The mystery of the stopped clock illusion.

Sometimes, when I look at a clock time seems to stand still. Maybe you’ve noticed this to your bemusement or horror as well. You’ll be in the middle of something, and flick your eyes up to an analogue clock on the wall to see what the time is. The second hand of the clock seems to hang in space, as if you’ve just caught the clock in a moment of laziness. After this pause, time seems to restart and the clock ticks on as normal.

It gives us the disconcerting idea that even something as undeniable as time can be a bit less reliable than we think.

This happened to me for years, but I never spoke about it. Secretly I thought it was either evidence of my special insight to reality, or final proof that I was a little unhinged (or both). But then I found out that it’s a normal experience. Psychologists even have a name for it – they call it the “stopped clock illusion”. Thanks psychologists, you really nailed that one.

An ingenious experiment from a team at University College London recreated the experience in the lab and managed to connect the experience of the stopped clock to the action of the person experiencing it. They asked volunteers to look away and then suddenly shift their gaze to a digital counter. When the subjects tried to judge how long they had been looking at the digit that first appeared, they systematically assumed it had been on for longer than it had.

Filling gaps

Moving our eyes from one point to another is so quick and automatic that most of us probably don’t even think about what we are doing. But when you move your eyes rapidly there is a momentary break in visual experience. You can get a feel for this now by stretching your arms out and moving your eyes between your two index fingers. (If you are reading this in a public place, feel free to pretend you are having a good stretch.) As you flick your eyes from left to right you should be able to detect an almost imperceptibly brief “flash” of darkness as input from your eyes is cut off.

It is this interruption in consciousness that leads to the illusion of the stopped clock. The theory is that our brains attempt to build a seamless story about the world from the ongoing input of our senses. Rapid eye movements create a break in information, which needs to be covered up. Always keen to hide its tracks, the brain fills in this gap with whatever comes after the break.

Normally this subterfuge is undetectable, but if you happen to move your eyes to something that is moving with precise regularity – like a clock – you will spot this pause in the form of an extra long “second”. Fitting with this theory, the UCL team also showed that longer eye-movements lead to longer pauses in the stopped clock.

It doesn’t have to be an eye movement that generates the stopped clock – all that appears to be important is that you shift your attention. (Although moving our eyes is the most obvious way we shift our attention, I’m guessing that the “inner eye” has gaps in processing in the same way our outer eyes do, and these are what cause the stopped clock illusion.) This accounts for a sister illusion we experience with our hearing – the so-called “dead phone illusion”, which is when you pick up an old-fashioned phone and catch an initial pause between the dial tone that seems to last longer than the others.

These, and other illusions show that something as basic as the experience of time passing is constructed by our brains – and that this is based on what we experience and what seems the most likely explanation for those experiences, rather than some reliable internal signal. Like with everything else, what we experience is our brain’s best guess about the world. We don’t ever get to know time directly. In this sense we are all time travellers.

Source: BBC.



A New Tickborne Viral Infection in the U.S. Heartland.

A novel phlebovirus caused a severe febrile illness in two patients in Missouri.

In 2011, a tickborne phlebovirus — so-called severe fever with thrombocytopenia syndrome virus (SFTSV) — was described as a cause of human disease in China. Now, illness closely resembling that caused by SFTSV has been reported in two men in northwestern Missouri.

The two patients had suffered tick bites 5 to 7 days before the onset of a severe febrile illness characterized by fatigue, diarrhea, thrombocytopenia, and leukopenia. Ehrlichiosis was the presumptive diagnosis in each case, but results from laboratory tests (serologic analysis, polymerase chain reaction assay, cell culture) were all negative. The men were hospitalized for 10 and 12 days.

Viral particles were isolated from the patients’ leukocytes in cell culture. Thin-section electron microscopy revealed characteristics of viruses in the Bunyaviridae family. Total RNA was recovered from the infected culture media and subjected to genomic sequencing; the resulting sequences were similar to those of phleboviruses in the Bunyaviridae family. Phylogenetic analysis demonstrated a distinct virus closely related to SFTSV. Enzyme-linked immunosorbent assay testing of serum samples collected from the patients >2 years after illness onset showed high titers of antibodies reactive to the novel virus (dubbed “Heartland” by the researchers).

Comment: Some patients who have been treated for anaplasmosis or ehrlichiosis may have had Heartland virus infection or coinfection. The list of tickborne illnesses in the U.S. and abroad continues to expand, as is evidenced by cases described in this article and other recent reports (JW Infect Dis Mar 16 2011 and Aug 3 2011).

Source: Journal Watch Infectious Diseases

The definition of acid rain and its causes.

Acid rain is a form of precipitation containing heavy concentration of sulfuric and nitric acids. The term is also commonly applied to snow, sleet and hail that manifest similar acidification. Such precipitation has become an increasingly serious environmental problem in many areas of North America and Europe. Although this form of pollution is most severe in and around large urban and industrial areas, substantial amounts of acid precipitation may be transported great distances.

The process that results in the formation of acid rain generally begins with emissions into the atmosphere of sulfur dioxide and nitrogen oxide. These gases are released by automobiles, certain industrial operations and electric power plants that burn such fossil fuels as coal and oil. The gases combine with water vapor in clouds to form sulfuric and nitric acids. When precipitation falls from the clouds, it is highly acidic, having a pH value of about 5.6 or lower. At several locations in the United States and Western Europe, pH values between 2 and 3 have been recorded. In areas such as Los Angeles and San Francisco, fog is often 10 or more times as acidic as the local precipitation.

