The blood test requires a 10 milliliter blood sample -- just two teaspoons. It takes about eight hours to send the blood across the 80,000 tiny columns so a specially designed antibody glue can latch onto passing cancer cells. It was used to detect cancer in 27 people and helped to track the progress of cancer in near real time. This will help determine what treatments are working and a genetic fingerprint of the current state of any tumor. This should lead to better cancer treatment and earlier detection and better disease monitoring
Haber and his colleagues analyzed blood samples from 27 patients with non-small cell lung cancer, 23 who had EGFR gene mutations and four who did not. CTCs were identified in all samples and in genetic analyses from mutations 92 percent of the time.
Mutations in EGFR, a protein, can help predict whether these tumors will respond to a family of drugs called tyrosine kinase inhibitors.
"Even in the three to four months that we followed patients, the genetic make-up of the tumors changed. Resistant mutations appear and other mutations appear, obviously because we're doing things [with drug therapy] to the cancer," Haber said. "But the way we practice oncology we don't typically test for that. We do one biopsy which takes a tiny, tiny amount and assume that for the rest of the course, the tumor is the same."
"It's important to know in real time what you're treating," he continued. "We need to be able to follow the patient without needing to re-biopsy the tumor every time."
A previous study published in Nature used the CTC (Circulating Tumor Cells) chip technology to look at CTCs in lung, pancreatic, prostate, breast and colon cancers. The CTC chip successfully found such cells in 99 percent of the samples.
Schiller, of the University of Texas Southwestern Medical Center in Dallas, said there are practical questions about whether enough cells can be extracted to make the technique effective and whether it will work for other types of tumors.
Haber said he believes it will.
The CTC chip, licensed to the privately held CellPoint Diagnostics in Mountain View, California, is 100 times more sensitive than a U.S. Food and Drug Administration-approved technique that uses magnetic beads to try to extract cancer cells, according to Haber.
"I think this is key to personalized medicine," said Dr. Daniel Haber, senior author of a paper detailing the technology, to be published in the July 24 issue of the New England Journal of Medicine but released early online Wednesday. "As we get to targeted therapies in increasing numbers, and increasing understanding about the genetics that guide targeted therapies, we need a way to know what we're treating."
The technology is in its infancy, however. "This is still in a very, very early stage where it takes a long time to handle every sample, to flow the blood through the chip," Haber said. "This is a proof of principle that we can do this. We need a much more automated system for larger clinical trials."
Dr. Len Horovitz, a pulmonary specialist at Lenox Hill Hospital in New York City, said that "you have to have some circulating cells to do this test, but it's very exciting because they're getting a genetic fingerprint of a tumor which will tell an oncologist what therapy the tumor might respond to or not respond to.
"It's expensive, but it may well be that if we can identify patients who can have a personalized regimen that works, we will be saving the cost of treating all those patients with regimens that don't work," he added.
FURTHER
Megpagetoday coverage
Web MD coverage of the CTC chip
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Laser light can be used to detect molecules in breath that may be markers for diseases like asthma or cancer.
Although it has yet to be tested in clinical trials, a new apparatus may allow doctors to screen people for certain diseases simply by sampling their breath, according to JILA, a joint institute of the National Institute of Standards and Technology (NIST) and the University of Colorado (CU-Boulder).
Known as optical frequency comb spectroscopy, the method is powerful enough to sort through all the molecules in human breath and sensitive enough to distinguish rare molecules that may be biomarkers for specific diseases, said Ye.
When many breath molecules are detected simultaneously, highly reliable, disease-specific information can be collected. Asthma, for example, can be detected much more reliably when carbonyl sulfide, carbon monoxide and hydrogen peroxide are all detected simultaneously with nitric oxide.
While current breath analysis using biomarkers is a noninvasive and low-cost procedure, approaches are limited because the equipment is either not selective enough to detect a diverse set of rare biomarkers or not sensitive enough to detect particular trace amounts of molecules exhaled in human breath.
"The new technique has the potential to be low-cost, rapid and reliable, and is sensitive enough to detect a much wider array of biomarkers all at once for a diverse set of diseases," Ye said.
To test the technology, Ye's team had several CU-Boulder volunteer students breathe into an optical cavity -- a space between two curved mirrors -- then directed sets of ultrafast laser pulses into the cavity. As the light pulses ricocheted around the cavity tens of thousands of times (covering a distance of several kilometers by the time it exited the cavity), the researchers determined which frequencies of light were absorbed, indicating which molecules -- and their quantities -- were present by the amount of light they absorbed.
