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Minimally invasive image-guided therapy for inoperable hepatocellular carcinoma

Curator & Reporter: Dror Nir, PhD

Large organs like the liver are good candidates for focused treatment. The following paper:

Minimally invasive image-guided therapy for inoperable hepatocellular carcinoma: What is the evidence today?

By Beatrijs A. Seinstra1, et. al. published mid-2010, gives a review of the state-of-the-art of the then available methods for local lesions’ ablation. As far as ablation techniques availability, I have found this review very much relevant to today’s technological reality. It is worthwhile noting that in the last couple of years, new imaging-based navigation and guidance applications were introduced into the market holding a promise to improve the accuracy of administrating such treatment. These are subject to clinical validation in large clinical studies.  From the above mentioned publication I have chosen to highlight the parts discussing the importance of imaging-based guidance to the effective application of localized ablation-type therapies.

The clinical need:

Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver that accounts for an important health problem worldwide. Primary liver cancer is the sixth most common cancer worldwide with an incidence of 626,000 patients a year, and the third most common cause of cancer-related death [1]. Only 10–15% of HCC patients are suitable candidates for hepatic resection and liver transplantation due to the advanced stage of the disease at time of diagnosis and shortage of donors.

Immerging solution:

In order to provide therapeutic options for patients with inoperable HCC, several minimally invasive image-guided therapies for locoregional treatment have been developed. HCC has a tendency to remain confined to the liver until the disease has advanced, making these treatments particularly attractive.

Minimally invasive image-guided therapies can be divided into the group of the tumor ablative techniques or the group of image-guided catheter-based techniques. Tumor ablative techniques are either based on thermal tumor destruction, as in radiofrequency ablation (RFA), cryoablation, microwave ablation, laser ablation and high-intensity focused ultrasound (HIFU), or chemical tumor destruction, as in percutaneous ethanol injection (PEI). These techniques are mostly used for early stage disease. Image-guided catheter-based techniques rely on intra-arterial delivery of embolic, chemoembolic, or radioembolic agents [22]. These techniques enable treatment of large lesions or whole liver treatment, and are as such used for intermediate stage HCC (Figure 1).

Minimally invasive image-guided ablation techniques and intra-arterial interventions may prolong survival, spare more functioning liver tissue in comparison to surgical resection (which can be very important in cirrhotic patients), allow retreatment if necessary, and may be an effective bridge to transplantation [23–27].

During the last 2 decades, minimally invasive image-guided therapies have revolutionized the management of inoperable HCC.

The value of image guidance

Accurate imaging is of great importance during minimally invasive loco-regional therapies to efficiently guide and monitor the treatment. It enables proper placement of instruments, like the probe in case of ablation or the catheter in case of intra-arterial therapy, and accurate monitoring of the progression of the necrotic zone during ablation.

can all be employed. In current clinical practice, placement of the catheter in intra-arterial procedures is usually performed under fluoroscopic guidance, while ablation may be guided by ultrasound, CT or MRI.

  • Ultrasound guidance allows probe insertion from every angle, offers real time visualization and correction for motion artifacts when targeting the tumor, and is low cost. However, the gas created during ablation (or ice in the case of cryoablation) hampers penetration of the ultrasound beams in tissue, causing acoustic shadowing and obscuring image details like the delineation between tumor borders and ablation zone.
  • CT is also frequently used to guide minimally invasive ablation therapy, and is a reliable modality to confirm treatment results. In comparison to US, it provides increased lesion discrimination, a more reliable depiction of ablated/non-ablated interfaces, and a better correlation to pathologic size [28]. However, due to its hypervascularity, small HCCs can only be clearly visualized in the arterial phase for a short period of time. Another disadvantage of CT is the exposure of the patient and physician to ionizing radiation.
  • Combining US imaging for probe placement and CT for ablation monitoring reduces this exposure. At the moment, hybrid systems are being developed, enabling combination of imaging techniques, like ultrasound and CT imaging, thereby improving the registration accuracy during treatment [29]. The interest in MRI-guided ablation is growing, as it produces a high-quality image allowing high-sensitivity tumor detection and accurate identification of the target region with multiplanar imaging.
  • MRI also enables real-time monitoring of the temperature evolution during treatment [30–35]. However, MRI is an expensive technique, and MRI-guided ablation is still limited in clinical practice. Currently, the most widely used ablation technique for percutaneous treatment of focal hepatic malignancies is radiofrequency ablation (RFA), which has been shown to be safe and effective for the treatment of early stage HCC [48–50]. During RFA, a small electrode is placed within the tumor, and a high-frequency alternating electric current (approximately 400 MHz) is generated, causing ionic agitation within the tissue. ….. Most frequently ultrasound is used for image guidance (Figs. 2, 3), but there are reports of groups who use CT, MRI, or fluoroscopic imaging.
Ultrasound guided RFA. a: HCC lesion in a non-surgical patient pre-treatment (pointed out by arrow). b: Just after start treatment, electrode placed centrally in the tumor. c: Gas formation during ablation causes acoustic shadowing

Ultrasound guided RFA. a: HCC lesion in a non-surgical patient pre-treatment (pointed out by arrow). b: Just after start treatment, electrode placed centrally in the tumor. c: Gas formation during ablation causes acoustic shadowing

Contrast-enhanced CT pre- and post-RFA. Same patient as in Fig. 2. a: Hypervascular lesion (biopsy proven HCC) in right liver lobe (pointed out by arrow) before treatment. b: Ablated lesion directly post ablation, with reactive hyperemia around the RFA lesion

Contrast-enhanced CT pre- and post-RFA. Same patient as in Fig. 2. a: Hypervascular lesion (biopsy proven HCC) in right liver lobe (pointed out by arrow) before treatment. b: Ablated lesion directly post ablation, with reactive hyperemia around the RFA lesion

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Other research papers related to the management of Prostate cancer were published on this Scientific Web site:

HBV and HCV-associated Liver Cancer: Important Insights from the Genome

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @ http://pharmaceuticalintelligence.com

Whole-body imaging as cancer screening tool; answering an unmet clinical need?

Personalized Medicine: Cancer Cell Biology and Minimally Invasive Surgery (MIS)

Read Full Post »

Science Budget FY’14: Stakeholders’ Reactions on Selective Budget Drops and Priorities Shift

Reporter: Aviva Lev-Ari, PhD, RN

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Reactions to Obama’s Science Budget

by Science News Staff on 12 April 2013, 12:00 PM

si-whitehouse.jpg

Credit: Francisco Diez

The words are flowing. Reactions are starting to trickle in to the research-related portions of President Barack Obama’s 2014 budget request, which was delivered to Congress. ScienceInsider will be tracking what groups are saying as they release statements.

Statement by the Task Force on American Innovation on the president’s FY ’14 budget (12:00 p.m. on 12 April):

Members of the Task Force on American Innovation—a coalition of industry, universities, and scientific societies—believe it is essential that the federal government maintain a robust investment in scientific research. We believe that Congress and the President can and must commit to such spending even as they work to reduce budget deficits.

In that context, the Task Force supports President Obama’s proposed increases in funding for the National Science Foundation, the Department of Energy Office of Science, Department of Defense basic research, and the National Institute of Standards and Technology.

The federal investment in scientific research is vital to the nation’s long-term economic growth and national security. Indeed, one of the reasons that deficit reduction is so important is to ensure that the government can afford this and other critical investments. We recognize that there are strong differences over how to reduce budget deficits. But we believe there should be bipartisan support for the research that is the foundation of innovation and economic competitiveness.

With both the House and Senate having approved budgets, and the President now having submitted his own, we continue to urge the nation’s leaders to come together and negotiate a major long-term budget agreement that not only protects coming generations from unsustainable debt but also ensures our ability to invest in their future.

The American Chemical Society responds (4:00 p.m. on 11 April):

WASHINGTON, April 11, 2013 — The American Chemical Society (ACS) applauds the release of the President’s FY14 budget and his continued recognition of the importance of science and technology as the fuel for economic growth and job creation.

The ACS sees the President’s budget, and those prepared by Congress, as excellent starting points toward enactment of a balanced and bipartisan FY14 budget for the country,” said ACS President Marinda Wu, Ph.D. “We fully appreciate that this has been, and will be, a challenging budget season. We encourage our national leaders to make a bipartisan effort to focus on achieving a balanced budget that helps put the U.S. economic house in order, while also putting forth a road map that fosters innovation and leads to economic growth and job creation.”

ACS believes strongly that economic growth in the U.S. is based on three foundations: sustained support for scientific and medical research that leads to technological innovations, a strong science education enterprise that prepares a world-class workforce and a robust business climate that will make American companies competitive with our international competitors. To accomplish this we need our nation’s leadership to prioritize continued and predictable investment in scientific research to identify and enable new opportunities for innovation.”

The three-part ACS public policy agenda is outlined in U.S. Innovation and Entrepreneurship, and specific policy recommendations are contained in positions on enhancing research and technology development,science education and the empowerment of U.S. businesses.

As scientists and engineers, we are confident in recommending that the FY 14 budget should — indeed, must — emphasize innovation. In the last sixty years, more than half of all growth in GDP has directly resulted from scientific research and subsequent commercialization of new products and processes. Our American roots lie in pioneering innovation! This is what we do best.

Representative Lamar Smith (R-TX), the chair of the Science, Space, and Technology Committee of the U.S. House of Representatives released the following (5:00 p.m. on 10 April):

Even after a two-month delay, the President’s budget still gets a failing grade. Filled with new spending and over one trillion dollars in tax increases, his proposal once again fails to balance the budget and continues to borrow 25 cents for every dollar the federal government spends. Hardworking taxpayers are tired of watching the government borrow and spend money it doesn’t have.

While getting points for creativity, a proposed NASA mission to ‘lasso’ an asteroid and drag it to the Moon’s orbit will require serious deliberation. Seemingly out of the blue, this mission has never been evaluated or recommended by the scientific community and has not received the scrutiny that a normal program would undergo.

I am also concerned that the Administration continues to favor subsidies associated with its green energy agenda over basic research that helps keep America competitive. The bankruptcies of Solyndra, Abound Solar and Beacon Power have demonstrated a lack of accountability within the President’s green energy initiatives. The President now wants more money to fund more pet projects, when it is clear that his administration has not been responsible with the taxpayer dollars that have already been spent.”

The Science Committee will hold hearings in the coming weeks to receive testimony on the President’s budget priorities.

The following is a statement from the LIVESTRONG Foundation (4:50 p.m. on 10 April):

The LIVESTRONG Foundation applauds President Obama’s budget proposal to increase funding for lifesaving cancer research at the National Institutes of Health and the National Cancer Institute. We are also encouraged that the Administration, through funding for the Department of State and the U.S. Agency for International Development, continues to make strengthening health systems globally a priority. These essential investments will fuel the discovery of new treatments and cures for the leading cause of death worldwide.

The Foundation is pleased the President’s budget aims to significantly reduce smoking’s deadly toll through a 94-cent increase in the federal tax on tobacco products. Tobacco taxes are a proven method of reducing smoking rates, especially among youth, and associated health care costs. With a tobacco tax increase also generating billions of dollars in revenue, it is a win-win for the health and economic vitality of our country.

Additionally, the Foundation is encouraged by the Administration’s proposal to put the necessary funding increases in place to support the advancement of electronic health records technology. The LIVESTRONG Foundation advocates for the rights of cancer patients to have the increased control of their records that electronic technology would bring, including the potential to improve and enhance many areas of medical care.

Our work is focused solely on addressing the needs of those facing cancer today, improving their quality of life and health outcomes through free support services, programs, tools, resources and advocacy efforts. Since our founding 16 years ago, we have mobilized more than $500 million to help 2.5 million individuals facing cancer. On behalf of the millions living with cancer today, the Foundation looks forward to working with the Administration and Congress to make these budget increases and priorities a reality.

Association of Public and Land-grant Universities (APLU) President Peter McPherson today released the following statement (4:40 p.m. on 10 April):

President Obama’s Fiscal Year 2014 budget proposal reflects a strong commitment to supporting research at our public universities while also providing financial assistance to help students pay for school. While we continue to review the administration’s budget documents in more detail, the overall figures reflect an understanding that continued investments in basic research and higher education will more than pay for themselves through the innovations and subsequent economic growth they generate. Research at our universities has led to the development of everything from the Internet, GPS and treatments for cancer and other devastating diseases. I greatly appreciate the President’s understanding that despite having more limited funding to allocate, we must continue to devote additional resources to the research that will lead to future economic gains.