Precipitation and fog of high acidity contaminate lakes and streams; they are particularly harmful to fish and other aquatic life in regions with thin soil and granitic rock, which provide little buffering to acidic inputs. It also has been discovered that aluminum is leached from the soil in such regions subjected to acid precipitation, and that dissolved aluminum seems to be extremely toxic to aquatic organisms. All forms of acid precipitation have been found to damage various kinds of vegetation, including agricultural crops and trees, chiefly by inhibiting nitrogen fixation and leaching nutrients from foliage. In addition, these pollutants can corrode the external surfaces of buildings and other man-made structures.


Why Nasa Experts Think The September 2012 Solar Storm Could Reduce America to a Developing Country.

Scientists now believe, the solar flare could change everything for our civilization as we know it today.Predictions are being made to the effect that a major solar storm is set to strike America and some parts of the world on September 21 2012.

NASA has warned that a virulent Solar storm is likely to hit America by September 2012  and the resultant damage could be so catastrophic that America and some of the well known Super power nations could instantly become developing countries. Information relayed down to earth from the Voyager 1 and 2 has now convinced NASA officials and  Scientists that a solar storm leading to the Carrington effect is inevitable and could strike our world in  on 21st September 2012 because as of now, the entire solar system is moving into the  Inter-stellar energy clouds which are so turbulent that they have started exciting/charging the sun and the atmosphere of our planet. As this charging goes on, the sun will become more active with greater energy output into our atmosphere leading to more serious Solar storms resulting into the Carrington effect.

The world was last hit by the most serious solar storm in 1859, an event still remembered as the Carrington event after a British amateur astronomer Richard Carrington who first explained to the world the cause of the event. The 1859 solar storm was an 8 day severe space weather that caused serious damage across the affected parts of the world. Scientists still say, the Carrington event of 1859 was by far the most powerful solar outburst the world has ever seen, this makes the anticipated 2012 solar storm very worrying to the scientists.

The solar storm could change everything for our civilization as we know it today and the following are some of the scientific analysis scientists give to present just how deadly this predicted solar storm really;

The Power Grid system

Because of the Power grid interdependence with systems that support lives, namely, water and sewage treatment, super market delivery infrastructure, power station controls, financial markets, hospital theaters, a severe solar storm would immediately melt and knock out 300 key transformers in US within 90 seconds, cutting off power to more than 130,000,000 people. From this first 90 second of the solar storm, the super-power status of America will have been dealt a terminal blow. This is very interesting because, usually with other forms of natural disasters, the less developed economies are most vulnerable, but with a Carrington event, the highly sophisticated economies based on grid systems will simply face instant collapse leading to thousands of deaths.

Drinking Water

Firstly, there will immediately be no drinking water for millions of people because the pumps will have gone silent. Anybody living in a high rise terrain will not benefit from the water flow through gravity, so water will simply be cut off with the black outs. For the rest on low lying ground, water may still come to the taps for a day or so but the taps would thereafter, go dry. Here in my country, we would rush to the available ponds without compromising our 3rd world status-imagining an American rushing to the Mississippi to draw drinking water for drinking and cooking would definitely make them a developing country.

Powered Transport

The electrically powered  transport systems will immediately grind to a halt-people will find themselves unable to use underground and over ground trains, the super markets will immediately have empty shelves, the ATM machines will no longer spit out money, cellphones will go silent and probably drums and bells will be used to send out communications. The delivery trucks may keep running until their tanks dry out, from that time on, there will be no electricity to pump fuel from the underground tanks at the gas stations.

Health care System

In Hospitals, backup generators would be made to run at certain key areas of the hospitals for about 3 days,  but as soon  as the fuel runs out, CT Scans cease to exist, x-rays become a crisis, surgery becomes a big risk and all in all, the modern health care system as we know it in America and other developed  countries will simply vanish and America will begin to look like some 3rd World.

Death due to lack of drugs

A solar storm would not spare Nuclear stations as well. Most Nuclear stations are programmed to Shut down in the event of grid power irregularities and are not reprogrammed to start running until the power grid problem has been rectified. Remember, September will be nearly the onset of winter, so with no power for heating, cooling systems, many people, especially the elderly will begin to die in droves. Loss  of power at the major pharmaceutical plans would mean, people who are suffering from chronic ailments like diabetes, asthma or HIV would all perish because the pharmaceuticals are not able to produces the life saving drugs.




Ozone Hole and The Global Climate Changes.

The release of CFCs or chlorofluorocarbons into the atmosphere through human activities has caused a massive hole in the ozone layer right above Antarctica and if unchecked, melting icecaps may inundate several regions of the earth in the future.

What is Ozone and Where Is It Found in The Earth’s Atmosphere?

Ozone is a gas with a pungent odor whose molecule contains three oxygen atoms. At about 6–10 miles above the Earth’s surface and extending up to 30 miles, in a region of space called the stratosphere, you will find 90% ozone. The stratospheric region with the highest ozone concentration is commonly known as the “ozone layer”. The remaining ozone, about 10%, is found in the troposphere, which is the lowest region of the atmosphere, between Earth’s surface and the stratosphere.

Ozone at ground level in the troposphere is bad because it causes photochemical smog. The smog results when ultra-violet light falls on and reacts with nitrogen oxide from vehicle exhausts. Because of this, Ozone affects lung function, aggravates asthma and other chronic respiratory diseases.

On the other hand, ozone in the stratosphere performs a very useful function by acting as a blanket that blocks most of the sun’s high-frequency ultraviolet rays. These UV rays can cause skin cancer and cataracts in humans, as well as reproductive problems in several forms of life including even the single-celled phytoplankton at the bottom of the ocean food chain.

How Does Ozone Form in the Atmosphere?

When ultraviolet light strikes oxygen molecules containing two oxygen atoms (O2), it splits them into individual oxygen atoms (atomic oxygen), which then combines with unbroken O2 to create ozone, O3. Being unstable, this ozone once again splits into a molecule of O2 and an atom of atomic oxygen under the action of ultraviolet light. This continuing process called the ozone-oxygen cycle.