The remarkable combination of a broad spectral coverage of the entire comb and a sharp spectral resolution of individual comb lines allows them to sensitively identify many different molecules, Ye said. They detected trace signatures of gases like ammonia, carbon monoxide and methane from the samples of volunteers. In one measurement, they detected carbon monoxide in a student smoker that was five times higher compared to a nonsmoking studen.
There is a podcast on this research
The university of Colorado podcast list is here
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A set of 15 proteins found in urine can distinguish healthy individuals from those who have coronary artery disease (CAD), a new study has found.
Coronary artery disease is the most common type of cardiovascular disease, occurring in about 5 to 9% (depending on sex and race) of people aged 20 and older.
In 2001, the death rate from coronary artery disease was 228 per 100,000 white men, 262 per 100,000 black men, 137 per 100,000 white women, and 177 per 100,000 black women. Over 1 million deaths per year worldwide.
Due to the ease of obtaining samples, urinary protein analysis is emerging as a powerful tool to detect and monitor disease.
The researchers next examined how predictive their protein panel was and found it could identify the presence of CAD 83% of the time. The panel had a sensitivity of over 98%, which means the test produced almost no false positives and thus inaccuracies are primarily misdiagnosing CAD individuals as healthy. The researchers also observed that the protein signatures of CAD individuals became more normal after exercise, suggesting these biomarkers can be used to both help diagnose CAD and monitor the progress of treatment.
FURTHER READING
A USB stick size device has been created for genetic screening in minutes for tens of dollar A similar cost device seems possible for screening for the proteins that identify coronary artery disease.
This is another major piece in the vision that I and many others have to transform public health with widespread use of frequent biomarker tracking to identify people in the early stages of disease or those just with the increased risk factors and transform medicine to cheaper prevention of disease development
This should also be used to change drug approvals by identifying earlier when a drug is having effect with improved biomarkers.
More papers by Anna Dominiczak
Cardiovascular disease statistics
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Since a journal article was submitted to the Royal Society of Chemistry, the U of Alberta researchers have already made the processor and unit smaller and have brought the cost of building a portable unit for genetic testing down to about $100 Cdn. In addition, these systems are also portable and even faster (they take only minutes). Backhouse, Elliott and McMullin are now demonstrating prototypes of a USB key-like system that may ultimately be as inexpensive as standard USB memory keys that are in common use – only tens of dollars. It could help with Pandemic disease control and detecting and controlling tainted water supplies.
This development fits in with my belief that there should be widespread inexpensive blood, biomarker and genetic tests to help catch disease early and to develop an understanding of biomarker changes to track disease and aging development. We can also create adaptive clinical trials to shorten the development and approval process for new medical procedures
The device is now much smaller than size of a shoe-box (USB stick size) with the optics and supporting electronics filling the space around the microchip
Canadian scientists have succeeded in building the least expensive portable device for rapid genetic testing ever made. The cost of carrying out a single genetic test currently varies from hundreds to thousands of pounds, and the wait for results can take weeks. Now a group led by Christopher Backhouse, University of Alberta, Edmonton, have developed a reusable microchip-based system that costs just 500 (pounds) to build, is small enough to be portable, and can be used for point-of-care medical testing.
To keep costs down, 'instead of using the very expensive confocal optics systems currently used in these types of devices we used a consumer-grade digital camera', Backhouse explained.
The device can be adapted for used in many different genetic tests. 'By making small changes to the system you could test for a person's predisposition to cancer, carry out pharmacogenetic tests for adverse drug reactions or even test for pathogens in a water supply,' said Backhouse.
The heart of the unit, the ‘chip,’ looks like a standard microscope slide etched with fine silver and gold lines. That microfabricated chip applies nano-biotechnologies within tiny volumes, sometimes working with only a few molecules of sample. Because of this highly integrated chip (containing microfluidics and microscale devices), the remainder of the system is inexpensive ($1,000) and fast.
There are many possible uses for such a portable genetic testing unit:
Backhouse notes that adverse drug reactions are a major problem in health care. By running a quick genetic test on a cancer patient, for example, doctors might pinpoint the type of cancer and determine the best drug and correct dosage for the individual.