Investments in student aid and research, the majority of which is conducted at our nation’s universities, did not cause our budget deficits. In fact, those deficits would be even higher had we not made those past investments. Along with other leaders in the research university community, I have repeatedly called for a balanced approach of entitlement reform that yields savings and tax reform that produces new revenue as a path toward reining in budget deficits. While details certainly need to be worked out, the President’s budget proposal provides the framework for such an approach and I hope Congress works with the White House to get a much-needed big deal done this year.

APLU has been working very hard to transform STEM education and teacher training through our Science and Mathematics Teacher Imperative (SMTI). We are very pleased to see the President continue his focus on training 100,000 new STEM teachers and producing 1 million new STEM graduates. This effort is incredibly important for increasing science literacy among all Americans and for producing the next generation of researchers and engineers who will discover and develop new technologies that will improve lives and power our economy for decades.

In recent years we’ve seen states cut funding for public universities at the same time those schools are taking on additional students, which has furthered the need for federal financial assistance to offset this shift in costs. To that end, I’m pleased that the President maintained investments in the Pell, Work Study, and other student aid programs. We also appreciate that the President’s budget seeks to prevent interest rates on federal student loans from doubling on July 1 as scheduled, and look forward to learning more about how the proposed fixed-variable rate would be funded.

Statement from Research!America President and CEO Mary Woolley (3:30 p.m. on 10 April):

The president’s FY14 budget proposal offers a lifeline for medical research to replace sequestration’s damaging footprints. The budget includes $31.3 billion for the National Institutes of Health, as well as increases for the Food and Drug Administration and National Science Foundation. These increases would take our nation in the right direction, but we’re concerned that budget proposals from Congress—one from each of the House and Senate—unlike the president, fail to reverse sequestration. Sequestration, 10 years of across-the-board spending cuts, will drag our nation down from its leadership position in research and development as other countries aggressively ramp up investments, attracting American businesses and young scientists concerned that federal funding is on the decline, that the U.S. no longer prioritizes research. Our nation has the most sophisticated medical research ecosystem in the world; yet our elected officials have ignored the short- and long-term consequences of dismantling it via sequestration—more deaths from preventable diseases, increased joblessness and soaring health care costs as more Baby boomers become afflicted with Alzheimer’s, cancer, heart disease and other life-threatening, costly illnesses. Policy makers must start acting in the best interests of this nation and tackle tax and entitlement reform to end sequestration. Without bold action by Congress and the administration, our nation’s research enterprise will sputter as other countries fuel their competitive edge.

Following is a statement by Hunter Rawlings, president of the Association of American Universities (AAU) (1:50 p.m. on 10 April):

AAU and its member research universities have frequently expressed our view that the nation can and should reduce budget deficits but maintain strong investments in research and education. Such spending is critical to the nation’s long-term economic growth, health, and national security.

We are pleased to see this approach reflected in the President’s FY14 budget. The President’s budget offers hope that the nation will continue to make science and education investments a top national priority while taking serious steps to reduce budget deficits. We strongly support the President’s proposals to eliminate the ill-considered across-the-board sequester and to increase funding for the National Institutes of Health, the National Science Foundation, the Department of Energy Office of Science, Department of Defense basic research, the National Endowment for the Humanities, and some key student financial aid programs.

While we have concerns about some of the specifics, we also appreciate that the Administration proposes taking steps to address entitlement programs, which are the most serious driver of spending increases, and to raise additional revenues, which also are essential to serious, balanced deficit reduction.

We do not agree with everything in this budget. But it is a strong start, and we will work with the Administration and with Republicans and Democrats in Congress to support balanced deficit reduction, elimination of the sequester, and strong and sustained investments in the nation’s future.

The following is a statement from United for Medical Research (UMR) in reaction to President Obama’s FY ’14 budget (1:50 p.m. on 10 April):

United for Medical Research applauds President Obama’s proposal to increase funding for the National Institutes of Health (NIH) in FY 2014. As the centerpiece of the medical innovation ecosystem, NIH not only supports the research that leads to treatments and cures for our most devastating diseases, but drives the life sciences economic engine, annually sustaining over 400,000 jobs and nearly $60 billion in economic activity nationwide. The President’s NIH budget proposal is an important step forward in restoring the crippling $1.6 billion cut the agency received as a result of the sequester.

We look forward to working with the Administration and Congress in making this increase in NIH funding a reality. Following a decade of decline in purchasing power, even as scientific opportunities have grown exponentially, increasing the NIH budget should be a critical national priority. In these perilous economic times, we cannot afford to underinvest in our nation’s most talented scientists. Their work, undertaken in all 50 states, has enabled the U.S. to lead the world in life science innovation.

Every year, NIH research on cancer, heart disease, stroke, and diabetes alone averts up to 1.35 million deaths annually while providing hope to millions of patients and their families. Funding roughly one-third of all U.S. medical research, NIH supports more than 300,000 research positions at over 2,500 research universities and institutions in all 50 states.

http://news.sciencemag.org/scienceinsider/2013/04/reactions-to-obamas-science-budg.html

Obama’s 2014 Science Budget: At CDC, Budget Drops and Priorities Shift

by Science News Staff on 11 April 2013, 4:00 PM 

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Talking money. White House science adviser John Holdren (left) discusses the research-related parts of President Barack Obama’s 2014 budget request to Congress at briefing at the Washington, D.C., headquarters of AAAS (publisher ofScienceInsider).
Credit: David Malakoff

On 10 April, President Barack Obama submitted to Congress his spending plan for the 2014 fiscal year that begins on 1 October. The document can be found at www.fdsys.gov. ScienceInsider is following the story closely, with regular updates on the requests of particular agencies and what those requests say about the president’s vision for science. Plus, reactions from the research community and around the web.

Laser Fusion Facility Faces Dimmer Spending

David Malakoff, 4:00 p.m. on 11 April

A controversial and perpetually troubled laser fusion project would get a hefty funding reduction under the president’s 2014 budget request for the Department of Energy (DOE). The cuts to the National Ignition Facility (NIF) at Lawrence Livermore National Laboratory in California appear to be a direct consequence of the project’s failure to create a burning fusion plasma by its 2012 goal.

NIF has long had critics, who contended even before the multibillion-dollar machine was built that it would never work. After numerous delays and cost overruns, NIF finally began operations in 2009, and managers set a 30 September 2012 goal of achieving “ignition” by using its 192 lasers to crush a tiny capsule of hydrogen fuel. But the device fell substantially short of that goal, and late last year officials told Congress that they weren’t sure NIF would ever be able create a burning plasma.

NIF advocates have argued that the project, even if it didn’t achieve ignition, is useful for conducting experiments that would help engineers understand and maintain the nation’s stockpile of nuclear weapons. That is now NIF’s focus, although some outside experts and members of Congress are skeptical of that use. They also question the wisdom of giving NIF any more time or money to achieve ignition.

The budget request appears to reflect some of that skepticism. To help pay for maintaining the nuclear stockpile during a time of austerity, “the Budget proposes to achieve savings by reducing investments in the National Ignition Facility, which failed to achieve ignition in 2012 as scheduled, and by implementing several management efficiencies,” it states. In particular, the budget calls for ending NIF accounting practices that allowed Livermore officials to charge some of the project’s costs to other programs—a practice that critics said effectively obscured NIF’s true cost.

It’s not clear exactly how big the proposed NIF cuts are, because the project receives funding from several programs within DOE’s National Nuclear Security Administration, which oversees the nation’s nuclear weapons program. A Livermore spokesperson tells ScienceInsider that NIF’s operating budget request is $329 million for 2014, down 20% from 2012.

Other NIF-affiliated budget lines also appear to take a hit, but it’s hard to calculate exact numbers, says Marylia Kelley, executive director of Tri-Valley CAREs, a watchdog group in Livermore that has been critical of the laser project. But NIF “is taking a smaller hit that I had anticipated; these are very modest cuts considering NIF’s abject failure to achieve ignition,” she says. Her group wants NIF to be managed by DOE’s Office of Science for civilian research. “We should run it as an unclassified user facility for 5 years, and then do an analysis of what kind of science the nation is getting for its money, and then decide whether to pull the plug,” she says.

At CDC, Budget Drops and Priorities Shift

Jennifer Couzin-Frankel, 3:25 p.m. on 11 April

For the Centers for Disease Control and Prevention (CDC), the 2014 budget request offers a mixed picture. CDC’s budget continues to trend downward, as it has over the last several years. President Barack Obama is requesting $6.6 billion for CDC, a drop of $270 million from 2012. But not every program will suffer: In particular, the administration touted extra money for emerging and zoonotic infectious disease initiatives, with a respectable increase of $70 million to $432 million. Forty million dollars would go to an “Advanced Molecular Detection Initiative,” which aims to do a better and quicker job of detecting and responding to threatening pathogens.

An increase of $35 million for injury prevention and control includes money for gun violence prevention research, which was touted by Obama in January.

None of these dollars are new, however. “If you’re putting additional money into one category, you’re taking it from the other,” says Richard Hamburg, deputy director of the Trust for America’s Health, an advocacy group in Washington, D.C., that focuses on public health. Losers in CDC’s budget include chronic disease prevention efforts and public health preparedness and response. The preparedness cuts would reduce funding to local and state health departments.

In a sense, the mix of increases and cuts suggests tension in how best to allocate resources when it comes to new infectious diseases, such as a novel coronavirus or worrying avian influenza cases in China. On the one hand, says Laura Kahn, an internist at Princeton University who works in public health, we need to quickly be able to identify new viruses and develop vaccines against them. She welcomes CDC’s proposed additional funding for emerging infectious diseases, although wonders how exactly the funds will be allocated.

“Now on the other hand, of course,” Kahn writes to Science in an e-mail, “is how to disseminate a new vaccine to a public without a well-funded public health infrastructure. That’s the downside to the budget cuts.”

NSF Basks in Double-Digit Increase

Jeffrey Mervis, 11:15 a.m. on 11 April

With enough money, many things are possible.

That’s the happy position in which the National Science Foundation (NSF) finds itself after the president proposed giving the agency an increase of $741 million in 2014, to $7.62 billion. That amount is 10.8% more than NSF’s current budget of $6.88 billion, although the administration describes it as an 8.4% boost over NSF’s 2012 budget. No matter how it’s painted, the request sets NSF apart from most federal agencies that are being asked to make do with level or reduced funding.

The double-digit increase, if endorsed by Congress, would allow NSF to expand activities across the foundation. The request would provide a 9.2% boost over 2012 levels for NSF’s core disciplinary research activities, to $6.21 billion. That includes a doubling of its investment in cyberinfrastructure, to $155 million, reflecting NSF’s lead role in a joint program on Big Data with the National Institutes of Health.

The 2014 request would also increase funding for several initiatives begun by Subra Suresh, who stepped down last month as NSF director to become president of Carnegie Mellon University. In particular, the Innovation Corps program to train would-be entrepreneurs would grow in size and geographic scope, and the INSPIRE program would be able to fund more unorthodox approaches to multidisciplinary research questions. A bigger budget would also let NSF start construction of the Large Synoptic Survey Telescope, a $665 million facility in Cerro Pachon, Chile, to which the Department of Energy has committed $160 million. And it would allow NSF to grow its prestigious graduate research fellowship program by one-third, boosting the next class to 2700.

In addition to having friends in the White House, NSF received strong support this year from Capitol Hill to lessen the blow of the mandatory, across-the-board 5% sequester that took effect in March at every civilian agency. (National security funding was cut by 7.2%.) Last-minute increases from a Senate funding panel left NSF’s 2013 budget only 2.1%, or $150 million, below its 2012 funding levels.

NSF’s operating plan for 2013, which spells out how much money each activity will receive, isn’t due to the White House until 22 April. So NSF officials aren’t able to predict how the sequester would affect the number of grants to be awarded in 2013 and the overall success rate of proposals. But, given the additional funding it has received, the agency’s original projection of 1000 fewer grants and a 3% dip in success rates is almost certainly too pessimistic.

NIST Manufactures Some Big Spending Dreams

David Malakoff, 6:20 p.m. on 10 April

The Department of Commerce’s National Institute of Standards and Technology (NIST) was one of the big research winners in today’s 2014 budget request rollout, with the White House requesting a 23%, $177.5 million increase over its 2012 spending, to $928.3 million.

