Time to Say Goodbye to the Plastic Bag?

In Hawaii, the ban was accomplished by each of the state’s counties banning them on an individual basis, rather than by a state law. Carlisle’s signature in the last county to ban the bags completed the act of essentially making it a statewide rule without ever having to go before the state legislature.

Some of the bans are already in place or scheduled to begin next year, with fines of up to $1,000 for each day of violation. The plastic bag issue is particularly important for Hawaii as it is in the middle of the ocean and it is very easy for bags to blow into the ocean.

Meanwhile, Los Angeles became the largest city in the United States to ban plastic bags at supermarket checkout lanes. The city gave stores 16 months to phase them out, at which time shoppers will have to bring their own reusable bags or pay 10 cents for each paper bag.

The trend seems to be picking up speed. San Jose, San Francisco, Pasadena, Monterey, Long Beach, and other cities in California have already banned them. Seattle, Washington’s bag ban, which was passed in December 2011, took effect in July 2012, and other areas, such as Aspen, Colorado, have adopted similar bans.

Around the world, countries including China and Ireland are taking a stand against the use of these highly polluting bags, adopting measures ranging from bans to fees on plastic bags in order to reduce their use. Bag taxes can also be incredibly effective. Washington DC put into effect a 5-cent tax on plastic bags two years ago, and the number of plastic bags given by businesses to customers dropped from 22.5 million per month in 2009 to a mere 3 million per month, almost as soon as the tax went into effect.

In Illinois, however, a bill is on the table (SB 34421) that requires plastic bag recycling programs, but would make it illegal for any city in the state to ban the use of plastic bags — and it’s currently waiting a decision from the governor.

Shocking Statistics About Plastic Bag Waste

For a succinct and entertaining introduction to the waste that is the plastic bag, I highly recommend the film “Bag It.”2 It is a truly eye-opening look to the vastness of the problem, and the immense waste that could be spared if more Americans toted a reusable bag with them to the grocery store. As their web site reports:3

“In the United States alone, an estimated 12 million barrels of oil is used annually to make the plastic bags that Americans consume. The United States International Trade Commission reported that 102 billion plastic bags were used in the U.S. in 2009. These bags, even when properly disposed of, are easily windblown and often wind up in waterways or on the landscape, becoming eyesores and degrading soil and water quality as they break down into toxic bits.

Their manufacture, transportation and disposal require large quantities of non-renewable resources and release equally large amounts of global-warming gases.”

On a worldwide scale, each year about 500 billion to 1 trillion plastic bags are used worldwide. At over 1 million bags per minute, that’s a lot of plastic bags, of which billions end up as litter each year, contaminating oceans and other waterways.

Plastic Bag Bits are Now Taking Over Our Oceans

Plastic bags, like the petroleum they are made from, don’t biodegrade very well at all, rather, they photodegrade. Meaning, they break down into smaller and smaller toxic bits, which contaminate soil and waterways, and enters the food chain — animals accidentally eat these bits and pieces, mistaking them for food. According to the National Oceanic and Atmospheric Administration (NOAA):4

“Studies have shown that fish and other marine life do eat plastic. Plastics could cause irritation or damage to the digestive system. If plastics are kept in the gut instead of passing through, the fish could feel full (of plastic not food) and this could lead to malnutrition or starvation.

… Plastic debris accumulates persistent organic pollutants (POPs) such as PCBs (polychlorinated biphenyls) up to 100,000 to 1,000,000 times the levels found in seawater (Mato et al. 2001). Oceanic fragments have also tested positive for other POPs, such as DDT, PAHs, and aliphatic hydrocarbons. Many of these pollutants, such as PCBs and DDTs, are known endocrine disruptors and developmental toxicants.”

The problem is so severe that multiple plastic “stews” have formed in the oceans. Scientists have dubbed one of the masses of plastic bags, jugs, bottles, nets, and other plastic junk the “Great Pacific Garbage Patch,” and its volume is growing at an alarming pace.  In some areas, it’s said that there are 40 times more plastic in the water than plankton!5

Of course, plastic bags aren’t only a problem in the oceans; they’re a problem on land, too. It’s estimated that plastic bag use in the United States create 300,000 tons of landfill waste each year, and those chemical-laden materials will not stay contained forever.

According to the Clean Air Council:6

“The barriers of all landfills will eventually break down and leak leachate into ground and surface water. Plastics are not inert, and many landfill liners and plastic pipes allow chemicals and gases to pass through while still intact.”

Is Recycling the Answer?