Or health-care professionals can easily look for the genetic signature for a virus or E. coli – also making it useful for testing water quality.
“From a public health point of view, it would be wonderful during an epidemic to be able to do a quick test on a patient when they walk into an emergency room and be able to say, ‘you have SARS, you need to go into that (isolation) room immediately.’ ”
A family doctor might determine a person’s genetic predisposition to an illness during an office visit and advise the patient on preventative lifestyle changes.
FURTHER READING
Microfabrication technologies research at the University of Alberta
Rapid genetic analysis
In collaboration with the Glerum Lab we have been developing microchip based implementations of genetic amplification (PCR - the polymerase chain reaction) and capillary electrophoresis (CE) that are extremely fast.
- Cancer diagnostics
- Cell manipulation on a chip
- On chip PCR (polymerase chain reaction)
- Single cell PCR
- DNA Sequencing
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By 2014 the Army may issue more than combat gear to deploying soldiers. University of Connecticut researchers are developing an implantable chip that would be injected under soldiers' skin to help monitor vital health information while they are out in the field.
These kinds of devices would help enable real time tracking of biomarkers for better preventative medicine and to transform medical research and drug approval
Embedding the sensor is more complex than simply getting a shot in the wrist, because of the body's immune system reaction. “The (body's) reaction is inflammation, what you typically see if you get scab or splinter. Inflammation is the body's reaction to get rid of foreign matters,” said Dianne Burgess, professor of pharmaceutics at UConn and member of the research team.
To trick the body into not attacking the sensor, researchers have created a gel coating that contains time-release anti-inflammatory medication. Burgess said they have created a sensor that would stay implanted in a person for at least three months.
A prototype of the sensor has been assembled and the university will use this new grant to work on synchronizing the implantable nanosensor with the wrist transmitter.
UConn researchers believe a fully functional device is five years away from human testing. But they are not the only researchers working in the field.
“The competition is unbelievable,” Papadimitrakopoulos said. “But we believe we are very advanced.”
Clemson University in South Carolina is also in the race to develop an implantable sensor to monitor soldiers' vital signs. In July the Department of Defense gave the school $1.6 million to develop similar technology.
UConn scientists are looking at ways to use the technology to help change the way diabetics monitor their blood sugar and live their lives.
“Right now (diabetics) prick their fingers five times a day and we don't have a picture of what happens in between,” Burgess said. This sensor would be “completely revolutionary.”
She said the nanosensor could be used by diabetics to help understand how their bodies respond to eating and exercise and in turn produce an individualized medication and care plan.
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I had previously proposed more widespread use of biomarkers for improved healthcare and medical research. I have now discovered the work that is already underway to realize that vision. The vision is to greatly shorten the time it takes to find and prove that a new drug or medical procedure is effective and to approve it for use and to personalize treatment and be able to model and monitor the effectiveness of treatment in real time.
A 41 page powerpoint presentation on using biomarkers to shorten clinical trials. Clinical trials for new drugs take 7 to 12 years and cost between $800 million to $1.7 billion. Clinical trials can take up to 15-18 years. 90% of new drugs fail during clinical trials because of toxicity or ADME issues. (ADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion)
Biomarkers can increase productivity by identifying potential failures early, saving both time and cost. Most new drugs “fail late”, after huge investment. Biomarkers can aid in early decision making on whether to drop a drug from consideration or to move it through trials. Biomarkers can help fail 90% of the drugs that wil not succeed early.
Survey of current and planned usage of biomarkers
Identification of biomarkers take a lot of science and effort
FDA Definitions: FDA Definitions:
Probable and Validated Biomarkers Probable and Validated Biomarkers
-A probable biomarker …has well established performance characteristics for which there is a scientific framework or body of evidence thatappears to elucidateits physiological, toxicological, pharmacological or clinical significance
-A validated biomarker …has well established performance characteristics for which there is wide spread agreementin the scientific and medical community about its physiological, toxicological, pharmacological or clinical significance
Current Drug Timeline & Trial Format
Pre-clinical 2-5 years
•Retrospective and/or pilot
Phase 1 6 months
•Safety
Phase 2 1-2 years
•Dose setting
Phase 3 1-5 years
•Efficacy
Phase 4 2-10 years
•Post approval additions
The shortest time to go through Phase 2 through phase 4 is about 4 years.