Within that total, NIST’s intramural laboratories would get a 21% hike to $754 million.

The increases are in line with a 2010 law that endorsed a doubling of NIST’s budget over a decade, but Congress hasn’t always come up with the money to stay on track with that goal.

“The FY 2014 budget increases will allow NIST to address high-priority scientific and technical issues that are critical to U.S. economic competitiveness and innovative capacity,” said NIST Director Patrick Gallagher in a statement. In all, he said, the proposal includes some $127 million in new research funding.

The administration is also proposing that NIST help coordinate a one-time $1 billion initiative to create a network of up to 15 manufacturing innovation institutes around the country. The National Network of Manufacturing Innovation would join companies, academic institutions, and government agencies in efforts to develop cutting-edge manufacturing technologies. The Obama administration has already set up one pilot center in an effort to demonstrate the value of the idea .

Smithsonian Outreach Gets a Boost

Elizabeth Pennisi, 6:15 p.m. on 10 April

President Barak Obama wants to tap the Smithsonian Institution’s expertise in informal science education as part of his plan to streamline STEM (science, technology, engineering, and mathematics) education. As part of his 2014 budget request, Obama is proposing a $25 million boost to the institution’s education efforts. “From Day 1, I knew that we could play a much bigger role in science education,” says Wayne Clough, secretary of the Smithsonian. “We have attributes and resources that other agencies don’t have.”

The Smithsonian, which is home to 19 museums, a zoo, and six science research centers, would receive $869 million from the federal government under the 2014 request, a $93 million, 12% increase over $776 million in 2013.

For 2013, the continuing resolution that Congress approved in March added $5 million dollars to staff the African American museum that is under construction and $2 million for roof repairs from Hurricane Sandy to its 2012 allocation of $810 million. But as part of the sequester, the Smithsonian had to come up with $41 million in cuts to that amount.

Those belt-tightening measures included taking all new major science instrumentation projects off the table. But the proposed 2014 budget includes $500,000 to begin to modify a 12-meter radio antenna telescope and move it from Arizona to Greenland. The telescope, which is expected to be operational in 2017, will be used in conjunction with Smithsonian telescopes in Chile and Hawaii to study black holes.

Otherwise, any increases for science programs are primarily for covering salary, rent, and other expenses, such as providing parity in salaries for Panamanians working at the Smithsonian Tropical Research Institute in Panama, says Smithsonian senior budget analyst George Thomas.

Thus, the big win for Smithsonian science is for STEM education. President Obama’s plan would shift $180 million from 90 STEM programs at 11 agencies to the U.S. Department of Education, the National Science Foundation, and the Smithsonian. The first two agencies would work to improve K-12 and undergraduate and graduate education. With its $25 million, the Smithsonian would improve informal education as it relates to the classroom. “The boundary between informal and formal education is breaking down,” Clough says.

The newly named Center for Learning and Digital Access will be expanding its efforts to provide teachers easy access to Smithsonian materials that are geared toward meeting education standards requirements. Already it has a database of 2000 documents, photos, podcasts, videos, and other material, says Michelle Smith, editorial director of the center.

Eventually that database will be expanded to include material from all over the federal government. “We would serve as the agent for other agencies,” Clough says. When Clough first came to the Smithsonian in 2008, the Smithsonian was just starting to reach out to students and teachers online and there was not much coordination among its 250 educators. Now the education effort is much more coordinated, Clough says, and he expects that a similar transformation can happen across the federal government. “We can deliver education to anybody in any place at any time,” he says.

Rock On! Asteroid Spending Hot Item for NASA

Yudhijit Bhattacharjee, 5:50 p.m. on 10 April

Asteroids are hot in the president’s 2014 budget for NASA. He wants the space agency to find them, move them, excavate them, and eventually dispatch astronauts to walk on them.

If NASA’s budget proposal for the next fiscal year contains one shiny new initiative, it is the science fiction-y plan to capture an approximately 454-tonne asteroid with a giant bag and drag it close to the moon where it can be studied in detail. After it has accomplished that feat, the agency will send astronauts to visit the rock, traveling in an Orion space capsule that is now under development. If the plan succeeds by an anticipated date of 2021, President Barack Obama may be able to tweet out a humble brag that might read thus: #Woohoo! Realized promise made at #KennedySpaceCenter.

The promise—made in a speech in April 2010, in which Obama laid out his vision for space—was to land humans on an asteroid by 2025. For 2 years, lawmakers questioned NASA officials on the specifics of how it would be done. Lawmakers have slammed the agency for not having a clear sense of direction. Finally, the agency seems to have come up with an answer that kills both birds with one stone.

“This mission raises the bar for human exploration and discovery,” NASA Administrator Charles Bolden said this afternoon in a media telecon about the budget. The idea, which will be kicked off in 2014 with a total funding of $105 million divided between NASA’s exploration, aeronautics, and science directorates, appears to have gained traction after the crash-landing of a meteorite over Russia in February. That event set off frenzied calls from lawmakers that asteroid detection and deflection should be a high priority for NASA.

The first step in the proposed capture and maneuver mission would be to find the right-sized asteroid. That’s why the administration wants to double the current level of funding for asteroid detection to $40 million. This piece of the new initiative will likely please lawmakers who have already conducted hearings on what NASA and private companies should be doing to tackle the asteroid threat.

The second step of the mission would involve developing new technologies to achieve the task, which dovetails with NASA’s stated goal of inspiring technological breakthroughs. And the final step would involve sending astronauts to the asteroid aboard the Orion space capsule, the development of which is another high priority. In other words, the mission helps tie together several disparate items on NASA’s agenda.

The agency has a number of other programs that have to do with asteroids. One is a mission to return a sample from a known carbonaceous asteroid by 2023. That mission, called OSIRIS-REx, is planned for a 2016 launch.

More Love for USDA’s Competitive Research

Erik Stokstad, 5:30 p.m. on 10 April

It’s no secret that the White House likes competitively awarded, peer-reviewed funding for research. For 2013, the administration asked for a 23% boost to the Agriculture and Food Research Initiative (AFRI) while keeping its requests for other research funding levels at the U.S. Department of Agriculture (USDA) relatively flat. But Congress didn’t deliver, instead keeping AFRI’s budget nearly constant at $266 million.

This year, the White House has doubled down and asked for a 44% boost to AFRI over 2013 levels, to $383 million.

“Great news!” extolled Karl Glasener, who directs science policy for the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America. Whether Congress will go along remains to be seen.

AFRI is part of the National Institute of Food and Agriculture, USDA’s extramural funding division. Existing programs at AFRI focus on food security, water and nutrient management, nutrition, food safety, biofuels, and climate change. They plan to add programs on agricultural education and outreach. While AFRI would see a big boost relative to its estimated FY 2013 budget, so-called formula funds, which are given to land-grant universities, would decline by 1% to $657 million.

As with previous years, the administration is asking for a small increase to R&D at the intramural Agricultural Research Service. As part of its request for a 1.6% increase over 2013 to $1.08 billion, USDA would boost efforts on food safety, human nutrition, and environmental stewardship while decreasing funding for agronomic research. In addition, USDA is asking for $155 million to fully renovate its Southeast Poultry Research Laboratory in Athens, Georgia. The aging facility has a biosafety level 2 lab and three agricultural labs and was identified as the top priority for modernization in a 2012 review of ARS labs.

*Correction, 11:30 a.m. on 11 April: The administration is asking for a small increase to R&D at the intramural Agricultural Research Service for a 1.6% increase over 2013, not a 15% increase as originally reported.

NIH Gets Slight Relief From Sequester Pain

Jocelyn Kaiser, 5:10 p.m. on 10 April

The president’s fiscal year 2014 budget offers the National Institutes of Health (NIH) only a modest 1.5% increase, to $31.3 billion, over 2012 levels. But that small boost would provide welcome relief from the staggering 5% cut that the agency received this year because of the mandatory across-the-board cuts known as sequestration.

“Everything’s relative,” said NIH Director Francis Collins after a press briefing today. “Considering what we’ve been going through in FY ’13, what’s being proposed here is really gratifying.” (Compared with NIH’s final 2013 budget of $29.3 billion, the increase would be 6.8%.) NIH would fund 10,269 new and competing grants, an increase of 351 compared with 2012.

The $471 million in new funding includes $40 million for the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative, a brain mapping project that the administration rolled out last week. (Other agencies are contributing about $70 million.) NIH also wants to spend $41 million on a “Big Data” initiative to improve ways to use and share large datasets, Collins said. Another $32 million would go toward anew program that would to attempt to bring more diversity to the biomedical workforce by encouraging minorities to pursue biomedical research careers.

Another favored area is Alzheimer’s research, which would receive $80 million in new grants for drug development at the National Institute on Aging—accounting for the entire increase that the institute is slated to receive.

The Cures Acceleration Network, a program aimed at supporting drug development within NIH’s National Center for Advancing Translational Sciences, would receive $50 million, a $40 million increase.

Biomedical research groups cautiously praised the increase for NIH. “We don’t want to sound unappreciative, but this continues the pattern of failing to keep pace with inflation” for a decade at NIH, said Dave Moore of the Association of American Medical Colleges. The budget also assumes that Congress finds a way out of the sequestration cuts mandated for the next 10 years, he adds. “It’s a little bit of good news, but I think it’s still very worrisome as to where this is all headed,” Moore said.

USGS Sees Budget Boost as Vote for Expanding Mission

Erik Stokstad, 5:05 p.m. on 10 April

The U.S. Geological Survey (USGS) patted itself on the back today for a proposed 8% increase in the president’s budget request, compared with its FY 2012-enacted budget. The $98.8 million boost would lift theagency’s budget to about $1.2 billion.

“This is a really significant increase,” said acting Director Suzette Kimball in a teleconference. “It’s largely due to USGS being recognized among the large science agencies as part of the larger R&D effort” and not just a mission agency to the Department of the Interior, in which it exists.

A request of an 8% increase is exceptional for USGS, which last year was slated for an overall 3% increase in the president’s request. Typically, the agency has seen increases on the order of 1% to 2%. The proposed budget would include a $13 million boost for research on hydraulic fracking, to $18.6 million. It would also raise the funding for stream gages, which monitor water levels and collect other data, by $7.2 million. That would buy about 400 new gages to supplement the existing network of some 3130. USGS has said that the budget cuts known as the sequester threaten the operation of about 350 existing gages. Other proposed increases include a 22% increase for climate change science, to $72 million. A3D-elevation mapping program would get started as well. Research into mineral deposits and the Water Resource Research Institutes would be cut, but details were not immediately available.

A Fundamental Shift at the Pentagon

Eliot Marshall, 4:35 p.m. on 10 April

To sustain an edge in military technology, the White House aims to spend more on key military research programs—particularly fundamental basic research—even as it trims the overall Pentagon budget next year.

The plan calls for a total of $526.6 billion in discretionary funding for the U.S. military in 2014, about 0.7% less than in 2012 and 2013. The administration foresees a sharp decline in the account that pays for weapons testing and evaluation, from $72 billion in 2012 to $68 billion next year. At the same time, it gives a boost to the blue-sky innovation agency known as DARPA (Defense Advanced Research Projects Agency); its budget would increase by 1.8%, to $2.9 billion. Funding for basic science and technology accounts would remain steady at around $11.9 billion, with a shift of about $200 million inside this category to emphasize fundamental work—including the kind of research carried out at universities.

This is a good sign, says Matthew Owens, an analyst at the Association of American Universities, the lobby for major research institutions based in Washington, D.C. He believes the administration is sticking with a theme articulated by the previous two secretaries of defense—investing in research not just to acquire advanced technology but also to draw talented people into the field of national security.

EPA Loses Out in R&D Budget

Erik Stokstad, 4:25 p.m. on 10 April

If you don’t have much nice to say, don’t say much. That pretty much sums up the Environmental Protection Agency’s (EPA’s) discussion of research when it rolled out its proposed budget for FY 2014, which includes a cut to the agency’s science program.

The request “reflects the Obama Administration’s commitment to drive strong economic growth by supporting innovative research” on pollution, climate change, and clean energy, the agency said in a statement. The agency’s more detailed “EPA Budget in Brief,” released today, stated that the R&D program “leverages expertise” to meet its challenges.