Recycling is clearly better than tossing a plastic bag in the trash, but the truth is that only about 5 percent of plastic bags are recycled7 and some estimates place that at closer to 1 percent. This isn’t only a matter of consumers not playing their part: the truth is that plastic bag recycling isn’t profitable like say, aluminum cans. It reportedly costs $4,000 to process and recycle one ton of plastic bags, which have a market value of only $32!8 And, adding insult to industry, many plastic bags that are recycled are shipped to China to do so, another major waste of energy. reported:9

“Many plastic bags collected for recycling are wastefully shipped to overseas processing facilities. According to a 2007 American Chemistry Council report, 10 the U.S. exports 57% of its postconsumer recovered film to China (25% of which consists of plastic bags, contained under the blanket term “mixed film”) where there once were “thousands” of plastic processing centers.

However, when the economic downturn happened in late 2008, many of these Chinese plastic processors went out of business. Bottom line: there is a glut of this material that is not getting recycled, leaving material recovery facilities with bales of collected recyclable plastic with no one to sell it to.”

Ready to Ditch Plastic Bags?

Plastic bags may seem like an insignificant issue, but they add up significantly over time. This is one area where virtually everyone can have a dramatic impact for change, especially if you encourage your friends, family and neighbors to follow your lead. You don’t need to wait for a legislative ban to come to your area – you can enact your own “ban” starting today. Top tips for ditching plastic bags, and other forms of plastic waste, include:

  • Carry reusable shopping bags – keep them in the trunk of your car, or stash a couple of the small fold-up varieties in your purse so you’re always prepared
  • Avoid plastic produce bags – put the produce right into your reusable cloth bag instead
  • Use reusable cloth bags for packaging your child’s school lunch and snacks
  • Ditch bottled water – opt for reusable glass or stainless steel bottles instead
  • Buy milk and other beverages in reusable glass bottles


Source: Dr. Mercola

Testing Strategies to Rule Out Acute Coronary Syndromes: Which Is Most Efficient?

Compared with standard evaluation, early CCTA shortened hospital stay but increased subsequent testing and radiation exposure with no reduction in overall cost of care.

Advances in technology have expanded the choices available for evaluating patients with acute chest pain but have also generated much controversy about the ideal testing strategy. In the ROMICAT-II trial, sponsored by the National Heart, Lung, and Blood Institute, investigators compared a strategy of early contrast-enhanced coronary computed tomographic angiography (CCTA) with standard emergency-department evaluation of adults with a suspected acute coronary syndrome (ACS) with respect to length of hospital stay, subsequent testing, cost, and radiation exposure.

Of 1273 patients assessed for eligibility, 1000 were randomized (mean age, 54; almost 50% women). Average hospital stay was 7.6 hours shorter in the CCTA group than in the standard-care group (P<0.001). In the 8% of patients with ACS, the length of hospital stay was similar in both groups. Clinical adverse events were rare and similar in both groups. The CCTA group underwent more diagnostic testing than the standard-evaluation group (2 tests, 23% vs. 11%; P<0.001). Mean cumulative radiation exposure was also higher in the CCTA group (13.9 mSV vs. 4.7 mSV; P<0.001). In 649 patients with detailed cost data available, the overall cost of the two strategies was similar.

Comment: These findings demonstrate that a coronary computed tomographic angiography strategy can decrease time in the emergency department at the cost of more radiation exposure and subsequent testing. However, an editorialist reasonably questions the study’s assumption that a standard evaluation in low-risk patients must involve any testing at all. Clearly, the results of this study will not end the debate.

Source: Journal Watch Cardiology

The Myth of a Safer Hospital Birth for Low-Risk Pregnancies?

Do you believe that a hospital is the safest place to give birth to a baby? Society certainly paints the picture this way, portraying the hospital as the savior of sorts where women must rush off to in the middle of the night at the first sign of labor.

However, a growing number of women are choosing to buck the status quo and deliver their babies right at home.

And wouldn’t you know it … this isn’t a new fad, it’s a return to the way women have been birthing babies for ages – and the research shows it’s often the safer way, too.

Home Birth is Safer for Most Low-Risk Pregnancies

In an article written by Judy Cohain, CNM, she highlights 17 studies conducted over the last 15 years that show attended planned home birth is safer for low-risk women than hospital birth. In 12 of the studies, rates of perinatal mortality (deaths that occur before, during or immediately after birth) were either lower or similar for home birth, while rates of maternal morbidity were significantly lower, compared to hospital birth.

She pointed out five studies that appeared to show home birth as less safe, but this was because they included high-risk cases in the mix. Cohain stated:1

“Another 5 studies claim home birth to have a higher perinatal mortality rate compared to hospital birth but they all include high risk births in the planned homebirth group.