The ozone layer  is very effective at screening out UV-B; Nevertheless, some UV-B, particularly at its longest wavelengths, reaches the surface. Ozone cannot stop UV-A, the longer wavelength ultraviolet radiation which  reaches the earth’s surface. However, this type of UV radiation is significantly less harmful to DNA.

The thickness of the ozone layer varies widely throughout the world, being smaller near the equator and larger towards the poles. It also varies with season, being in general thicker during the spring and thinner during the autumn in the northern hemisphere.

Ozone ‘Hole’

In May 1985 scientists with the British Antarctic Survey announced the discovery of a huge hole in the ozone layer over Antarctica. They announced that Ozone levels over the northern hemisphere had been dropping by 4% per decade. They described the larger seasonal drops in the ozone levels around the south pole as a ozone hole.

The ozone hole is not technically a “hole” with no ozone is present, but is actually a region of exceptionally depleted ozone in the stratosphere over the Antarctic during the Southern Hemisphere spring (August–October).

Stratospheric temperatures in the Northern Hemisphere during winter/spring are generally slightly warmer than those in the Southern Hemisphere. Therefore ozone losses over the Arctic have been much smaller than over the Antarctic during the 1980s and early 1990s. However, the Arctic stratosphere has gradually cooled over the past few decades, and Ozone holes have been observed at the Arctic regions too recently. This is a dangerous trend, because unlike the Southern Polar hemisphere, the Northern Polar hemisphere is well populated.

Ozone hole is caused by chemicals called CFCs, or chlorofluorocarbons. CFCs escape into the atmosphere from refrigeration and propellant devices and processes. In the lower atmosphere, they are so stable that they persist for decades. Eventually, some of the CFCs reach the stratosphere where chemical reactions take place primarily on the surface of polar stratospheric clouds, ice particles, or liquid droplets, which form at high altitudes in the extreme cold of the polar regions. Ultraviolet light breaks the bond holding chlorine atoms (Cl) to the CFC molecule. Chlorine then destroys ozone molecules by “stealing” their oxygen atoms. The breakdown of ozone in the stratosphere makes it unable to absorb ultraviolet radiation. Consequently, the unabsorbed ultraviolet-B radiation is able to reach the Earth’s surface. The extent of ozone destruction is extremely sensitive to small changes in stratospheric temperature.

Another culprit responsible for the ozone depletion is nitrous oxide (N2O). The major sources of nitrous oxide are industrial processes and combustion engines of various vehicles. They are also emitted from livestock manure and sewage. Like CFCs, Nitrous oxide  is stable when emitted at ground level, but breaks down when it reaches the stratosphere to form nitrogen oxides that trigger ozone-destroying reactions.

In 1987 several UN countries gathered at Montreal, Canada, and signed a treaty to protect the stratospheric ozone layer. The Montreal Protocol stipulated that the production and consumption of compounds that deplete ozone in the stratosphere—chlorofluorocarbons, halons, carbon tetrachloride, and methyl chloroform—are to be phased out by 2005.

Chemical manufacturers soon created substitutes for CFCs with little added costs; thus, our life styles remained greatly unaffected by the switch-over from CFC’s. This has had the effect of putting a slow stopper on the Ozone hole.

Now, the issue of a possible connection between ozone hole and global warming is a controversial subject even among scientists. In fact, there is no unanimity in either of the assertions that Antarctica is warming or cooling. The British Antarctic Survey says categorically Antarctica to be both warming around the edges and cooling at the center at the same time. Thus it is not possible to say whether it is warming or cooling overall. Because there are too many parameters governing the global temperatures, it is difficult to correlate the theoretical temperature rise at the Antarctic caused by a thinner ozone layer with global climatic changes. It is useful to remember here that Ozone itself is a greenhouse gas and its thinning over the region reduces heat trapped over it and helps create sea spray that forms reflective, cooling clouds.



Green Energy Tips for The Home.

Green energy essentially refers to renewable energy which can be used with the least damaging effect on the environment. Starting from our homes, there are different ways to use green energy.

Green energy essentially refers to renewable energy which can be used with the least damaging effect on the environment. Starting from our homes, there are different ways to use green energy.

Do not allow your freezer and refrigerator to stay open longer than necessary. Aside from the effect that doing so will spoil your food, it can likewise consume a lot of energy. Simply put,  keep your refrigerator or freezer closed immediately after getting something from it.

Recycle used coffee grinds as fertilizers for plants. Because coffee grinds are nitrogen-rich these make excellent plant nourishment. If this is done, it keeps coffee grinds out of the landfill, thus lessening the city dump. In return, you also save money on purchasing chemical plant food, your plants will benefit from the natural fertilizer, and thus provide more oxygen the atmosphere.

Insulate your pipes to lessen their chances of freezing, which eventually cut the costs for hot water.  This will also benefit those who live in a state wherein the government reimburses homeowners to up to 30 percent for employing efficient home insulation. Check with your local utility or green energy companies to know more about these benefits.

Use solar energy your home. Install large windows or sun rooms on the side of your home where you can allow the morning sunlight to enter. This is free energy which will warm your room for a couple of hours every morning and thus save on heating costs.

Frequently, the water heater lets water reach a scalding temperature. You may turn the maximum heat level on the water heater by twenty degrees lower. Doing so will definitely decrease your electricity bills. Using tankless water heaters is another green energy option for the home.


You may use a pellet stove for heating the home. Pellets are fundamentally composed of compacted sawdust: they burn with the least emission and are a lot easier to store and transport than a bundle of firewood. When you plan to invest in a pellet stove, you should know where you can buy affordable pellets first.