The agency overall would see a 4% whack from its funding under the 2013 continuing resolution to $8.2 billion, continuing its slide in recent years. The research program, which was funded at $568 million in FY 2012, would drop by 1.9% from that level in 2014. About $16 million would be taken from the popular STAR fellowships as part of an administration proposal to reorganize STEM programs across the government.

Research on drinking water would decline by $2.3 million, endocrine disruptors by $1.2 million, and four other programs by $1 million each. EPA would expand its cooperative research with the U.S. Geological Survey and DOE on the environmental impact of hydraulic fracking, and increase its funding on minimizing chemical hazards by $4.1 million and climate change by $3.2 million. Baseline funding for these programs was not immediately available.

Outside the science division, EPA’s Greenhouse Gas Reporting Program would get a $2.4 million boost. And the Air, Climate, and Energy Research program would see a 7.9% increase to $105 million over FY 2012 levels for research on environmental and health impacts from air pollution, climate change, and biofuels.

Nanotechnology Initiative Would Get Smaller

David Malakoff, 4:05 p.m. on 10 April

A 13-year-old nanotechnology research initiative would take a cut of $159 million, or 8.5%, to $1.7 billion under the president’s budget request to Congress.

The National Nanotechnology Initiative (NNI), launched in 2001, coordinates an array of nanoscale science projects across about 15 federal departments and agencies. In 2013, the Obama administration requested a 4.1% increase for NNI, to $1.77 billion. This year’s budget documents offer no explanation for the turnabout.

Historically, about two-thirds of NNI funding has gone to academic research, with the remainder supporting science at government and industry laboratories.

Climate Change Research Gets a Warm Reception

David Malakoff, 2:35 p.m. on 10 April

Spending on climate change research at 13 federal agencies would rise by a total of 6%, to $2.65 billion, over 2012 levels under the president’s 2014 budget request to Congress.

The biggest winner would be NASA, which would get a $71 million, 5% increase to $1.49 billion. In contrast, the National Science Foundation would see a decrease of $7 million, or 2.1%, to $326 million.

The 13 agencies are part of the U.S. Global Change Research Program (USGCRP), an initiative that cuts across the U.S. government.

More details on the USGCRP request can be found on this White House fact sheet.

Big Bump-Up for Department of Energy Research

Adrian Cho, 2:10 p.m. on 10 April

The details have not yet been released, but the proposed 2014 budget for the Department of Energy (DOE) appears to be a researcher’s dream. DOE’s basic research arm, the Office of Science would get a 5.7% increase from the level enacted for fiscal 2012—the last budget that Congress passed—to $5.15 billion. (Last month, Congress essentially extended the 2012 budget through the rest of fiscal year 2013, which ends on 30 September.)

Even more impressive, the Advanced Research Projects Agency-Energy (ARPA-E) would see its budget climb 38% from the 2012 level to $379 million. ARPA-E aims to cherry-pick the most promising ideas from energy-related basic research and quickly develop them into commercially viable technologies.

Within the Office of Science, the biggest winner by far is the fusion energy science program, which would see its budget soar 14% to $458 million. Such a boost is desperately needed, researchers say, as the U.S. contributions to the international fusion experiment ITER, under construction in Cadarache, France, threaten to consume much of the United States’ domestic fusion research.

Otherwise, the trend toward research that is more applicable to clean energy continues. Funding would increase by 10.3% from the 2012 level to $1.862 billion for the basic energy science program—which funds materials science, condensed matter physics, chemistry, and related fields and runs many of DOE’s x-ray sources and other “user facilities.” Advanced scientific computing research would jump 5.7% to $466 million. Biological and environmental research would edge up 2.6% to $625 million. And nuclear physics would climb 4.2%, to $570 million.

In contrast, DOE’s high-energy physics program, which funds work in elementary particle physics, would see its budget fall 1.7% from the 2012 level to $777 million.

All of this ignores the effects of the automatic budget cuts known as sequestration, which are required by the Budget Control Act of 2011. Unless it is reversed, sequestration would knock DOE budget levels for 2014 down 7.2%, leaving the Office of Science a net loser instead of a winner.

Homeland Security Would Move Ahead With Controversial Agrosecurity Laboratory

David Malakoff, 1:45 p.m. on 10 April

The Department of Homeland Security’s (DHS’s) science and technology directorate would see its current budget roughly double, to $1.4 billion, if the president’s request is enacted. Essentially all of the increase, $714 million, would go to building the National Bio and Agro-Defense Facility (NBAF), a controversial high-security laboratory slated for Manhattan, Kansas, that would study diseases that threaten humans and livestock. NBAF is supposed to replace the Plum Island Animal Disease Center in New York, which the budget request says “will soon reach the end of its useful life.”

Last year, the White House surprised many by omitting funding for NBAF in its 2013 request. Officials said that they needed to take a fresh look at the project in light of safety and budget concerns, as well as opposition from some well-placed members of Congress. Several generally positive outside reviews conducted by the U.S. National Academies, however, appear to have helped persuade the White House to fully back the effort.

There is certain to be congressional opposition to building NBAF. Representatives Tim Bishop (D-NY) and Joe Courtney (D-CT) have vowed to block NBAF funding, saying the money would be better spent upgrading Plum Island in New York. Senator Jon Tester (D-MT) has also expressed concern about NBAF, reflecting fears among the livestock industry that disease could escape from the facility and threaten U.S. livestock herds.

The new budget requests $467 million for the directorate’s primary research account, extending the program’s recent rebound. In 2012, Congress slashed that account by 52%, to $265 million, as a result of an unrelated battle over disaster assistance spending and concerns about the program’s effectiveness. If Congress approves the 2014 request, the account would return to 2011 levels. But that number would be more than $130 million below where spending stood in 2010.

NASA Budget Includes Money to Send New Rover to Mars, Capture Asteroid

Yudhijit Bhattacharjee, 12:55 p.m. on 10 April

The administration wants to hold NASA’s overall budget line for 2014 at nearly the same level as what the agency is getting this year. But it wants to make some key changes in how some of that $17.7 billion would be spent.

It wants the agency to launch a robotic mission to capture a small asteroid in space and drag it close to the moon. “Astronauts would later visit the asteroid and return samples to Earth,” according to NASA budget highlights posted on the White House’s Web site this morning. The budget provides $78 million to develop technologies for the mission.

The budget also provides money for “multiple missions focused on Mars exploration, including a new large rover to be launched in 2020.” NASA has been considering various ideas for exploring Mars after last year’s pullout from the European-led ExoMars program, and sending another rover to the Red Planet seems to be what the administration has settled on.

Another key change that the administration wants to make is to shrink the agency’s budget for education and outreach by $47.5 million, which would be redirected to other agencies. “NASA’s assets will be used more effectively through coordination with the National Science Foundation, the Department of Education and the Smithsonian Institution to achieve the Administration’s wider STEM [science, technology, engineering, and mathematics] education goals,” according to the White House’s summary of highlights.

Most Civilian Agencies Get a Boost

Jeffrey Mervis, 12:40 p.m. on 10 April

President Obama today proposed a significant increase in federal spending on civilian research for 2014. His support for science comes as part of an otherwise flat budget that aims to shrink the federal deficit through clamping down on entitlement programs and raising money by altering the tax code.

The president has requested a total of $143 billion in 2014 for research and development. That’s level with current spending and up 1% from 2012. But within that total, civilian research spending would jump by 9% over 2012.

The increases for research, if approved by Congress, would allow most research agencies to recover from the cuts to their current budgets under the across-the-board sequester that went into effect last month. But that’s a huge if. And there are also some caveats in what the president has proposed.

As in past years, the National Science Foundation (NSF), the Department of Energy’s Office of Science, and the National Institute of Standards and Technology would receive hefty boosts in line with a 2010 law that endorses a doubling of their budgets over a decade. NSF’s budget would jump by 8.4%, for example, to $7.6 billion, and the Office of Science would rise by 5.7%, to $5.1 billion. In contrast, the budget for the National Institutes of Health would inch up by 1.6%, to $31.3 billion.

All of those numbers are based on a comparison with 2012 spending levels. That’s because Congress didn’t complete work on the 2013 spending bill until 21 March, too late to be included in the president’s request. The proposed increases would be considerably larger if compared with 2013, because sequestration sliced 5% off every civilian agency’s budget.

The president’s budget also fails to take into account how much agencies would lose in 2014 under sequestration, the 2011 budget law that requires across-the-board cuts to lower the federal deficit over the next decade. For 2014, civilian agencies would suffer a cut of 7.9%. But the White House maintains that sequestration is bad policy and has urged Congress to repeal the law. Hence, it is not a factor in the president’s request.

As the day goes on, we’ll bring you more details on the president’s science budget.

http://news.sciencemag.org/scienceinsider/2013/04/obamas-2014-science-budget.html

#FY2014: Scientific Community Responds to President’s Spending Plan

http://news.sciencemag.org/scienceinsider/budget_2014/react.html

As White House Embraces BRAIN Initiative, Questions Linger

by Emily Underwood on 3 April 2013, 5:00 PM 

si-brain_whitehouse.jpg

A lot of nerves. President Barack Obama is introduced by Francis Collins, director of the National Institutes of Health, at the BRAIN Initiative event in the East Room of the White House on 2 April.
Credit: Official White House Photo by Chuck Kennedy

For neuroscientist Rafael Yuste, sitting in an ornate White House chamber yesterday listening to President Barack Obama heap praise—and some $100 million—on a brain-mapping initiative that he helped hatch was a “luminous” experience. “It felt like history,” says the researcher, who works at Columbia University.

“There is this enormous mystery waiting to be unlocked,” Obama told the East Room crowd packed with leaders of American neuroscience during a 12-minute paean to brain research (likely the most expansive yet delivered by an American president). By “giving scientists the tools they need to get a dynamic picture of the brain in action,” he said, the new initiative will help scientists find a cure for complex brain processes such as traumatic brain injury and Parkinson’s, and create jobs that “we haven’t even dreamt up yet.”

For all the lofty rhetoric, however, the White House didn’t provide many details about how the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative will accomplish its mission. And the lack of detail is worrying not only BRAIN skeptics—who argue that it targets the wrong goal and could detract from other research efforts—but also even some staunch advocates such as Yuste. The way that the White House has packaged and plans to fund and coordinate the initiative, they say, is creating some unease.

“As the proposal stands, it’s still awfully vague, so it’s hard not to have some reservations,” says biophysicist Jeremy Berg of the University of Pittsburgh in Pennsylvania, who is a former director of the National Institute of General Medical Sciences at the National Institutes of Health (NIH).

Several years ago, Yuste and other scientists originally pitched BRAIN to U.S. government officials as the Brain Activity Map, a 10-year, $3 billion effort to develop tools in nanotechnology, optogenetics, and synthetic biology that could measure “every spike from every neuron” in a neural circuit. In a 2012 paper in Neuron, based on meetings organized by the Oxnard, California-based Kavli Foundation, Yuste and colleagues laid out a plan to progress gradually from mapping the brain activity of simple model organisms such as the fruit fly to charting the brains of creatures that contain roughly 1 million neurons, such as the Etruscan shrew. Human applications were couched as the ultimate aim, but not an immediate goal.

Since the idea was adopted by the White House, however, it has evolved substantially. The plan that Obama unveiled yesterday calls for BRAIN to be funded by three federal agencies as well as private foundations. Officials say the president’s fiscal year 2014 budget request, to be released on 10 April, will request approximately:

  • $40 million for NIH’s Blueprint for Neuroscience Research, a project which spans 15 institutes and centers
  • $50 million for the Defense Advanced Research Projects Agency, for research that could improve treatment and diagnosis of combat-related conditions such as post-traumatic stress, brain injury, and memory loss
  • $20 million for the National Science Foundation (NSF), to support research into the development of nanoscale probes that can record the activity of neural networks; information processing technology that can handle the flood of data generated by BRAIN research; and better understanding of the neural representation of thoughts, emotions, actions, and memories

Four private groups—the Allen Institute for Brain Science, the Howard Hughes Medical Institute, the Kavli Foundation, and the Salk Institute for Biological Studies—say they will support the project by funding BRAIN related research at their institutions. (See this infographic for more details.)

The initiative will be steered by an NIH-backed working group of 15 neuroscientists, co-chaired by Cornelia Bargmann of Rockefeller University in New York City and William Newsome of Stanford University in Palo Alto, California.