Instead of excluding the high risk births from both groups, they include the home birth outcomes of premature births at 34-37 weeks gestation, breech and twins, lethal anomalies incompatible with life, unattended home births, unplanned home births, or women who became risked out of home birth by becoming high risk at the end of pregnancy, had hospital births, but are included in the home birth group.

These 5 studies conclude that home birth is less safe than hospital birth, when what these papers actually found is that low risk births are safer at home but premature births have better outcomes in hospital.  

Possible explanations for the false conclusion of these studies could be paternalistic power games over women or hospital birth being not only the most common but also the most profitable reason for hospitalization. Remove the high risk births from those studies and they also confirm that home birth is safer for low risk women than hospital birth.”

What Makes Hospital Births Risky for Low-Risk Women?

When you enter a hospital setting, birth, an inherently natural experience, is automatically turned into a medical condition. Many women are given the drug Pitocin, a synthetic form of oxytocin, to jumpstart labor and intensify contractions, or their membranes are artificially ruptured, which then can set off a cascade of biological changes that increase the need for more medical interventions, and ultimately Caesarean section (C-section).

C-section is the most common operation performed in the United States, and accounts for nearly one-third of all births. According to the World Health Organization, no country is justified in having a cesarean rate greater than 10 percent to 15 percent. The United States’ rate, at nearly 32 percent, is so high that even The American College of Obstetricians and Gynecologists admits it is worrisome.

This is actually the highest rate ever reported in the United States, and a rate higher than in most other developed countries. One study in the British Medical Journal found that a woman’s risk of death during delivery is three to five times higher during cesarean than a natural delivery, her risk of hysterectomy four times higher, and her risk of being admitted to intensive care is two times higher.2

C-section rates are lower among home births, as well as midwife-attended births. At one small hospital run by the Navajo Nation, where midwives deliver most babies born vaginally, the C-section rate is only 13.5 percent. According to Cohain, these are some of the factors that may make a hospital birth more dangerous for a low-risk pregnancy:

Planned delivery in hospital indicates women fear a bad outcome, which can be a self-fulfilling prophesy Increased fear releases adrenalin and other adrenergic neurotransmitters which can slow down or even stop the birth process Unfamiliar environment, strangers, people in uniform, unfamiliar smells during labor counter mammalian birth instinct Hospital staff reservoir of bacteria, which the mother/baby lacks immunity to Lower access to food, drink can cause hypoglycemia and dehydration
Car accidents on the way to hospital Fear and unfamiliar environment increase pain level, which sends stress signals to fetus, provoking negative influence on fetal heart rate Collusion among hospital workers takes precedence over commitment to client and safe protocol Lack of accountability of staff to patients contributes to poor outcomes Laying on back compresses the aorta and vena cava decreasing oxygen delivery to fetus
Continuous fetal monitoring increases pain, decreases oxygenation of fetus, decreases mobility and increases anxiety Hourly vaginal exams push bacteria up into uterus, causing increased rate of infection after 3 exams Overuse of antibiotics kills healthy flora, lowering immune system capability Artificial rupture of membranes (AROM) can cause cord prolapse, increased infection and pain Induction can cause cord prolapse, uterine rupture, amniotic fluid embolism, increased postpartum hemorrhage
Epidural causes fever in 15% of women, which increases neonatal seizures, which can cause brain damage Episiotomy can cause hemorrhage, third and fourth degree extensions,  permanent disability. Vacuum increases rate of third and fourth degree tears, causing life long incontinence of urine and feces and sexual disability and increased hemorrhage and for the baby: intracranial hemorrhage, scull fractures, and, rarely, brain damage or fetal death Shoulder dystocia because of delivering in a hospital bed instead of on all 4s Cesarean can cause maternal and perinatal death, and increased maternal and fetal morbidity, lifelong scar pain, infertility, adhesions, decreased nursing success, increased stillbirth and placenta accreta on subsequent pregnancies.

What Conditions are Better Dealt With at the Hospital?

Ruptured uterus and placental abruption most often occur in high-risk cases, which ordinarily should not be considered candidates for home birth, which leave essentially only two acute conditions that have better outcomes in the hospital versus at home: cord prolapse and Amniotic Fluid Embolism (AFE). So while there are certainly cases where a hospital birth is preferable, this typically applies to most high-risk cases, along with the four emergency situations:

  1. Cord prolapse
  2. Ruptured uterus
  3. Amniotic Fluid Embolism (AFE)
  4. Placental abruption

As home births have been increasing (by nearly 30 percent from 2004 to 20093) it is common for the media to highlight the rare home birth tragedies, when a baby might have been saved had the birth taken place in a hospital. This does occur, but it is rare … far more rare than babies who end up dying due to unnecessary medical interventions or hospital errors.