Energy can also be conserved by using less water. One way to reduce excessive water use is to install a toilet system which uses minimal water for flushing. Water bill is one expense in many homes. Using this type of toilet system will further reduce water utility expenses.

Shut down your computer when your leave the desk or home for some hours and before retiring at the end of the day. Also activate your computer’s sleep mode if it is idle for five minutes. Doing these two simple acts on everyday can reduce the energy usage of your computer by 85 percent.

Now you know better about green living at home, thus there is no reason why it shouldn’t be done. Green lifestyle not only helps you save on costs, but also helps the environment in the long run.



Warfarin plus Aspirin After Aortic Valve Prosthesis Placement?

An observational study suggests that the combination reduces mortality, at the cost of increased bleeding, when used in the 3 months after surgery.

Patients receiving an aortic bioprosthesis have a low overall risk for thromboembolism, but controversy surrounds whether they benefit from anticoagulation in the first months after surgery. To address this issue, researchers used the Society of Thoracic Surgeons Adult Cardiac Surgery Database to compare the effectiveness of the early use of aspirin alone, aspirin plus warfarin, and warfarin alone.

The sample included 25,656 patients aged 65 (median age, 77; 39% women) who received an isolated aortic valve prosthesis at 797 hospitals from 2004 through 2006. At 3 months, the mortality rate was 3.0% in the aspirin-only group, 3.1% in the aspirin-plus-warfarin group, and 4.0% in the warfarin-only group. In the multivariable analysis, the addition of warfarin to aspirin was associated with a 20% relative reduction in risk for death (0.6% absolute risk reduction). Mortality with warfarin alone was no different than with aspirin alone. The addition of warfarin to aspirin was associated with 48% relative reduction in the risk for embolic events (0.4% absolute risk reduction). Again, warfarin alone was not associated with a reduction. Bleeding was more common in patients treated with warfarin plus aspirin than in those treated with aspirin only or warfarin only (2.8% vs. 1.0% and 1.4%, respectively).

Comment: Absolute risks for death and embolic events are low in the 3 months after the placement of an aortic valve bioprosthesis, but the addition of warfarin to aspirin provided additional risk reduction in this observational study, at the cost of more bleeding. The authors recommend warfarin plus aspirin for those at low risk for bleeding, and I agree — we ought to be personalizing treatment based on the bleeding risk.

Source: Journal Watch Cardiology

Whales & Sharks from Above: A Fish Spotter’s Amazing Tale.

Wayne Davis has been spotting fish for 40 years, flying his airplane low over the water in search of bluefin tuna and swordfish. Usually he guides commercial fishermen to them.

But in all of his flights over the Atlantic from his home in Wakefield, R.I., he’s seen a lot of other animals, including sharks and whales. And he’s taken photographs.

“A lot of people don’t believe me when I tell them about seeing these animals in New England,” Davis said. The photographs are proof.

Having worked with fishermen since purchasing his single-engine Citabria airplane in 1973, he recently tired of chasing fish. So he has strayed even farther from shore to find whale sharks, hammerheads, great white sharksbasking sharks, humpback whales, mobula rays and other giants of the deep.

He’s partnered with underwater cinematographers and researchers to help them film and study these amazing animals. [Images: Sharks & Whales from Above]

Hammerhead close encounter

Two weeks ago, on Aug. 22, Davis helped underwater cinematographers Tom Burns and Eric Savetsky find a school of about 20 hammerhead sharks above Oceanographer’s Canyon, 100 miles (160 kilometers) southeast of Nantucket, Mass. Davis saw the sharks from his plane and radioed their position to Burns and Savetsky. They piloted their boat toward the sharks and hopped into the water.

After failing at first to get close to the scalloped hammerheads, which are usually pretty shy, the school approached and surrounded the duo, Savetsky told OurAmazingPlanet. “It was fantastic from a visual experience, but a little unnerving because they were acting bolder than I typically know them to be,” he said. But they didn’t get too close, and swam off after a couple passes.

“It was an amazing experience, to swim among them, that never would have been possible without Wayne,” Burns said.

At some point, Savetsky took his eye off the camera to gauge his surroundings. “When I looked up, there was a 500-pound [230 kilograms] tiger shark about 10 feet [3 meters] away, and I actually screamed into my snorkel,” he said.

Savetsky put his camera in front of him not only to film the animal but to protect himself, since tiger sharks can occasionally become aggressive toward swimmers on the surface. Luckily it seemed merely to be curious, and it soon disappeared into the deep.

Finding great whites

Davis has also worked with Greg Skomal, a scientist with the Massachusetts Division of Marine Fisheries, helping Skomal find great white sharks and other animals. On Aug. 27, 2010, off the coast of Chatham, Mass., Davis helped guide Skomal and other researchers to the carcass of a dead humpback whale, which was being circled by a great white.

The researchers tied the humpback whale to the boat and put down a cage to observe the shark up close. This also allowed them to tag the animal, to find out where it spends its time. Sharks are often found near dead whales, which they feed upon.

Davis grew up in New England and was always interested in flying. After serving in Vietnam, he decided to become a spotter pilot and bought his own plane. For 25 years he did hard labor as a deckhand on commercial vessels and worked a fish-spotter in the offseason. Now he just flies.

Skomal said Davis’ expertise is invaluable in finding and correctly identifying animals, as is his ability to photograph what he sees. Sometimes Davis will tell Skomal if he finds anything interesting, and other times Skomal will hire Davis to locate animals.

Davis’ photographs allow Skomal to know what animals show up where, but they also give an idea of the animals’ size and condition. The photograph of the great white, for example, tells Skomal the animal is about 18 feet (5 m) long, as it’s half the size of the 35-foot (11 m) boat. The animals are known to reach about 22 feet (6.7 m) in length.