Although that group will not release a detailed research spending plan until later this year, BRAIN is expected to put a greater emphasis on human applications than its original planners envisioned, says neuroscientist John Donoghue of Brown University, one of two researchers from the Kavli-led effort that has been named to the BRAIN steering committee (neuroscientist Terrence Sejnowski of the Salk Institute is the other).Human applications and animal research are now being thought of as “a parallel rather than a serial effort,” he says. And NIH Director Francis Collins confirms that human applications will be of great interest: “We don’t want to waste any time moving to science that has direct human applications,” he said during a press teleconference yesterday.

That shift has created some worries. Yuste, for example, says that keeping human benefits in mind is important, but he wonders whether the project’s original sharp focus on tool development may be diluted if the NIH advisory panel is dominated by traditional neuroscientists, rather than a more interdisciplinary mix of scientists including nanoscientists, optogeneticists, and synthetic biologists. “Neither Bargmann or Newsome are tool builders, so it’s a worry that they are packing the committee with users, rather than tool builders,” Yuste says, adding that he and some allies are asking NIH to add members to the panel. “We are asking for more technologists.”

Just 2 months ago, Bargmann herself expressed skepticism about the project. “Based on my conversations, there is great concern in the neuroscience community that this sounds like a big central planning project that will take resources away from creative work,” she wrote in a February e-mail to Science. “The project needs to make sense to those who care deeply about neurological disease and neuroscience, and we haven’t seen the leaders in those areas involved yet.” (ScienceInsider has not been able to reach Bargmann for comment since she was named co-chair to the working group.)

Although Pittsburgh’s Berg was skeptical of the 10-year, $3 billion Brain Activity Map proposal, “now that it’s been downsized somewhat and focused on technology development I feel much more comfortable with the project,” he says. Based on his experience at NIH, Berg says that the emphasis on technology development is “a very good thing,” because groups within the agency tend to struggle with developing new technologies” because they are “focused on what problem they’re trying to solve rather than the technology development per se.”

Allowing the system to be flexible and adapt over time is crucial, he says. The fact that Bargmann and Newsome are on the advisory group “adds a lot of comfort for me.” While both are “spectacular contributors” to neuroscience, Berg says, they also have a broad view of how to administer both small and large science projects.

Like any big project, the success of BRAIN will ultimately depend on its leadership, Donoghue agrees: “There are a lot of people involved in this who have built independent careers running labs on their own. … The question is whether they will all pull together in the same direction.”

Still unclear is whether BRAIN’s funding will siphon money from other research efforts and if the $100 million will be followed by further investments in coming years. “My understanding is that it’s coming from new money” not previously allocated to neuroscience research, Donoghue says. Yuste’s initial reaction to the figure was that it was “much too low” to accomplish the project’s original goals.

But “that money has to be seen as something that can be built around, from which you can build forward,” says Alan Leshner, CEO of AAAS (publisher of ScienceInsider). “At a time when funding is so tight across the government,” White House support for neuroscience research is a “major opportunity,” says Leshner, a former director of NIH’s National Institute on Drug Abuse and acting director of the National Institute of Mental Health. “If the scientific community doesn’t rise to the moment, shame on us.”

Although there’s no predicting whether Congress will approve the president’s request, “there has historically been and there seems to be today bipartisan interest in this kind of innovative research,” said White House press secretary Jay Carney yesterday during his daily briefing.

One top Republican leader in Congress has already expressed his support. “Mapping the human brain is exactly the type of research we should be funding,” said Representative Eric Cantor (R-VA), the majority leader of the U.S. House of Representatives, in a statement. “It’s great science.”

(Obama, meanwhile, joked during his remarks that “presumably my life would be simpler” if scientists could map the brain. “It could explain all kinds of things that go on in Washington. We could prescribe something.”)

Despite their concerns, many of the researchers who laid the foundation for BRAIN are simply happy to see at least part of their idea being realized. On the evening before the president’s announcement, Yuste and more than a dozen other colleagues involved in the effort met for dinner in downtown Washington, D.C., for what they jokingly described as their “Last Supper.” The feeling of accomplishment was “bittersweet,” Yuste says. They were pleased that the Obama administration has embraced the project, he says, but now “it’s out of our hands.”

http://news.sciencemag.org/scienceinsider/2013/04/as-white-house-embraces-brain-in.html

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MIT Skoltech Initiative: 61 Experts from 20 different Countries identified 120 Universities in the field of Entrepreneurship and Innovation

MIT Skoltech Initiative: 61 Experts from 20 different Countries identified 120 Universities in the field of Entrepreneurship and Innovation

Reporter: Aviva Lev-Ari, PhD, RN

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WordCloud Image Produced by Adam Tubman

The Technion – Israel Institute of Technology was today ranked 6th in the world by a survey conducted by MIT. The study evaluated entrepreneurship and innovation in higher education institutions worldwide. The ranking was compiled by 61 experts from 20 different countries. It identified 120 universities which demonstrate “a decisive impact and significant contribution in the field of entrepreneurship and innovation.”

oraclead

Technion followed MIT, Stanford, Cambridge, Imperial College and Oxford, but preceded the University of San Diego, Berkeley, ETH Swiss and the National University of Singapore. The report also placed  Israel 3rd  in terms of entrepreneurship and innovation, after the US and the UK, but ahead of Sweden, Singapore, Germany, the Netherlands, China and Canada.The survey, which was carried out in partnership with the Skolkovo Institute of Science and Technology in Russia, also placed the Technion first in the category of universities that create or support technological innovation even though they operate in a challenging environment.Instituting an institutional E&I culture – for entrepreneurship and innovation – is considered among experts as the essential ingredient for sustaining a successful system. In this respect, the Technion is mentioned as an institution that possesses the ethos of aspiration and achievement.This is the first stage (out of three) in the comprehensive survey. In his reaction to these most favorable results, Technion President Professor Peretz Lavie said, “Technion’s position among the top ten leading universities in the world in the areas of innovation and entrepreneurship brings us closer to fulfilling our mission goals: to be counted among the top ten leading universities in the world. This is not the first time the Technion has earned international acclaim such as this,” he continued. “The university’s contribution to Israel’s advanced technology industry is recognized around the world. Not by coincidence did we prevail in the New York City’s tender last year to establish a scientific-engineering research center in partnership with Cornell University. The city’s mayor, Michael Bloomberg, said then that the Technion is the only university in the world capable of successfully turning the economic tide of an entire country, from exporters of citrus fruit to a global center for advanced industry and an authority of knowledge. To date, 61 experts from around the world have endorsed this statement.”

VIEW VIDEO – OUTSTANDING  predictions!!

Inventors, Novel Prize Winners & Technology Leaders: IIT

The Technion-Israel Institute of Technology is a major source of the innovation and brainpower that drives the Israeli economy, and a key to Israel’s reputation as the world’s “Start-Up Nation.” Its three Nobel Prize winners exemplify academic excellence.

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Treatment for Infective Endocarditis

Curator: Larry H Bernstein, MD, FACP

UPDATED on 3/4/2019

WATCH VIDEO

https://consultqd.clevelandclinic.org/tricuspid-valve-reconstruction-for-infective-endocarditis-operative-highlights-video/amp/?__twitter_impression=true

Tricuspid Valve Reconstruction for Infective Endocarditis: Operative Highlights (Video)

There are no easy solutions for acute infective tricuspid valve endocarditis in IV drug users, as the risk of prosthetic endocarditis in this population is high. Complete valve resection without replacement is feasible but leads to progressive right-sided heart failure. Reconstruction of the tricuspid valve with autologous pericardium is an alternative option, as demonstrated in the video case study below.

A 29-year-old female drug abuser with fever, hemoptysis and MRSA bacteremia was started on IV antibiotics. She looked frail and had prominent jugular venous pressure as well as 95 percent saturation on 2 liters of nasal cannula oxygen. She was not on inotropes and had a pulmonary artery pressure of 40/20 mmHg with a good cardiac index. Chest CT showed a large left pleural effusion with associated atelectasis of the left lung. The right lung had manifestations of septic emboli and a smaller pleural effusion.

A Cleveland Clinic surgical team led by cardiothoracic surgeon Faisal Bakaeen, MD, proceeded to excise the patient’s extensive infected and devitalized tissue around the tricuspid valve, leaving only a portion of the anterior leaflet to serve as a reference for reconstruction using autologous pericardium. Dr. Bakaeen walks us through the essential surgical steps — and their underlying rationale — in the narrated operative video below.

SOURCE

https://consultqd.clevelandclinic.org/tricuspid-valve-reconstruction-for-infective-endocarditis-operative-highlights-video/amp/?__twitter_impression=true

 

An article that appeared in NEJM compares early surgery versus conventional treatment for infective endocarditis.
Early Surgery versus Conventional Treatment for Infective Endocarditis
Duk-Hyun Kang, Yong-Jin Kim, Sung-Han Kim, Byung Joo Sun, et al.

N Engl J Med June 28, 2012; 366:2466-2473. http://doi.org/10.1056/NEJMoa1112843

Background and Purpose: While current guidelines advocate surgical management for complicated left-sided infective endocarditis and early surgery for patients with infective endocarditis and congestive heart failure, the indications for surgical intervention to prevent systemic embolism remain unclear. Surgery is favored by experience with complete excision of infected tissue and valve repair, and low operative mortality, but it does not remove concerns about residual active infection, which results in two sets of guidelines, the 2006 ACC-AHA for class IIa indication only for recurrent emboli and persistent vegetation, and the 2009 ESC guidelines for class IIb indication for very large, isolated vegetations. The Early Surgery versus Conventional Treatment in Infective Endocarditis (EASE) trial was conducted to determine whether early surgical intervention woulddecrease rate of death or embolic events.

Patient Enrollment: The study enrolled 76 consecutive patients, 18 years of age or older, with left-sided, native-valve infective endocarditis and a high risk of embolism. For all patients with suspected infective endocarditis, blood cultures were obtained and transthoracic echocardiography was performed within 24 hours after hospitalization. Patients were only eligible for enrollment if they had received a diagnosis of definite infective endocarditis and had severe mitral valve or aortic valve disease and vegetation with a diameter greater than 10 mm. Patients were excluded if they had moderate-to-severe congestive heart failure, infective endocarditis complicated by heart block, annular or aortic abscess, destructive penetrating lesions requiring urgent surgery, or fungal endocarditis, or were over 80 years age, or coexisting major embolic stroke with a risk of hemorrhagic transformation at the time of diagnosis, and a serious coexisting condition. Patients were also excluded if they had infective endocarditis involving a prosthetic valve, right-sided vegetations, or small vegetations (diameter, ≤10 mm) or had been referred from another hospital more than 7 days after the diagnosis of infective endocarditis.
The protocol specified that patients who were assigned to the early-surgery group should undergo surgery within 48 hours after randomization. Patients assigned to the conventional-treatment group were treated according to the AHA guidelines, and surgery was performed only if complications requiring urgent surgery developed during medical treatment or if symptoms persisted after the completion of antibiotic therapy. Details of the study procedures are provided in the Supplementary Appendix, available at NEJM.org.

Study End Points: The primary end point was a composite of in-hospital death or clinical embolic events that occurred within 6 weeks after randomization. An embolic event was defined as a systemic embolism fulfilling both prespecified criteria: the acute onset of clinical symptoms or signs of embolism and the occurrence of new lesions, as confirmed by follow-up imaging studies. Prespecified secondary end points, at 6 months of follow-up, included death from any cause, embolic events, recurrence of infective endocarditis, and repeat hospitalization due to the development of congestive heart failure.

Clinical and Echocardiographic Characteristics of the Patients at Baseline, According to Treatment Group:

The mean age of the patients was 47 years, and 67% were men. The mitral valve was involved in 45 patients, the aortic valve in 22, and both valves in 9. Severe mitral regurgitation was observed in 45 patients, severe aortic regurgitation in 23, severe aortic stenosis in 3, severe mitral regurgitation and stenosis in 1, and both severe mitral regurgitation and aortic regurgitation in 4. The median diameter of vegetation was 12 mm (interquartile range, 11 to 17). All patients met the Duke criteria for definite endocarditis; the most common pathogens in both groups were viridans streptococci (in 30% of all patients), other streptococci (in 30%), and Staphylococcus aureus (in 11%). Characteristics of Antibiotic Therapy, According to Treatment Group: There were no significant between-group differences in terms of control of the underlying infection, the antibiotic regimen used, or the duration of antibiotic therapy.