Cohain concludes:

“The deaths caused by rare acute condition at planned attended low risk home birth that might have had a better outcome in hospital are outweighed by the deaths and morbidity due to common acute conditions caused by hospital interventions. Planned attended home birth outshines hospital birth for low risk women in every category of acute emergency.

Today research wrongly considers hospital birth as the gold standard. Bias towards hospital births causes the majority of researchers to ignore the fact that women could achieve even better outcomes than hospital birth, at planned attended home birth.”

Are You Interested in Having a Home Birth?

In the United States it often takes a lot of diligence and determination to go against the norm and find a physician or midwife who performs home births. It is rare to find an obstetrician that will agree to a home birth in the United States, and while certified nurse midwives (CNMs) can legally attend home births in any state, most do not and choose to practice in hospitals instead.

Only 27 states currently license or regulate direct-entry midwives (or certified professional midwives (CPMs), who have undergone training and met national standards to attend home births. In the other 23, midwife-attended births are illegal, however women often end up finding a midwife on the “black market,” who because of a lack of any type of regulatory oversight may or may not have adequate training.

It is certainly possible to find highly qualified and trained midwives practicing on the underground market. These women often believe strongly in women’s right to choose home birth, and risk being arrested and prosecuted for practicing medicine or nursing without a license to offer their services.

There are also people practicing as midwives who have not received adequate training that can also be found in this underground home birth market, so if you do go this route it’s imperative that you thoroughly check out and reference the person you are working with. A campaign is currently underway to expand state licensing of CPMs so that women who want a home birth can choose from a qualified pool of applicants, but until that happens you have a few legal options for home birth:

  • Find a certified nurse midwife (CNM) who attends home births in your state or in a nearby state (then travel to that state to give birth)
  • Find a CPM who is either licensed by your state or in a nearby state (then travel to that state to give birth)
  • Use a CNM but give birth in a hospital or birth center (a compromise). If you decide to go this route, make a detailed birth plan. This is a document that states the expectant mother’s or couple’s interests or desires for their birth experience.

It is not a legal document but is an important way of letting the doctors and hospital staff know of your wishes regarding medical interventions for mom and baby. Discuss your birth plan with your doctor or midwife ahead of time, and also be sure your nurse and any other hospital staff receive a copy upon admittance.

Source: Dr. Mercola

Outbreak of Illness and Death Among Children in Cambodia.

The outbreak appears to have been caused by enterovirus 71.

In early July 2012, an outbreak of severe illness with high mortality was reported by the Ministry of Health in Cambodia. According to a WHO report dated July 13, 78 cases in 14 provinces had been identified since April, mostly in children aged ❤ years.

Investigation focused on the 61 children who met the case definition, of whom 54 had died. Illness manifestations included respiratory symptoms, fever, and generalized neurological abnormalities; children who died usually did so within 24 hours after hospital admission. Samples from 31 patients were tested for a variety of pathogens by Institut Pasteur du Cambodge, and “most” tested positive for enterovirus 71 (EV-71); a few also tested positive for dengue virus or Streptococcus suis. On July 15, 2012, authorities announced that no additional cases had been noted in Cambodia. Investigators believed that the use of steroids, which can suppress the immune system, worsened the illness in many of the patients.

Comment: EV 71 — a member of the picornavirus family — was first isolated in the late 1960s. It has been associated with outbreaks worldwide, most recently in Asia. Infection with EV 71, like that with other enteroviruses, ranges from asymptomatic to lethal and can manifest as rashes, diarrhea, respiratory symptoms, meningitis, hand-foot-mouth disease (HFMD), or myocarditis. Less commonly, it has been associated with acute flaccid paralysis, encephalitis, Guillain-Barré syndrome, and pulmonary edema and hemorrhage.

HFMD is most often caused by coxsackievirus A16 (another enterovirus) but is also caused by EV 71. According to the WHO, HFMD usually begins with fever, poor appetite, malaise, and sore throat. One or 2 days after fever onset, painful sores develop on the tongue, gums, and inside of the cheeks, beginning as small red blistering spots and then often becoming ulcers. A nonitchy skin rash develops over 1 or 2 days, with flat or raised red spots that may blister. Usually located on the palms of the hands and soles of the feet, the rash can also appear on the buttocks or genitals. Generally, HFMD is spread from person to person by direct contact with nose or throat discharges, saliva, fluid from blisters, or stool of infected persons. Transmissibility is greatest during the first week of the illness but can last for several weeks. No vaccine or antiviral agent has proven effective in preventing or treating EV 71 infection.