“That was a big one,” Skomal said.

Source: Amazing planet

Targeting Invasive Glioma Cells.

Name of the Trial
Phase I Trial of AZD7451, a Tropomyosin-Receptor Kinase (TRK) Inhibitor, for Adults with Recurrent Gliomas (NCI-12-C-0005). See the protocol summary.

Principal Investigators
Dr. Katharine McNeill, NCI Center for Cancer Research, and Dr. Howard Fine, New York University Cancer Institute

Why This Trial Is Important

Glioblastoma is the most common malignant brain tumor in adults, with about 12,000 new cases diagnosed each year in the United States. It is also one of the deadliest, with a median survival following diagnosis of about 14 months.

Surgery to remove as much of the tumor as possible is the standard primary treatment for glioblastoma. After surgery, doctors use radiation therapy and treatment with the chemotherapy drug temozolomide to try to delay the growth of the remaining cancer. Although these measures may delay disease progression for a while, they cannot prevent it, and death usually occurs within a few months. Currently, the only therapy that has proven effective in delaying death in patients with progressive glioblastoma is bevacizumab, which helps block the tumor’s ability to induce the formation of new blood vessels.

Glioblastoma is particularly difficult to treat because of its highly invasive nature. Although the bulk of the tumor may be well defined, malignant cells have usually migrated away from the tumor by the time it is discovered. Some of these cells inevitably remain behind after surgery and, if left unchecked, will eventually kill the patient.

Progress in the treatment of glioblastoma has been hampered by the absence of preclinical tumor models that mimic the invasiveness of the cancer. However, NCI researchers recently developed new cell lines from a subset of glioblastoma tumor-initiating cells that more accurately replicate the invasiveness of human glioblastoma in animal models. Using the new models, they were able to determine that cells near the edge of glioblastoma tumors express a set of proteins that help make them highly invasive. Subsequently, they identified a compound that may be effective in blocking the function of one of these key proteins.

A protein called tropomyosin-receptor kinase, or Trk, is commonly found on brain cells and helps regulate the development, function, and survival of nerve cells. In glioblastoma, Trk is highly expressed on the cells around the edges of the tumor and on the infiltrative cells that have migrated away from the tumor mass, whereas those cells in the bulk of the tumor show lower levels of Trk expression. Doctors want to see if inhibiting the function of Trk will help block the invasiveness of glioblastoma cells and reduce the likelihood that the tumor will progress.

In this first-in-class phase I trial, patients with glioblastoma that has not responded to standard postoperative therapy or that has progressed will be treated with varying amounts of a Trk inhibitor called AZD7451 to determine the maximum tolerated dose and the side effects of this drug. Doctors will also look for signs of clinical activity.

“Regardless of the extent of tumor resection, there are always residual tumor cells because these cells are highly invasive and infiltrate normal brain tissue,” said Dr. Fine, former chief of NCI’s Neuro-Oncology Branch. “So surgery is never curative in this disease; some type of postoperative therapy is always required to try to address these remaining infiltrative tumor cells.

“We became interested in trying to study this invasive process in the laboratory in hopes of identifying new molecular targets for therapy,” he continued. “We were able to find that this molecule called Trk was expressed specifically on glioblastoma cells that were invading and [that] Trk was signaling to these tumor cells in a way that was important for the cells to move within the brain. Further, by inhibiting Trk we were able to shut off the invasive process in these models.”

The trial is taking place at the NIH Clinical Center in Bethesda, MD, and at the New York University Cancer Institute in New York City.


AZD7451 for Recurrent Gliomas

Basic Trial Information






Protocol IDs

Phase I Biomarker/Laboratory analysis, Treatment Active 18 and over NCI 120005
12-C-0005, NCT01468324

Trial Description



  • AZD7451 is a drug that may help interfere with brain tumor cell growth. It can prevent glioma cells from entering into normal brain tissue, and slow or stop the growth of additional tumors. Researchers want to see if AZD7451 is effective against gliomas that have not responded to surgery, radiation, or chemotherapy.


  • To see if AZD7451 is a safe and effective treatment for gliomas that have not responded to standard treatments.


  • Individuals at least 18 years of age who have gliomas that have not responded to standard treatments.


  • Participants will be screened with a physical exam, medical history, blood and urine tests, heart function tests, an eye exam, and imaging studies.
  • Participants will take AZD7451 daily by mouth for 28-day cycles of treatment.
  • Participants will keep a medication diary and record any side effects. Treatment will be monitored with frequent blood tests and imaging studies.
  • Treatment will continue as long as there are no serious side effects and the tumor does not start growing again….

Further Study Information


Recurrent glioma patients have very limited treatment options. A major cause of gliomarelated morbidity and mortality is the extensive infiltrative and invasive nature of glioma cells. Thus, inhibition of glioma invasion is a potentially promising strategy.

Work in the laboratory of Dr. Howard Fine has identified TrkA as an important signaling receptor for mediating glioma cell invasion. Both genetic and pharmacological inhibition of Trk potently inhibits glioma invasion and tumor progression in vitro and in vivo.

AZD7451 is a first in-class inhibitor of Trk.


To establish the maximally tolerated dose (MTD) of continuous once daily AZD7451 in patients with recurrent malignant gliomas not on enzyme-inducing anti-epileptic drugs (EIAED).

To generate pharmacokinetic data on continuous twice a daily AZD7451 dosing.


Patients with histologically proven glioblastoma are eligible for this study. Patients should have failed prior standard treatment with radiotherapy.