Benefits of adaptive clinical trials
Examples of using biomarkers in past clinical trials
Tools for adaptive clinical trials
Many drugs fail because they are toxic at the doses required for optimum efficacy
-Often, this does not become evident until after phase 3 studies, and can even arise post-release
-Biomarkers may potentially:
•predict toxicity in early trials
•monitor toxicity in later trials
•help avoid toxicity in the clinic
The value of biomarkers in clinical research and in the drug development process is becoming increasingly more crucial. The old concept of a single marker for a given indication has been replaced with the new “panel”paradigm. As these biomarker panels increase in complexity, so does the effort involved in their evaluation. Decision Biomarkers has developed a system to simplify this process with the incorporation of array multiplexing, microfluidics, assay automation, and on-board data analysis
FURTHER READING
A related topic is the development an inexpensive microfluidics chip which could lead to earlier cancer detection and treatment 
When blood flows through a new microfluidics device, designed by researchers at Massachusetts General Hospital, cancer cells (one cell shown in yellow) in the blood stick to microscopic posts lining the chip (shown in blue). Detecting these cells could aid with cancer monitoring and treatment.
Credit: Massachusetts General Hospital BioMEMS Resource Center
Malignant tumors continually shed cancer cells into the bloodstream, and these cells can spread the disease to other tissues. This process, known as metastasis, is the deadliest aspect of cancer: it is the culprit in nine out of ten cancer deaths. But the circulating tumor cells are so rare--with a concentration of onlyone in a billion cells in the bloodstream--that scientists haven't been able to detect them easily or accurately enough to be clinically useful. Now Mehmet Toner, a bioengineer at MGH and Harvard Medical School, and his colleagues have designed a microfluidics device that can analyze whole blood in large enough volumes to detect these scarce cells.
"I think this device is going to turn the field of metastasis upside down," says Toner, who led the work. "It finds the circulating tumor cells that end up killing people." He adds that the sensitivity of the test is "high enough for clinical applications."
The device consists of a business-card-size silicon chip dotted with 80,000 microscopic posts. Each post is coated with a molecule that binds to a specific protein found on most cells originating from solid tumors, such as breast, lung, or prostate cancer. As blood flows through the chip, tumor cells stick to the posts.
Initial tests show that the device is highly sensitive. An analysis of blood samples from 68 patients with five types of cancer detected cancer cells in all but one sample, according to findings published today in the journal Nature. Researchers also found that changes in the number of circulating cancer cells accurately reflected changes in the size of patients' tumors during treatment. Oncologists often use tumor size as a measure of how well a treatment is working, with the goal of shrinking the tumor.
Such blood tests could ultimately prove to be an inexpensive and noninvasive complement to the CT scans and tissue biopsies that oncologists traditionally use to characterize tumors. For example, regular blood tests assessing tumor cell count might be used to determine if a particular treatment is effective. That might allow "the treatment regimen to be modified much earlier than if physicians had to rely solely on changes in tumor size," says Jonathan Uhr, a scientist at the University of Texas Southwestern Medical Center, in Dallas, who wrote a commentary accompanying the paper in Nature.
Toner likens the circulating tumor cell count to viral loads in HIV, which doctors use to assess how effective antiviral drugs are. "If we're going to turn cancer into a chronic disease, we need to monitor the patient accordingly," he says.
Researchers can also examine the cells captured on the chip for molecular markers that suggest a more aggressive form of cancer or a tumor that will respond to specific cancer drugs. The researchers ultimately hope to use the chip to analyze genetic changes in the tumor, which might signal the need to change treatments.
The ability to monitor changes in the levels of circulating tumor cells might also reshape physicians' view of cancer. For example, a preliminary study of patients with prostate cancer showed that a subset of people diagnosed as having localized cancer actually had circulating tumor cells. "It may be that cancer needs to be defined more molecularly than morphologically," says Toner
. [so instead of the currently broadly defined stages of cancer there could be more detailed modeling of the molecular progression.]
A powerpoint of the FDA's critical path initiativeAdaptive Clinical Trials Are Steppingstone toward Personalized Medicine.At the 2006 Conference on Adaptive Trial Design, FDA Deputy Commissioner for Medical and Scientific Affairs Scott Gottlieb emphasized how important it is to pursue alternatives to the traditional, highly empiric statistical approach to conducting clinical trials, by designing ones that can be adapted.
How Technology is Accelerating Adaptive Clinical Trials.The journal of drug discovery and development
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