Source: Journal Watch Infectious Diseases



Tumors May Resist Cancer Drugs with Help from Neighboring Cells.

Researchers have identified a protein secreted by nontumor cells that may help nearby tumors evade the effects of anticancer drugs. The results, published online in Nature on July 4, add to a body of evidence that interactions between cancer cells and surrounding cells in the tumor microenvironment may influence the growth of tumors and their responses to treatments.

Patients with cancer rarely have complete responses to targeted drugs, and this suggests that there are mechanisms that can render a substantial proportion of tumor cells innately resistant to therapies. Although genetic mutations that allow tumors to acquire resistance over time have been identified, less is known about sources of innate resistance.

To identify nontumor sources of innate resistance, Dr. Todd Golub of the Broad Institute and his colleagues grew cancer cells along with cells from the body’s connective tissue, or stroma, in the lab. When they exposed these mixtures of stromal cells and cancer cells to targeted anticancer drugs, the cancer cells were resistant to 15 of the 23 agents evaluated.

An analysis of more than 500 factors secreted by noncancer cells indicated that a protein called hepatocyte growth factor (HGF) may make melanomas with BRAF gene mutations resistant to treatment with vemurafenib, a recently approved drug that targets BRAF-mutated melanoma cells.

When the authors tested 34 samples from patients with melanoma, they found a correlation between HGF levels and the amount of tumor shrinkage following vemurafenib treatment. They also found evidence of resistance mediated by the microenvironment in other cancers.

Several drugs that inhibit HGF or MET, the receptor on tumor cells for HGF, are in development or have been approved for other indications, the authors noted. Combination clinical trials in BRAF-mutant melanoma, colorectal cancer, and possibly other tumor types could be considered, they added.

“It is increasingly recognized that both the tumor and its microenvironment will need to be therapeutically targeted for maximum efficacy,” commented Dr. Dinah Singer, director of NCI’s Division of Cancer Biology. “This study provides an explicit example of a therapeutic strategy to address this.”

Understanding the role of the tumor microenvironment in the initiation, progression, and spread of cancer, Dr. Singer added, is a goal of the Tumor Microenvironment Network, an initiative sponsored by NCI.

This research was supported in part by the National Institutes of Health (P50-CA093683 and U54-CA112962).

Source: NCI






Observation as Good as Surgery for Some Men with Prostate Cancer.

Many men diagnosed with early-stage prostate cancer could forego radical prostatectomy and live as long as men who have immediate surgery, according to long-awaited results from a clinical trial published last week in the New England Journal of Medicine (NEJM).

The results of the trial, called PIVOT, were initially presented last year at the American Urological Association annual meeting. But many researchers and clinicians have been anxious to see the published paper so they can delve into the trial’s details and better gauge how the results will affect clinical practice.

The trial took place from 1994 to 2002, when screening for prostate cancer with the prostate-specific antigen (PSA) test was becoming widespread. The 731 men in the trial, whose median age was 67, were diagnosed with localized prostate cancer based on PSA test results and a biopsy. They were then randomly assigned to undergo either a radical prostatectomy or observation, sometimes called “watchful waiting.”

Overall, after follow-up for as long as 15 years (median of 10 years), the percentage of men who died from any cause was similar in both groups: 47 percent in men assigned to surgery versus 49.9 percent in men who underwent observation, a difference that was not statistically significant. The absolute difference in the risk of dying from prostate cancer was very similar, 5.8 percent versus 8.4 percent, and was also not statistically significant.

The data suggested, however, that men in the surgery group whose PSA level was above 10 ng/mL had a lower risk of dying from any cause including prostate cancer, Dr. Timothy Wilt of the Veterans Affairs Center for Chronic Disease Outcomes Research in Minneapolis, MN, and his colleagues reported. A similar, but not statistically significant, trend was seen among men whose cancer was considered to be at intermediate or high risk of progressing.

“Our findings add to evidence supporting observation, and possibly active surveillance, for most men who receive a diagnosis of localized prostate cancer, especially those with a low PSA value or low-risk disease,” they wrote.

The trial is “not necessarily definitive,” said Dr. Barry Kramer, director of NCI’s Division of Cancer Prevention. But the results, he continued, “are important findings that men can incorporate into the decision-making process” as they consider their options.

Dr. Kramer cautioned against extrapolating too much from the subset analyses that suggested a benefit from surgery for men with a PSA score above 10 ng/mL or high-risk disease. When the overall results of a study are not statistically significant, subgroup analyses “can give you variable and conflicting results,” he said. “You have to be careful in interpreting those findings.”