This study will accrue up to 60 evaluable patients. Cohorts of 3 to 6 patients will receive continuous AZD7451 twice a day orally for 28 days. The MTD will be based on the tolerability observed during the first 4 weeks of treatment only. Up to three patients may be enrolled simultaneously at each dose level. The dose of AZD7451 can be progressively escalated if only 0/3 or 1/6 patients experience a dose limiting toxicity at the prior dose level.

At the end of Cycle 1, patients may choose to continue to receive AZD7451 until disease progression or until they experience unmanageable drug related toxicity, as long as they are continuing to derive clinical benefit and do not fulfill any of the criteria for removal from protocol therapy. Each cycle during this extension period will last 28 days.

Eligibility Criteria

  • Patients with histologically proven malignant primary gliomas who have progressive disease after radiotherapy will be eligible for this protocol.
  • Patients must have an MRI scan performed within 14 days prior to registration and on a fixed dose of steroids for at least 5 days. If the steroid dose is increased between the date of imaging and registration a new baseline MRI is required.
  • Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply:

1. Patients will be eligible four weeks after surgery if they have recovered from the effects of surgery.

2. Residual disease following resection of recurrent tumor is not mandated for eligibility into the study. To best assess the extent of residual disease postoperatively, an MRI should be done:

  • no later than 96 hours in the immediate post-operative period or
  • at least 4 weeks post-operatively, and
  • within 14 days of registration, and
  • on a stable steroid dosage for at least 5 days.

If the 96 hour scan is more than 14 days before registration, the scan needs to be repeated. If the steroid dose is increased between the date of imaging and registration, a new baseline MRI is required on a stable steroid dosage for at least 5 days.

  • Patients must have failed prior radiation therapy.
  • Ability of subject or Legally Authorized Representative (LAR) (if the patient is deemed by the treating physician to be cognitively impaired or questionably impaired in such a way that the ability of the patient to give informed consent is questionable) to understand and the willingness to sign a written informed consent document indicating that they are aware of the investigational nature of this study.
  • Patients must be greater than or equal to18 years old, and must have a life expectancy > 8 weeks. Because no dosing or adverse event data are currently available on the use of AZD7451 in patients < 18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.
  • Patients must have a Karnofsky performance status of greater than or equal to 60
  • Patients must be at least 4 weeks from radiation therapy. Additionally, patients must be at least 6 weeks from nitrosoureas, 4 weeks from temozolomide, 3 weeks from procarbazine, 2 weeks from vincristine and 2 weeks from last bevacizumab administration. Patients must be at least 4 weeks from other cytotoxic therapies not listed above and 2 weeks for non-cytotoxic agents (e.g., interferon, tamoxifen) including investigative agents. With the exception of alopecia, all toxicities from prior therapies should be resolved to CTCAE less than or equal to grade 1.
  • Patients must have adequate bone marrow function (WBC less than or equal to 3,000/microl, ANC > 1,500/mm(3), platelet count of > 100,000/mm(3), and hemoglobin greater than or equal to 9 gm/dl), adequate liver function (AST, ALT and alkaline phosphatase less than or equal to 2.5 times ULN and bilirubin less than or equal to 1.5 times ULN), and adequate renal function (creatinine less than or equal to 1.5 times ULN and/or creatinine clearance less than or equal to 50 cc/min calculated by Cockcroft-Gault) before starting therapy. Patients must also have serum potassium greater than or equal to 3.5 mmol/L, magnesium greater than or equal to 0.75 mmol/L, phosphate and calcium levels within normal levels; supplementation is allowed. In cases where the serum calcium is below the normal range, 2 options would be available: 1) the calcium adjusted for albumin is to be obtained and substituted for the measured serum value. Exclusion is to then be based on the adjusted for albumin values falling below the normal limit. 2) Determine the ionized calcium levels. Exclusion is then to be based on whether these ionized calcium levels are out of normal range despite supplementation. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.
  • Patients must either not be receiving steroids, or be on a stable dose of steroids for at least five days prior to registration.
  • The effects of AZD7451 on the developing human fetus are unknown. For this reason and because AZD7451 is known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or herpartner is participating in this study, the treating physician should be informed immediately.
  • A 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial entry with QTc less than or equal to 470 msec.
  • Patients must have normal left ventricular ejection fraction (LVEF greater than or equal to 55% or normal by NIH Clinical Center criteria).


  • Patients who, in the view of the treating physician, have significant active hepatic, renal, pulmonary or psychiatric diseases are ineligible.
  • 2 Prior treatment with AZD7451.
  • History of hypersensitivity to active metabolites or excipients of AZD7451.
  • Clinically significant cardiovascular event (e.g. myocardial infarction, angina pectoris, coronary artery bypass graft, angioplasty, vascular stent, superior vena cava syndrome (SVC), New York Heart Association (NYHA, Appendix I) classification of heart disease > 2 within 6 months before entry; or presence of cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia.
  • Hemorrhagic or ischemic stroke, including transient ischemic attacks and other central nervous system bleeding in the preceding 6 months that were not related to glioma surgery. History of prior intratumoral bleeding is not an exclusion criterion; patients with history of prior intratumoral bleeding, however, need to undergo a non-contrast head CT to exclude acute blood.
  • Ventricular arrhythmias requiring continuous therapy or asymptomatic sustained ventricular tachycardia within 12 months before study entry. Continuous or intermittent atrial fibrillation requiring treatment. Patients with significant ECG abnormalities such as complete left bundle block and third degree heart block are not eligible.
  • QTc prolongation with other medications that required discontinuation of that medication.
  • Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age. QTc with Bazett’s correction that is unmeasurable, or > 470 msec on screening ECG. (Note: If a subject has a QTc interval > 470 msec on screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be less than or equal to 470 msec in order for the subject to be eligible for the study. Patients who are receiving a drug that has a risk of QTc prolongation are excluded if QTc is greater than or equal to 460 msec.
  • Any concurrent medication that may cause QTc prolongation or induce

Torsades de Pointes 1) Drugs listed in Appendix H, Table 2, that in the investigator’s opinion cannot be discontinued are allowed; however, must be monitored closely.