Surgical Procedures: All patients in the early-surgery group underwent valve surgery within 48 hours after randomization; the median time between randomization and surgery was 24 hours (interquartile range, 7 to 45). Of the 22 patients with involvement of the mitral valve, 8 patients underwent mitral-valve repair and 14 underwent mitral-valve replacement with a mechanical valve. Of the 15 patients with involvement of the aortic valve or both the mitral and aortic valves, 14 underwent mechanical-valve replacement and 1 underwent valve replacement with a biologic prosthesis. Concomitant coronary-artery bypass grafting at the time of valve surgery was performed in 2 patients (5%).

Conventional Therapy: Of the 39 patients assigned to the conventional-treatment group, 30 (77%) underwent surgery during the initial hospitalization (27 patients) or during follow-up (3). The surgical procedures included 11 mitral-valve repairs, 6 mitral-valve replacements (with 5 patients receiving a mechanical valve and 1 a biologic prosthesis), 11 aortic-valve replacements (with 9 patients receiving a mechanical valve and 2 a biologic prosthesis), and 2 combined aortic-valve replacements (with 1 patient receiving a mechanical valve and 1 a biologic prosthesis) and mitral-valve repairs. In 8 patients (21%), indications for urgent surgery developed during hospitalization (median time to surgery after randomization, 6.5 days [interquartile range, 6 to 10]). Elective surgery was performed in an additional 22 patients owing to symptoms or left ventricular dysfunction more than 2 weeks after randomization. Surgical results are shown in the Supplementary Appendix.

Primary End Point: The primary end point of in-hospital death or embolic events within the first 6 weeks after randomization occurred in one patient (3%) in the early-surgery group, as compared with nine (23%) in the conventional-treatment group (hazard ratio, 0.10; 95% confidence interval [CI], 0.01 to 0.82; P=0.03). In the early-surgery group, one patient died in the hospital and no patients had embolic events; in the conventional-treatment group, one patient died in the hospital and eight patients had embolic events (Table 3TABLE 3).
http://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nejm/2012/nejm_2012.366.issue-26/nejmoa1112843/production/images/small/nejmoa1112843_t3.gif

At 6 weeks after randomization, the rate of embolism was 0% in the early-surgery group, as compared with 21% in the conventional-treatment group (P=0.005). No patient in either group had an embolic event or was hospitalized for congestive heart failure during follow-up. Recurrence of infective endocarditis within 6 months after discharge was not observed in any patient in the early-surgery group but was reported in 1 patient in the conventional-treatment group. Among the 11 patients (28%) in the conventional-treatment group who were treated medically and discharged without undergoing surgery, 1 (3%) died suddenly, 7 (18%) had symptoms related to severe valve disease or recurrence of infective endocarditis (3 of whom underwent surgery during follow-up), and 3 (8%) had no symptoms or embolic events (Table S3 in the Supplementary Appendix).
There was no significant difference between the early-surgery and conventional-treatment groups in all-cause mortality at 6 months (3% and 5%, respectively; hazard ratio, 0.51; 95% CI, 0.05 to 5.66; P=0.59) (Figure 2AFIGURE 2).
http://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nejm/2012/nejm_2012.366.issue-26/nejmoa1112843/production/images/small/nejmoa1112843_f2.gif
Kaplan–Meier Curves for the Cumulative Probabilities of Death and of the Composite End Point at 6 Months, According to Treatment Group.

At 6 months, the rate of the composite of death from any cause, embolic events, recurrence of infective endocarditis, or repeat hospitalization due to the development of congestive heart failure was 3% in the early-surgery group, as compared with 28% in the conventional-treatment group (hazard ratio, 0.08; 95% CI, 0.01 to 0.65; P=0.02). The estimated actuarial rate of end points was significantly lower in the early-surgery group than in the conventional-treatment group (P=0.009 by the log-rank test) (Figure 2B).

Conclusion: Early surgery performed within 48 hours after diagnosis reduced the composite primary end point of death from any cause or embolic events by effectively reducing the risk of systemic embolism. Moreover, these improvements in clinical outcomes were achieved without an increase in operative mortality or recurrence of infective endocarditis.

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Imaging Guided Cancer-Therapy – a Discipline in Need of Guidance

 Author – Writer: Dror Nir, PhD

The use of imaging in cancer management is broadly established. During the past two decades, advancements in imaging; image quality, precision and reproducibility lead to introduction of localized, minimally invasive treatments of cancer lesions.

 A statement-paper, published online: 17 January 2013: Radiologists’ leading position in image-guided therapy, which presents the thoughts of the Image-Guided Therapy Working Group within the Research Committee of the European Society of Radiology, give hope that the policy-makers in the European radiology society are becoming aware of the need to guide this process.

Although the authors are addressing imaging guided therapy (IGT) in its broad sense, most of their examples are related to treatment of cancer. The main reason for provided for being concerned with what is happening in this domain is: “This means that the planning, performing and monitoring, as well as the control of the therapeutic procedure, are based and dependent on the “virtual reality” provided by imaging investigations.”

The most interesting points raised by the authors are:

 1. The realization that IGT is involving many “non-radiologist”, and this fact cannot be ignored: “This role is mainly driven by the sophisticated opportunities offered by medical computing and radiological image guidance with regard to precision and minimal invasiveness [2]. However, the impact of radiology on the regulatory medico-legal, technical and radioprotection issues in this field have not yet been defined. Since an increasing number of procedures will probably be performed by non-radiologists, several main questions have to be addressed:

  • How should the radiology training requirements for non-radiologists be provided?
  • How should the technical and radioprotection related responsibilities for radiological imaging systems used by non-radiologists be organised?
  • How should radiologists be involved in the practical routine use of non-radiological image-guided procedures in clinical practice?

Considering the almost pan-European medical reality with decreasing staff resources and increasing diversification and subspecialisation, radiologists have to stress the fact that within a cooperative, goal-oriented and multidisciplinary environment, the specialty-specific knowledge should confer upon radiologists a significant impact on the overall responsibility for all imaging-related processes in various non-radiological specialties (such as purchase, servicing, quality management, radiation protection and documentation). Furthermore, radiologists should take responsibility for the definition and compliance with the legal requirements regarding all radiological imaging, especially if non-radiologists have to be trained in the use of imaging technology for guidance of therapy.”

2. Quality assurance and service standards needs to be established; “Performing IGT necessitates specific quality management tools for establishing standards and maintaining levels of excellence…. A European task force group on IGT might be necessary to further develop certification guidelines and establish requirements for IGT practice according to known standards, focused on common recommendations and certification guidelines.”

3. Controlling the process of introducing new medical devices into this niche-market: “IGT research can be broadly divided into two categories, target specific research (e.g. the type of tumour or vascular lesion by imaging biomarkers) and technical research (e.g. evaluation of a new device or procedure). Understanding the efficacy and application of new and emerging technologies is a critical first step, which then leads to target-specific research. The focus of this research is aimed at understanding when, where and in whom the therapy can provide clear clinical benefit and how to use IGT in conjunction with, or as an alternative to, more established therapies. This also clearly includes research on the development and implementation of imaging biomarkers, defined as objectively measured indicators of normal biological processes, pathological changes, or responses to a therapeutic intervention [9]…..

4. An unusual remark is made in respect to the way new devices are introduced: “Clinical specialists who lack the knowledge and expertise required to champion IGT and who are often already over-committed in pursuing their own research goals often dominate committees in control of other funding streams….”

5. Clear recognition that “health-care costs” is of outmost importance: “Demonstration of the cost effectiveness of IGT methods of treatment and targeting with formal quantification of financial as well as patient benefit would encourage their wider adoption. In a broad perspective, health technology assessment (HTA) might be the way for the systematic evaluation of health-relevant IGT procedures and methods, the effectiveness, safety and economic viability of a health intervention, as well as its social, ethical, legal and organisational effects; and for providing a basis for decisions in the health system.”

 References

1.

Solomon SB, Silverman SG (2010) Imaging in interventional oncology. Radiology 257(3):624–40PubMedCrossRef

2.

Levy MA, Rubin DL (2011) Current and future trends in imaging informatics for oncology. Cancer J 17(4):203–10PubMedCrossRef

3.

Council Directive 97/43 Euratom, on health protection of individuals against the dangers of ionizing radiation in relation to medical exposure, and repealing Directive 84/466 Euratom, 1997

4.

DIMOND. Measures for optimising radiological information and dose in digital imaging and interventional radiology. European Commission. Fifth Framework Programme. 1998–2002

5.

SENTINEL. Safety and efficacy for new techniques and imaging using new equipment to support European legislation. European Coordination Action. 2005–2007

6.

http://www.sirweb.org/about-us/IRSocietiesAroundTheWorld.shtml

7.

UNSCEAR (2000) Sources and effects of ionising radiation. United Nations Scientific Committee on the Effects of Atomic Radiation Report to the General Assembly with Scientific Annexes

8.

The 2007 recommendations of the international commission on radiological protection

9.

European Society of Radiology (2010) White paper on imaging biomarkers. Insights Imaging 1(2):42–45CrossRef

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Minimally Invasive Structural CVD Repairs: FDA grants 510(k) Clearance to Philips’ EchoNavigator – X-ray and 3-D Ultrasound Image Fused.

Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 7/15/2018

The growing role of echocardiography in interventional cardiology: The present and the future

Open Access funded by Hellenic Cardiological Society
Under a Creative Commons license

Abstract

As structural heart disease interventions continue to evolve to a sophisticated level, accurate and reliable imaging is required for pre-procedural selection of cases, intra-procedural guidance, post-procedural evaluation, and long-term follow-up of patients.

Traditionally, cardiovascular procedures in the catheterization laboratory are guided by fluoroscopy and angiography. Advances in echocardiography can overcome most limitations of conventional imaging modalities and provide successful completion of each step of any catheter–based treatment. Echocardiography’s unique characteristics rendered it the ideal technique for percutaneous catheter-based procedures.

The purpose of this review is to demonstrate the use of the most common and up-to-date echocardiographic techniques in recent non-coronary percutaneous interventional procedures, underlining its inevitable and growing role, as well as illustrating areas of weakness and limitations, and to provide future perspectives.

SOURCE

https://www.sciencedirect.com/science/article/pii/S1109966617300258

 

On January 28, we reported on several FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology

http://pharmaceuticalintelligence.com/2013/01/28/fda-pending-510k-for-the-latest-cardiovascular-imaging-technology/

On March 7, 2013 a very significant, pending clearance event, in favor of Philips Healthcare, was announced:

U.S. FDA Clears Philips’ EchoNavigator for Fused TEE-Angiography Image Guidance

March 7, 2013

March 7, 2013 — Philips Healthcare announced it has received 510(k) clearance from the U.S. Food and Drug Administration (FDA) for its EchoNavigator live image-guidance tool. The technology helps interventional cardiologists and cardiac surgeons perform minimally invasive structural heart disease repairs by providing an intelligently integrated view of live X-ray and 3-D ultrasound images.

Following the CE marking of EchoNavigator in Europe, Philips will now be able to introduce the system globally, with systems already installed in Europe and the United States.

EchoNavigator was developed in response to an upward trend in the use of both X-ray imaging and 3-D cardiac ultrasound imaging (echocardiography) during structural heart disease procedures — an area of interventional cardiology that is growing at around 40 percent per year. During such procedures, ultrasound imaging provides critical insights into the heart’s soft tissue anatomy, while X-ray imaging has particular strengths in visualizing the catheters and heart implants. EchoNavigator was designed to address the unique challenges associated with working with live X-ray and 3-D ultrasound images simultaneously.

“Together with Philips, we set out to bring two separate medical imaging techniques together in a way that provides clear visual guidance,” said John Carroll, M.D., interventional cardiologist, University of Colorado Hospital, Denver. “EchoNavigator is enabling us to use X-ray images combined with real-time 3-D ultrasound images to navigate catheters and deploy implants in the right position in the heart, making such treatments more straightforward.”

EchoNavigator will enable clinicians to perform procedures more efficiently by providing intelligently integrated X-ray and 3-D ultrasound images into one intuitive and interactive view, as well as providing easy-to-use system navigation and better communication between the multidisciplinary team carrying out the procedure.