In an accompanying editorial in NEJM, Drs. Ian Thompson of the University of Texas Health Science Center and Catherine Tangen of the Fred Hutchinson Cancer Research Center argued that the trial’s size likely affected its results. PIVOT was originally designed to enroll 2,000 patients, but, due to difficulties in recruiting patients, the design was altered. In the end, Drs. Thompson and Tangen wrote, there were too few patients to provide the necessary statistical power to show whether surgery could reduce mortality.

The finding that men with low-risk cancer who underwent surgery had no reduction in the risk of dying is consistent with other studies of active surveillance, the editorialists continued, and “strongly supports this approach” for those men. “On the other hand, high-grade, aggressive prostate cancers usually have a lethal course if left untreated,” wrote Drs. Thompson and Tangen. “It is these men who are at greatest risk for death from cancer and who are most likely to benefit from therapy but whom we must treat effectively.”

Although PIVOT compared surgery with watchful waiting, active surveillance appears to be a more commonly used approach than watchful waiting. A number of cancer centers have established active surveillance programs, said Dr. Ethan Basch of Memorial Sloan-Kettering Cancer Center in New York. Dr. Basch chaired a panel assembled by the American Society of Clinical Oncology (ASCO) that issued recommendations on PSA screening for prostate cancer 2 days before the publication of the PIVOT results. (See the box below.)

“When you put all of the available data together, you can begin to piece together a vision of a screening strategy” for prostate cancer, Dr. Basch said. Younger men who opt for PSA screening and are diagnosed with intermediate- or high-grade cancer would discuss potential treatments, while men diagnosed with low-grade disease would go into a surveillance program, he continued.

“That could potentially lead to a very different risk-benefit ratio for many men,” said Dr. Basch, one with a greater likelihood of benefit and a smaller risk of harms. He cautioned, however, that such a strategy needs to be tested prospectively in clinical trials.

Source: NCI.



Drug May Make Bone Marrow Transplants to Treat Blood Cancers Safer.

Results from a small clinical trial suggest that a drug used to treat HIV infection may help prevent a potentially lethal complication of bone marrow transplants to treat patients with blood cancers. The drug, maraviroc, appears to work by altering the activity of immune system cells that are chiefly responsible for graft-versus-host disease (GVHD). The findings were published July 12 in the New England Journal of Medicine.

Allogeneic stem cell transplantation is often required to treat patients with leukemia and lymphoma. GVHD occurs when immune cells in the transplanted cell population attack the patient’s body, typically organs such as the liver, skin, and gut.

Dr. Ran Reshef of the University of Pennsylvania Abramson Cancer Center and his colleagues conducted a 38-patient clinical trial to test whether a 33-day course of maraviroc might limit or prevent GVHD. The drug targets a receptor on certain immune cells that helps direct them as they move throughout the body.

Overall, 35 patients could be evaluated, all of whom underwent reduced-intensity conditioning stem cell transplants. In this procedure, lower doses of drugs are used to kill cancer cells and suppress immune cells in the patients’ bone marrow before they receive stem cells. The 35 patients also received maraviroc and two other drugs commonly used to prevent or limit GVHD.

Six months after the transplants, about 6 percent of patients had experienced serious GVHD (grade III and IV)—more than 70 percent lower than what is usually seen after reduced-intensity-conditioning transplants, the authors reported. The treatment was most effective at preventing GVHD in the liver and gut, which can produce debilitating and even fatal outcomes.

In the first 100 days after the transplants, no patient had GVHD in the liver or gut; 6 months after the transplants, the rates were approximately 3 percent and 9 percent, respectively, which Dr. Reshef noted “is still very low.”

The rates of cancer relapse and death were nearly identical to what is typically seen with reduced-intensity conditioning transplants, a finding that Dr. Reshef said supports the hypothesis that maraviroc does not significantly suppress the immune system. “Disease relapse is a major concern of any trial of GVHD prevention,” he explained. “You may reduce GVHD, but you can pay the price of increased relapse. We were encouraged that we did not see this in our trial.”

More studies are needed to better understand the drug’s impact, Dr. Reshef stressed. The Abramson team is planning another small trial to test a longer course of maraviroc treatment, and they have begun discussions with the NCI-supported Blood and Marrow Transplant Clinical Trials Networkto conduct a larger, multicenter trial.

This research was supported in part by the National Institutes of Health (P30-CA16520, K24-CA117879, and U01-HL069286).

Source: NCI.

Mapping the Molecular Changes in Colorectal Cancer.