  • Concomitant medications that are moderate or potent inducers or inhibitors of CYP3A4 are not permitted within the specified wash-out periods prior to or during treatment with AZD7451
  • Patients with a history of corneal disease such as corneal ulcers, corneal dystrophies, keratoconus.
  • Refractory nausea and vomiting or significant gastrointestinal impairment, as judged by the investigator, that would significantly affect the absorption of AZD7451, including the ability to swallow the oral solution.
  • Patients known to have active hepatitis B or C (testing not required for entry on study).
  • Other concomitant anti-cancer therapy except corticosteroids.
  • Patients with a peripheral neuropathy CTCAE > 1 in the prior 4 weeks or active muscle diseases (including dermatomyositis, polymyositis, inclusion body myositis, muscular dystrophy and metabolic myopathy) or family history of myopathy. Patients with pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi syndrome or renal tubular acidosis.
  • Evidence of active infection or active bleeding diatheses.
  • Pregnant women are excluded from this study because AZD7451 is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD7451, breastfeeding should be discontinued if the mother is treated with AZD7451. Female patients must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening:
  • Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
  • Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
  • Patients known to have a malignancy (other than their malignant glioblastoma) that has required treatment in the last 12 months and/or is expected to require treatment in the next 12 months (except for non-melanoma skin cancer, carcinoma in situ in the cervix or ductal carcinoma in situ).
  • Major surgery within 4 weeks or incompletely healed surgical incision before starting therapy.
  • Patients known to be HIV-positive (testing is not required for entry on study) and on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD7451. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Howard A Fine, M.D. Principal Investigator


Tracy Cropper, R.N. Ph: (301) 402-6298


Howard A Fine, M.D. Ph: (301) 402-6298


Source: NCI




Clinical Pathways in Cancer Care Catching On.

For a woman diagnosed with HER2-negative, estrogen-receptor negative breast cancer that has spread to the lymph nodes, guidelines from the National Comprehensive Cancer Network (NCCN) recommend chemotherapy following surgery.

Within this recommendation, however, is a lot of room for variation. In fact, there are 16 possible chemotherapy regimens, explained Dr. Bruce Feinberg, chief medical officer of Cardinal Health Specialty Solutions, based in Dublin, OH. Many of these regimens are similar, “but most of them will never be tested head to head” to determine which are the most effective, least toxic, and least costly, he said.

Clinical pathways can help physicians choose the best treatments for individual patients from several possible regimens.

As a result, even within the same oncology practice, two similar patients may get very different treatments, often because their oncologists prefer or are more comfortable with one particular regimen than another.

Enter “clinical pathways”—programs that are being designed and implemented by large networks and smaller practices to limit such variation. The programs do this by helping doctors select what the available evidence indicates are the best regimens for a particular patient. That evidence is derived from sources that can include clinical trial data and professional guidelines.

In the breast cancer example above, the clinical pathway used by many Michigan oncologists narrows the first-line treatment options from 16 to 4 regimens, explained Dr. Feinberg, who ran a large Atlanta-based oncology practice for 23 years.

Pathways programs that Cardinal Health has helped to establish in Michigan, Maryland, Pennsylvania, and several other states have “reduced variation, and allowed those oncologists to gain more refinement and better knowledge of the treatments,” Dr. Feinberg said. And that, proponents of clinical pathways believe, can improve the quality of care.

Pathways may also save money, by reducing treatment complications and the unnecessary use of some drugs, for example. And with annual direct costs of cancer treatment in the United States estimated to reach $173 billion by 2020, any way of cutting costs—without sacrificing quality—is under serious consideration.

Building a Pathway

The pathways concept appears to be picking up steam. In a small survey conducted at NCCN’s 2012 annual conference, for example, nearly 60 percent of respondents said they had implemented or were considering implementing clinical pathways.

Clinical pathways are just one route the oncology community is pursuing to improve the quality and efficiency of care, explained Dr. Steven Clauser, chief of the Outcomes Research Branch in NCI’s Division of Cancer Control and Population Sciences (DCCPS).

“In the last few years, we’ve begun to see a real emphasis on trying to improve and measure quality,” Dr. Clauser said. That includes efforts to track adherence to clinical guidelines, “and using [the resulting] data to better understand an organization’s clinical environment and how they’re treating their patients,” he continued.

Clinical pathways are similar to clinical guidelines, but they take the concept one step further.

The US Oncology Network, a nationwide network with approximately 1,000 oncologists, develops its clinical pathways following a specific formula, explained Dr. Roy Beveridge, chief medical officer for McKesson Specialty Health. (McKesson acquired US Oncology in 2010.)

“First, we look at randomized controlled trials…which we believe are the most important data,” Dr. Beveridge said. “We want to see the manuscript, and we look for definitive trials.”

When a randomized trial shows that one treatment is significantly better than “anything else out there,” he continued, “then that is the top choice in the pathway. Period.”  In cases where two treatments are equally effective but differ in toxicity, the less-toxic regimen is favored. And in cases where efficacy and toxicity are similar, then cost—in the form of what insurers pay—is taken into account.

The idea that adherence to a guideline or a pathway is a measure of quality is complicated. That’s the part we have to be careful about.

—Dr. Stephen Taplin

Cardinal Health and Via Oncology, a spinoff of a clinical pathways program developed at the University of Pittsburgh Medical Center (UPMC) Cancer Center, follow similar criteria. All three companies rely on physician-led committees to review clinical trial results, published studies, and, with the exception of Via Oncology, professional clinical guidelines to develop each pathway.