“We have learned that ideally two live imaging technologies are needed to guide catheter-based repairs to the heart, and a multidisciplinary team is needed to perform it,” said Roberto Corti, M.D., interventional cardiologist, University Hospital Zurich, Switzerland. “This adds to the complexity of such procedures. The development of a more sophisticated imaging technology such as EchoNavigator will definitely provide us with a better understanding of the complex structures of the heart and their repair.”

“As the global market leader in interventional cardiology, we have worked with our partners to lead the way with pioneering solutions such as our real-time 3-D ultrasound technology and more recently our HeartNavigator navigation tool,” said Gene Saragnese, CEO for Imaging Systems at Philips Healthcare. “EchoNavigator is further evidence of our commitment to transforming healthcare through the introduction of innovations that enable best in class minimally invasive procedures.”

“In the emerging field of complex structural heart disease interventions, the information obtained by merging imaging technologies, as now possible with HeartNavigator and EchoNavigator, will be of tremendous value to the interventionalist, and in turn to the patient,” said Carlos Ruiz, M.D., director of the structural and congenital heart disease program, department of interventional cardiology, Lenox Hill Hospital, New York.

For more information: http://www.healthcare.philips.com

SOURCE:

http://www.dicardiology.com/article/us-fda-clears-philips’-echonavigator-fused-tee-angiography-image-guidance?goback=%2Egde_3693995_member_223204362

 With certainty we ascertain that:

3-D, 4-D Enhancements May Be the Future of Ultrasound

Written By:

Dave Fornell

May 15, 2012
A single-beat, short-axis 4-D echo imaged by GE’s Vivid E9. The system also offers software to reduce the number of clicks needed for exams. Photo courtesy of GE Healthcare

Hardware and software advances are enabling echocardiography to greatly expand its capability with increased quantification accuracy, ease-of-use, increased workflow efficiencies and wider use outside of echo labs. Today, cardiovascular ultrasound systems are being integrated into point-of-care for triage, and in operating rooms and cath labs for procedural guidance to cut the use of contrast and ionizing radiation. Advances in 4-D echo are making it an enhanced tool for structural heart evaluation and visualization during procedures.

3-D, 4-D Echo Advances

3-D echo images a volume of data (similar to a computed tomography [CT] dataset) rather than the traditional 2-D image rendering. These volumes can be manipulated with advanced visualization software just like a CT, slicing images on any plane and enabling the creation of 3-D images that can be rotated.

The proliferation of 3-D echo was previously handicapped by the large amount of labor involved in creating images from a volume dataset, explained Stephen Little, M.D., FRCPC, FACC, FASE, cardiovascular imaging section, department of cardiology, Methodist DeBakey. He said earlier generation systems required 30 or 40 mouse clicks to create an image.

“3-D required a lot of manual processing to slice and dice the images. It just took too long to do anything,” Little explained.

However, he said the newer 3-D systems are making the technology more viable with automation. He said echo is following the same path previously followed by CT advanced visualization software, where automation made a big difference in its wider market adoption for daily use.

Two big technology innovations have recently made 3-D and 4-D systems more commercially viable for everyday use. First, there has been a rapid increase in computing power in less expensive, smaller packages. Second, the automation of many advanced visualization functions drastically simplifies use and reduces the staff time required to manipulate volumes.

The introduction of 4-D echo (the fourth dimension is the addition of time) has opened new possibilities in ultrasound imaging. The analogy of 4-D is the difference between video and a still photograph. The technology allows 3-D images to be continuously updated for a live video view. The platforms with this feature require very fast processors to reconstruct large volumes of data into 3-D images over and over in milliseconds.

4-D ultrasound offers several advantages. It offers real-time color flow to assess hemodynamic information in the same heart cycle. It offers very accurate qualification of the left ventricle, free of geometric and shape assumptions used in 2-D echo. By using a 3-D volume of data, left ventricular wall motion tracking analysis can be done using the raw data volumes acquired. Vendors say this increases the accuracy of quantification.

It also offers multi-dimensional imaging, where operators can simultaneously acquire bi-plane and tri-plane images from the same heartbeat without moving the probe’s position.  This offers two or three different axis views concurrently or as a composite view of the heart in real-time, offering a new field-of-view that previously could not be obtained.  This helps acquire more information in fewer steps.

Real-time 4-D can produce images that are incredibly lifelike. This makes them easier to interpret and offers more meaningful information, including better procedural guidance. As technology continues to advance, 4-D echo will offer images comparable to CT 3-D reconstructions. Surgeons are now using 3-D echo reconstructions to aid procedural planning.

Use of 4-D greatly aids assessment of congenital heart diseases. Siemens recently introduced an updated version of its SC2000 cardiac ultrasound that quantifies volumetric color blood flow when evaluating holes in the heart (ASDs, VSDs, PFOs). The system uses a 3-D representation to show the true surface area and helps estimate the size of the holes for procedural planning.

Innovations in 4-D make possible real-time, comprehensive analysis of the beating heart during the entire cardiac cycle and allows even more detailed surgical-like views of the anatomy.

Toshiba’s new Aplio 500 shows the future of 4-D, where it can reconstruct volumes into color, fly-through video of vessel lumens. It works with peripheral vessels, but the heart is still too fast for the new technology to capture coronary vessels or ventricles. Image quality is similar to CT virtual colonoscopy.

Practical Application of 3-D

Methodist DeBakey Heart and Vascular Center has its own imaging center, which uses 3-D echo extensively. The center also images patients with both magnetic resonance imaging (MRI) and 3-D echo for comparative effectiveness research.

In the echo lab, 3-D echo is very good at estimating left ventricular ejection fractions (LVEF). However, there is a need for standardization between vendors before this technology will be used mainstream, Little said. Each 3-D echo machine is slightly different, so the workflow is not the same from vendor to vendor, and each requires use of proprietary workstations.

He explained 3-D offers a more accurate picture of cardiac function, but the basic concepts of 2-D echo still apply.

“3-D is not magic. It starts with a good 2-D image and you face all the same physics challenges as you do with 2-D technology,” Little said.

At DeBakey, echo contrast is often used to improve 2-D image quality when imaging obese patients, but they found 3-D has some limitations with contrast, said Miguel A. Quiñones, M.D., MACC, chairman, department of cardiology.  The software uses automated 3-D tracking of the borders of the ventricle, he explained, but the automated tracking system is confused by the contrast and has issues. However, an operator can overcome this by switching to a manual mode.

Little said hospitals need to assess whether there is a need for 3-D. “It depends on what they plan to do with the system. If you plan to use it for surgical procedures, then it might be worth investing in a 3-D system. If you are involved in activities with more emphasis on structural heart, then 3-D has a lot of application.”

Expanding TEE Use

Little said DeBakey makes extensive use of 3-D echo transesophogeal echo (TEE) to better guide mitral valve prolapse and regurgitation repairs, atrial septal defects (ASDs) and trans-aortic valve repair (TAVR). In TAVR, he said  TEE helps accurately place the angiographic pigtail catheter in the non-coronary cusp of the aortic root.  It also offers Doppler flow imaging to evaluate the hemodynamics of the valves and check for paravalvular leaks.

Little explained 3-D TEE offers a definite imaging advantage during complex interventions. The use of an X-plane (also referred to as bi-plane) TEE probe allows visualization from two different angles. He said these views are displayed on the main screen in a cath lab or hybrid OR to better visualize where a catheter or device is located in the anatomy more clearly than 2-D angiography. This helps with procedural navigation and in cutting the radiation dose from fluoroscopy.

“You can get two views simultaneously from two different perspectives, which helps speed things up,” Little said. “It adds a level of confidence to show you where wires and devices are inside the heart.”

DeBakey uses 3-D echo from various vendors, including Philips, GE and Siemens, but only the Philips system had offered 3-D TEE, Little said.

Siemens recently introduced syngo FourSight 3-D TEE. It can scan the whole heart in one volume instead of stitching two or three images to create a whole-heart image.

GE Healthcare also has a new 4-D  TEE system pending FDA review, which it previewed as a work-in-progress in March at American College of Cardiology (ACC) 2012 .

Comparison Chart

This article served as an introduction to the cardiovascular ultrasound systems comparison chart in the May-June 2012 issue of DAIC. Participants included:

Esaote North America –http://www.esaoteusa.com

GE Healthcare – http://www.gehealthcare.com

Mindray – http://www.mindray.com

Philips – http://www.philips.com

Siemens – http://www.medical.siemens.com

Toshiba – http://www.medical.toshiba.com

SOURCE:

http://www.dicardiology.com/article/3-d-4-d-enhancements-may-be-future-ultrasound

New Software to aid Interventional Cardiologists and Cardiac Surgeons in TAVI Procedures.

We covered the procedure and the technologies in the following curated article:

Clinical Trials on transcatheter aortic valve replacement (TAVR) to be conducted by American College of Cardiology and the Society of Thoracic Surgeons

http://pharmaceuticalintelligence.com/2013/02/12/american-college-of-cardiologys-and-the-society-of-thoracic-surgeons-entrance-into-clinical-trials-is-noteworthy-read-more-two-medical-societies-jump-into-clinical-trial-effort-for-tavr-tech-f/

TAVI Planning Software Introduced

Software enables selection of patients and access routes; aids procedure navigation, annulus sizing
Written By:

Dave Fornell

February 1, 2012
Philips received FDA clearance in December 2011 for its Heart Navigator TAVI planning and image guidance tool.
With the approval of the Sapien valve in November 2011, transcatheter aortic valve implantation (TAVI) technology is expected to revolutionize heart valve replacement with a minimally invasive procedure to replace open-heart surgery. However, it requires a good deal of planning, sizing and anatomical assessment of access routes using computed tomography (CT) scans with manipulation by advanced visualization software.
The success of this new procedure depends on correct patient selection and reliable pre-operative planning. In the conventional procedure, the necessary measurements are made during the actual surgery under direct visualization, but with TAVI, this can only be done pre-operatively with the aid of image data. A clear appreciation of the involved anatomy is crucial, and due to the fact that aortic anatomy is complex, 3-D visualization and measurement tools may enable more accurate and efficient pre- and post-intervention planning, which can be further enhanced with stereoscopic 3-D.At the 2011 Radiological Society of North America (RSNA) annual meeting, TeraRecon and Qi Imaging (formerly Ziosoft) both unveiled  TAVI planning and tool set software packages. The software helps automate manipulation of a CT dataset to quickly extract only the anatomy of interest and measurements, such as sizing of the aortic valve annulus and evaluation of clearance between the new valve and the right and left main coronary arteries. The software helps evaluate the aortic anatomy of patients to see if the route is clear for the larger delivery catheters required for the procedure. A heavily calcified aorta may disqualify a patient from the femoral access route.
Qi Imaging applied its super-computing, deformable registration software to its TAVI package, allowing lifelike motion of the cardiac cycle. This may offer a more accurate assessment of the motion of annulus for better valve sizing.
Philips Healthcare received FDA clearance in December for its HeartNavigator procedure planning and image guidance tool to help perform minimally invasive heart valve replacements. The technology merges pre-operatively acquired 3-D CT scans of the patient’s heart with the live interventional X-ray views. Using this technology, physicians can now simultaneously see the detailed 3-D anatomy of the patient’s heart together with the positioning of the catheter and the placement and deployment of the artificial valve.
TAVI has been available in Europe since March 2010. In August 2010, Siemens introduced its syngo Aortic ValveGuide in Europe to aid in TAVI procedures. It uses rotational angiography dataset images in the hybrid OR to help surgeons and interventional cardiologists navigate during transcatheter valve implantations. The software processes CT-like images of the heart from images acquired with the angiography system and creates 3-D overlay images on the live fluoroscopy. The software also finds the correct optimal C-arm angulation with a perpendicular view on the aortic root.
  • Siemens’ syngo Aortic ValveGuide aids TAVI navigation with rotational angiography image overlays.

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Accurate Identification and Treatment of Emergent Cardiac Events

Accurate Identification and Treatment of Emergent Cardiac Events

Author: Larry H Bernstein, MD, FCAP
In the immediately preceding article, I discussed the difficulties in predicting long-term safety for developing drugs, and the cost of failure in early identification.