A molecular analysis of colon and rectal tumors has yielded insights that could lead to more targeted treatments for patients with this disease, according to a report by investigators from The Cancer Genome Atlas (TCGA) Research Network. Their findings are publicly available (here and here) and summarized in Nature this month.

TCGA investigators have previously reported on the molecular changes underlying ovarian cancer and glioblastoma, an often deadly brain cancer. In the new analysis, the researchers comprehensively characterized the genomes of 224 colon or rectal tumors, as well as matched normal DNA from the donors.

After excluding from their analysis tumors that had abnormally high rates of genetic mutation (hypermutated tumors), the researchers found no significant genomic differences between colon and rectal tumors, based on a variety of measures, including the number of copies of genes and the gene expression profiles of the tumors.

But an analysis of the molecular pathways in colorectal tumors showed that pathways could be disrupted in a number of ways. Some tumors had potentially cancer-related changes in multiple pathways, suggesting to the researchers that targeting a single pathway would not be sufficient to treat these tumors.

Most of the approved treatments for colorectal cancer are chemotherapies that produce poor response rates, noted Dr. Raju Kucherlapati of Harvard Medical School, who co-led the study. The new findings could form the basis for developing and testing therapies that target the molecular changes driving the disease, he added.

“There are a number of genetic changes present [in the tumors we examined], and drugs that target many of these changes are already in development,” Dr. Kucherlapati continued. For selected patients, new targeted drugs “have the potential to be highly effective.”

He and his colleagues in the TCGA Research Network also found that 16 percent of the tumors were hypermutated. This phenomenon may be caused by defects in a cell’s ability to repair damaged DNA. Hypermutated tumors may also be aggressive.

Three-quarters of the specimens had a genetic change called microsatellite instability, which is associated with a better prognosis.

The researchers also found that the gene IGF2, which plays a role in cell proliferation, was altered in some tumors. Drugs that target the product of this gene or its receptor are in development and could be tested in patients whose tumors have alterations in IGF2.

The data from this study “provide an unprecedented resource for understanding this deadly disease and identifying possibilities for treating it in a targeted way,” the authors concluded.

Source: NCI.

Active Surveillance May Be Preferred Option in Some Men with Prostate Cancer.

Findings of a recent study, the largest and longest of its kind, provide strong evidence supporting a conservative approach to managing prostate cancer in some men. The study was not a randomized clinical trial; rather, it was a long-term analysis of a cohort of men diagnosed with what is called very-low-risk prostate cancer. Instead of immediately undergoing surgery or radiation therapy, the men had opted to undergo a process known as active surveillance at the Johns Hopkins University School of Medicine.

A diagnosis of very-low-risk prostate cancer means that the disease is highly unlikely to become a clinically significant, life-threatening cancer. These men could be safely monitored by active surveillance, the study found, with only a modest percentage eventually requiring some form of treatment and none dying from prostate cancer. The results were published online April 4 in the Journal of Clinical Oncology (JCO).

As is the case with prostate cancer in general in the United States, most of the men in the study were 65 or older. The results provide very strong evidence that active surveillance is the “preferred option” for most men in this age group with very-low-risk disease, said the study’s senior investigator, Dr. H. Ballentine Carter. In fact, he continued, “The overwhelming evidence says that for men over 65 who are diagnosed with low-risk disease, their first question should be whether any therapy is appropriate for them, not which therapy.”

The clinical relevance of the findings is hard to overstate, Dr. Carter stressed. Among the 217,000 men in the United States diagnosed each year with prostate cancer, a substantial proportion has very-low-risk or low-risk disease. The vast majority of these men immediately undergo some form of treatment, including men aged 75 and over, despite the fact that many would be unlikely to experience significant symptoms, let alone die from prostate cancer.

Defining Very-Low-Risk Prostate Cancer

The Johns Hopkins definition of very-low-risk prostate cancer is similar to the NCCN definition. For the study in JCO, very-low-risk was defined as:

  • Clinical stage T1c (no palpable disease, biopsy recommended based on abnormal PSA)
  • Gleason score of 6 or less
  • PSA density (ratio of PSA level to prostate gland size) of 0.15 ng/mL or less
  • Two or fewer biopsy cores in which cancer is present, and less than 50 percent cancer present in any involved core

Patient Selection, Compliance Are Key

At Hopkins, the active surveillance program involves a semi-annual check-up and an annual biopsy. Patient selection is very important, Dr. Carter explained.