In the physician networks that implement pathways, oncologists can review and comment on draft pathways before they’re finalized. These committees convene regularly to review the latest data and determine whether a pathway needs to be updated.

The pathways are not iron clad, nor should they be, explained Dr. Peter Ellis, Via Oncology’s medical director. In all of the major pathway programs, the rule of thumb for adhering to a pathway is 80 percent, a threshold that appears to be based primarily on clinical experience, not firm data.

If an individual oncologist has an adherence rate above 80 percent, “we’re worried about it,” said Dr. Ellis. Adherence above 80 percent “could mean that they’re not thinking through the needs of individual patients. There are going to be circumstances when a patient really should be on something other than the pathway choice.”

UPMC, Dr. Ellis said, has a compliance rate of 77 percent with its available pathways, which now cover approximately 90 percent of cancer treatment decisions, as well as tests, post-treatment surveillance, radiation therapy, and supportive care.

The pathways concept isn’t always welcomed with open arms, though. Practicing oncologists must “deal with reality, where variances [to pathways] go by different names, such as vomiting, fever, drug shortages, pulmonary emboli, frustration, grief,” Dr. Craig Hildreth, an oncologist in St. Louis, wrote last year on his Cheerful Oncologistblog. (Free registration is required to access the blog.)

In some cases, medical practices within a health care network that has implemented a pathways program have refused to use them.

At practices in the US Oncology Network, Dr. Beveridge said, the response has been good. “Our Level I Pathways is an evidence-based medicine initiative,” he said. “The buy-in has been high because these treatment guidelines are physician-led and developed based on proven evidence.”

A practice’s setting will also likely influence the decision to implement clinical pathways, said Dr. George Weiner, director of the University of Iowa Holden Comprehensive Cancer Center. Academic medical centers with tumor boards and “strong in-house multidisciplinary programs,” where there is a significant amount of collaboration and discussion among the different clinicians involved in patient care, may be less likely to go the pathways route, he believes.

Do Pathways Improve Care, Save Money?

The Systems around the Pathways

The US Oncology Network’s clinical pathways are built into the organization’s electronic health record (EHR) system, iKnowMed. The EHR lists the “on-pathway” treatments for a given diagnosis and the documentation to support their inclusion in the pathway.

The documentation of the evidence to support a pathway is particularly helpful for oncologists caring for patients with less common cancers, said Dr. Debra Patt, medical director of the US Oncology Network Pathways Task Force and a breast cancer specialist at Texas Oncology, a network affiliate.

The documentation can also help patients, she continued. “It’s a wonderful experience to show patients…the hyperlinks to the studies, then hyperlinks to the Pathways Task Force committee report,” Dr. Patt said. “It’s a great educational tool, and I can say to them, ‘This is the evidence to support the recommended treatment,’ and it helps them to participate in informed decision making.”

Building a robust IT infrastructure around clinical pathways has been a top priority and a big financial investment for Via Oncology, Dr. Ellis explained. The most recent version of the company’s web-based pathways portal can connect directly into a practice management system, so pathway choices are incorporated into the doctor’s schedule for each patient visit.

The concept of clinical pathways is a strong one, said Dr. Stephen Taplin, chief of the Process of Care Research Branch in DCCPS. But, he cautioned, it’s unclear whether clinical pathways improve quality.

“The idea that adherence to a guideline or a pathway is a measure of quality is complicated,” Dr. Taplin said. “That’s the part we have to be careful about.”

Oncologists must consider factors like patient preference and suitability for treatment when making decisions about care, he stressed.

The best way to develop and use pathways will need to be closely studied, noted Dr. Weiner.  “How rigorous should they be? How much flexibility should they include?”

Dr. Ellis acknowledges that it’s difficult to prove that clinical pathways improve care quality.  Even so, he argued, “If a pathways system can document that evidence-based care is given, then it naturally follows that the quality of care will improve.”

But at this point, Dr. Feinberg noted, the idea that pathways improve care quality is “largely an act of faith…. You have to look for behavior changes that you believe represent better care.”

Some documented behavior changes include less use of combination chemotherapy as third- and fourth-line treatments. Patients treated on a pathway also have fewer emergency room and hospital admissions because of chemotherapy side effects, the US Oncology Network and Cardinal Health have reported.

The US Oncology Network is, thus far, the only group to publish data on potential cost savings. Using electronic medical record data from eight of its affiliated practices, they found that, over 1 year, outpatient treatment costs were 35 percent lower ($18,000 versus $28,000) for patients with non-small cell lung cancer treated on-pathway than off-pathway.

Some insurers have been skeptical about whether pathways can improve care or reduce costs, Dr. Beveridge acknowledged. “That’s why we conducted the study,” he said. “Because of our study results, I believe most payers are now interested in learning more about a pathways approach.”

Insurers are central to the model used by Cardinal Health, which facilitates collaborations with insurers and oncology groups on pathway development. As part of that collaboration, the insurers provide financial incentives to practices that participate in the program and meet compliance benchmarks.

Even with the uncertainty, clinical pathways are proliferating. The US Oncology Network has licensed its pathways to several hospital systems and practices, Dr. Beveridge said. Hospitals and oncology practices in 11 states are using Via Oncology’s pathways. The most recent addition came just last month with Indiana University Health System, which will implement the pathways at the central site and its affiliated oncology practices.

With the advent of accountable care organizations and other efforts to measure quality of care and reduce costs, clinical pathways—or something like them—may very well be part of the future for all hospitals and medical practices, Dr. Ellis believes.

“There’s got to be more accountability and proof of quality of care,” he said. “You’re not going to be able to say to patients and payers, ‘Trust me, I’m a good doctor.’”

Source: NCI