Among the 769 men enrolled in Hopkins’ active surveillance program between 1995 and 2010, approximately 80 percent had very-low-risk disease. Whether a patient has very-low-risk disease is determined based on factors such as the Gleason score (a common measure of tumor aggressiveness) and the extent of cancer in the biopsy samples, or cores, from the prostate gland. (See the sidebar for all of the factors.)

The remaining men had at least one biopsy feature that precluded their disease from being considered very-low-risk, Dr. Carter explained. These men were typically older and had other health problems, he continued, which made active surveillance more attractive than treatment with surgery or radiation, both of which can have significant side effects.

Compliance with the approach has been quite strong, the Hopkins team reported, with nearly 90 percent of participants completing their annual biopsies.

Although no men in the study died of prostate cancer, 255 did undergo some form of treatment, 74 percent of whom did so because their disease was reclassified based on the findings of an annual biopsy.

Overall, 41 percent of men in the study did not require any form of treatment, even after 10 years of follow-up, a “remarkable” finding, said Dr. Bhupinder Mann from NCI’s Division of Cancer Treatment and Diagnosis. “This study adds to the accumulating evidence that, in carefully selected patients, active surveillance is safe.”

The results “strongly support” recent revisions to prostate cancer treatment guidelines from the National Comprehensive Cancer Network (NCCN), said the guidelines’ panel chair, Dr. James Mohler from the Roswell Park Cancer Institute. Updated last year, the guidelines recommend that physicians advise men with very-low-risk disease who have a life expectancy of up to 20 years to pursue active surveillance.

Findings like these on active surveillance, combined with related research on the growing problem of overdiagnosis and overtreatment of prostate cancer linked to PSA screening, appear to be reaching down into the community setting, Dr. Mohler believes.

“I think men and their doctors are becoming more educated about the overtreatment issue,” he said.

As evidence, Dr. Mohler pointed to the START trial, a phase III clinical trial being led by NCI-Canada, in collaboration with the U.S. NCI, in which men diagnosed with very-low-risk or low-risk disease are being randomly assigned to active surveillance or immediate treatment. When the trial opened in 2007, most men who declined to enroll did so because they did not want to take the risk of being assigned to the active surveillance arm. “Now most men are declining to participate because they want active surveillance,” Dr. Mohler said.

Having a strong system in place to ensure that men pursuing active surveillance are followed and receive reminders for their check-ups and biopsies is extremely important, Dr. Carter stressed.

At the moment, the Hopkins surveillance program is managed primarily by an administrator using a manual process. But the program is moving to a Web-based approach for monitoring and following patients, he added.

Approaches Can Vary

Although the evidence in favor of active surveillance continues to accumulate, the optimal approach to managing the process is not yet defined, Dr. Mann noted. This is particularly true with respect to how patients’ disease is tracked.

At Hopkins, men are followed via check-ups and annual biopsies. Any reclassification of their disease is typically based on biopsy findings, such as a change in Gleason score, which might then produce a recommendation for treatment. But many other centers, such as Roswell Park, do not require men who choose active surveillance to undergo regular biopsies. Rather, they use some form of what is commonly called PSA kinetics, which are changes in PSA levels over time (for instance, how long it takes for PSA levels to double).

Results from several studies, however, have raised doubts about the value of PSA kinetics in initially identifying or managing prostate cancer. Based on their experience, PSA kinetics is “not reliable for predicting the presence of high-grade cancer on an individual basis,” the Hopkins team wrote in JCO. “Thus, if the goal of surveillance is to identify and treat higher-risk cancers, we believe that annual biopsies may be necessary to ensure patient safety.”

But regular biopsies are by no means without their own risks. A small percentage of men end up in the hospital with antibiotic resistant infections as a result of a prostate biopsy, Dr. Mohler said, and repeat biopsies can lead to inflammation and scar tissue formation that can preclude nerve-sparing surgery to treat the prostate cancer in some men whose disease progresses.

According to Dr. Carter, Hopkins researchers are now studying whether men who have had two consecutive biopsies that show no evidence of disease progression can safely have the interval between routine biopsies extended. In the meantime, the NCCN guidelines are being revised again, Dr. Mohler said, using data from large active surveillance programs at Hopkins, the University of Toronto, and the University of California, San Francisco, to provide recommendations on managing men who choose this conservative approach.

Further clarity on this matter should be forthcoming, Dr. Mann said. In addition to the START trial, which will follow men using both PSA measures and prostate core biopsies, a similar trial is being conducted in the United Kingdom that is using only PSA levels to monitor patients. Also, in December, NCI and CDC are sponsoring an NIH State-of-the-Science Conference to review the role of active surveillance in managing localized prostate cancer and to help guide future research in this area.

Source: NCI.