It is not the same scale of issue as for the patient emergently presenting to the ED. Despite enormous efforts to reduce the development of and the complications of acute ischemia related cardiac events, the accurate diagnosis of the patient presenting to the emergency room is still, as always, reliant on clinical history, physical examination, effective use of the laboratory, and increasingly helpful imaging technology. The main issue that we have a consensus agreement that PLAQUE RUPTURE is not the only basis for a cardiac ischemic event. The introduction of  high sensitivity troponin tests has made it no less difficult after throwing out the receiver-operator characteristic curve (ROC) and assuming that any amount of cardiac troponin released from the heart is pathognomonic of an acute ischemic event.  This has resulted in a consensus agreement that

  • ctn measurement at a coefficient of variant (CV) measurement in excess of 2 Std dev of the upper limit of normal is a “red flag”
  • signaling AMI? or other cardiomyopathic disorder

This is the catch.  The ROC curve established AMI in ctn(s) that were accurate for NSTEMI – (and probably not needed with STEMI or new Q-wave, not previously seen) –

  1. ST-depression
  2. T-wave inversion
    • in the presence of other findings
    • suspicious for AMI

Wouldn’t it be nice if it was like seeing a robin on your lawn after a harsh winter?  Life isn’t like that.  When acute illness hits the patient may well present with ambiguous findings.   We are accustomed to relying on

  1. clinical history
  2. family history
  3. co-morbidities, eg., diabetes, obesity, limited activity?, diet?
    1. stroke and/or peripheral vascular disease
    2. hypertension and/or renal vascular disease
    3. aortic atherosclerosis or valvular heart disease
      • these are evidence, and they make up syndromic classes
  4. Electrocardiogram – 12 lead EKG (as above)
  5. Laboratory tests
    1. isoenzyme MB of creatine kinase (CK)… which declines after 12-18 hours
    2. isoenzyme-1 of LD if the time of appearance is > day-1 after initial symptoms (no longer used)
    3. cardiac troponin cTnI or cTnT
      • genome testing
      • advanced analysis of EKG

This may result in more consults for cardiologists, but it lays the ground for better evaluation of the patient, in the long run.  When you look at the amount of information that has to be presented to the physician, there is serious need for improvement in the electronic medical record to benefit the patient and the caregivers.  Recently, we have a publication on a new test that has been evaluated, closely related to the C-reactive protein (CRP), a test that has generated much discussion over the effect of treatment for patients who have elevated CRP in the absence of increased LDL cholesterol, diabetes, or obvious atherosclerotic comorbidities.  The serum pentraxin 3 test is related to cell mediated immunity, and an evaluation has been published in the Journal of Investigative Medicine.

Journal of Investigative Medicine Feb 2013; 61 (2): 278–285.
http://dx.doi.org/10.231/JIM.0b013e31827c2971

Serum Pentraxin 3 Levels Are Associated With the Complexity and Severity of Coronary Artery Disease in Patients With Stable Angina Pectoris
Karakas, Mehmet Fatih MD*; Buyukkaya, Eyup MD*; Kurt, Mustafa MD*; et al.
From the Departments of Cardiology and,Clinical Biochemistry, Mustafa Kemal University, Tayfur Ata Sokmen Medical School, Hatay, Turkey.
Reprints: Mehmet Fatih Karakas, MD, Antakya 31005, Turkey. E-mail: mfkarakas@hotmail.com.

Abstract
Background: Atherosclerosis is a complex inflammatory process. Although pentraxin 3 (PTX-3), a newly identified inflammatory marker, was associated with adverse outcomes in stable angina pectoris,

  • an association between PTX-3 and the complexity of coronary artery disease (CAD) has not been reported.

The aim of the present study is to assess

  • the association between the level of PTX-3 and
  • the complexity and severity of CAD assessed with
  • SYNTAX and Gensini scores in patients with stable angina pectoris.

Methods: The study population is 2 groups:

  • 161 patients with anginal symptoms and evidence of ischemia
    • who underwent coronary angiography and
  • 50 age- and sex- matched control subjects without evidence of ischemia .

Patients were grouped into 3 groups according to the complexity and severity of coronary lesions

  • assessed by the SYNTAX score (30 patients with a SYNTAX score of 0 were excluded).

Serum PTX-3 and high-sensitivity C-reactive protein (hs-CRP) levels were measured in both groups.

Results: The PTX-3 levels demonstrated

  • an increase from low to high SYNTAX groups (r = 0.72, P < 0.001).

Whereas the low SYNTAX group had statistically significantly higher PTX-3 levels when compared with the control group (0.50 ± 0.01 vs 0.24 ± 0.01 ng/mL, P < 0.001),

  • the hs-CRP levels were not different (0.81 ± 0.42 vs 0.86 ± 0.53 mg/dL, P = 0.96).
  • but  the intermediate SYNTAX group had higher hs-CRP levels compared with the low SYNTAX group (1.3 ± 0.66 vs 0.86 ± 0.53 mg/dL, P = 0.002).

Serum PTX-3 levels and hs-CRP levels were both correlated with the SYNTAX scores and Gensini scores (for SYNTAX: r = 0.87 [P < 0.001] and r = 0.36 [P = 0.01]; for Gensini: r = 0.75 [P < 0.001] and r = 0.27 [P = 0.002], respectively), and

  • according to the results of univariate and multivariate analyses, for “intermediate and high” SYNTAX scores, age, diabetes mellitus, low-density lipoprotein cholesterol, hs-CRP, and PTX-3
  • were found to be independent predictors, whereas
  • for the presence of “high” SYNTAX score only PTX-3 was found to be an independent predictor.
  • The receiver operating characteristic curve analysis further revealed that the PTX-3 level was
    • a strong indicator of high SYNTAX score with an area under the curve of 0.91 (95% confidence interval, 0.86–0.96).

Conclusions: Pentraxin 3, a novel inflammatory marker, was more tightly associated with the complexity and severity of CAD than hs-CRP and

    • it was found to be an independent predictor for high SYNTAX score.

The association between atherosclerosis and inflammation has been more understood during recent years. Currently, atherosclerosis is considered as a complex inflammatory process in which

    • leukocytes and inflammatory markers are involved.1

Several inflammatory markers

  1.  high-sensitivity C-reactive protein (hs-CRP),
  2. fibrinogen, and
  3. complement C3…. are associated with cardiovascular events.1–5

Pentraxin 3 (PTX-3), that resembles CRP both in structure and function,1 is produced both by

  • hematopoietic cells such as macrophages, dendritic cells, neutrophils, and by
  • nonhematopoietic cells such as fibroblasts and vascular endothelial cells.2

Plasma PTX-3 levels may be elevated in patients with

  1. vasculitis,6
  2. acute myocardial infarction,7,8 and
  3. systemic inflammation or sepsis,9
  4. psoriasis,
  5. unstable angina pectoris, and
  6. heart failure.10–13

Dubin et al14 reported that PTX-3 levels are associated with with adverse outcomes in stable angina pectoris (SAP). Despite reports about the association of PTX-3 and coronary artery disease (CAD),

an association between the level of PTX-3 and the complexity and severity of CAD is not established.15,16 Thus, the aim of this study was

  • to assess the association between the level of PTX-3 and the complexity and severity of CAD assessed with SYNTAX and Gensini scores in SAP patients.

MATERIALS AND METHODS

Of 211 patients were prospectively recruited,  161 SAP patients with evidence of ischemia (positive treadmill or myocardial perfusion scan) underwent coronary angiography for suspected CAD, and 50 age- and sex- matched outpatient subjects with a negative treadmill or myocardial perfusion scan test were taken as the control group. Patients were excluded if they had

  •  acute coronary syndrome
  • history of previous myocardial infarction;
  • coronary artery bypass grafting or percutaneous coronary intervention;
  • secondary hypertension (HT);
  • renal failure;
  • hepatic failure;
  • chronic obstructive lung disease and/or
  • manifest heart disease, such as
    • cardiac failure (left ventricular ejection fraction <50%),
    • atrial fibrillation, and
    • moderate to severe cardiac valve disease; and
    • SYNTAX score of zero

Similarly, patients were excluded with

  • infection,
  • acute stress, or chronic systemic inflammatory disease and
  • those who had been receiving medications affecting the number of leukocytes .

Thirty patients were excluded from the study because the coronary angiograms revealed normal coronary arteries (SYNTAX score of 0). All the participants included in the study were informed about the study, and they voluntarily consented to participate. The Serum PTX-3 level was measured on blood samples collected after 12-hour fast just prior to coronary angiography and kept at −80°C until the assays were performed. PTX3 was measured by enzyme immunoassay (EIA) using quantitative kit (human PTX-3/TSG-14 immunoassay, DPTX30; R&D Systems, Inc, Minneapolis, MN). The intra-assay and interassay coefficients of variation ranged from 3.8% to 4.4% and 4.1% to 6.1%, respectively (minimum detectable concentration, 0.025 ng/mL). High-sensitivity CRP was measured in serum by EIA (Immage hs-CRP EIA Kit; Beckman Coulter Inc, Brea, CA). Transthoracic echocardiography was performed, and biplane Simpson’s ejection fraction (%) was calculated before coronary angiography. Hypertension was defined as having at least 2 blood pressure measurements greater than 140/90 mm Hg or using antihypertensive drugs, whereas diabetes mellitus (DM) was defined as having at least 2 fasting blood sugar measurements greater than 126 mg/dL or using antidiabetic drugs. Smoking was categorized into current smokers and nonsmokers. Nonsmokers included ex-smokers who had quit smoking for at least 6 months before the study. Body mass index (BMI) values were calculated based on the height and weight of each patient. Medications used before the coronary angiography were noted. The study was approved by the local ethics committee.
SYNTAX and Gensini Scores
To grade the complexity of CAD, the SYNTAX score was used. Each coronary lesion with a stenosis diameter of 50% or greater in vessels of 1.5 mm or greater was scored. Parameters used in the SYNTAX scoring are shown in Table 1. The latest online updated version (2.11) was used in the calculation of the SYNTAX scores (www.syntaxscore.com).17 The SYNTAX score was classified as follows:

  1. low SYNTAX score (≤22),
  2. intermediate SYNTAX score (23–32)
  3. high SYNTAX score (≥33).

Table 1   http://images.journals.lww.com/jinvestigativemed/LargeThumb.00042871-201302000-00007.TT1.jpeg

The severity of CAD was determined by the Gensini score, which

  • measures the extent of coronary stenosis according to degree and location.18

In the Gensini scoring system,

  • larger segments are more heavily weighted ranging from 0.5 to 5.0
    • left main coronary artery × 5;
    • proximal segment of the left anterior descending coronary artery [LAD] × 2.5;
    • proximal segment of the circumflex artery × 2.5;
    • midsegment of the LAD × 1.5;
    • right coronary artery distal segment of the LAD,
    • posterolateral artery, and obtuse marginal artery × 1;
    • and others × 0.5.

The narrowing of the coronary artery lumen is rated

  1. 2 for 0% to 25% stenosis,
  2. 4 for 26% to 50%,
  3. 8 for 51% to 75%,
  4. 16 for 76% to 90%,
  5. 32 for 91% to 99%,
  6. 64 for 100%.

The Gensini index is the sum of the total weights for each segment. All angiographic variables of the SYNTAX and Gensini score were computed by

  • 2 experienced cardiologists who were blinded to the procedural data and clinical outcomes.

The final decision was reached by consensus when a conflict occurred.The number of diseased vessels with

  • greater than 50% luminal stenosis was scored from 1 to 3 (namely, 1-, 2-, or 3-vessel disease), and
  • a lesion greater than 50% in the left main coronary artery was regarded as a 2-vessel disease.

Statistical Analyses

Statistical analyses were conducted with SPSS 17 (SPSS Inc, Chicago, IL) software package program.
Continuous variables were expressed as mean ± SD or median ± interquartile range values, whereas categorical variables were presented as percentages.
The differences between normally distributed numeric variables were evaluated by Student t test or 1-way analysis of variance, whereas

  • non–normally distributed variables were analyzed by Mann-Whitney U test or Kruskal-Wallis variance analysis as appropriate.

χ2 Test was used for the comparison of categorical variables. Pearson test was used for correlation analysis.
To determine the independent predictors of “intermediate and high” SYNTAX scores and only “high” SYNTAX scores,

  • 2 different sets of univariate and multivariate analyses were performed
    • (in the first model SYNTAX cutoff was 22, whereas
    • in the second model SYNTAX cutoff was 33).

The standardized parameters that were found to have a significance (P < 0.10) in the univariate analysis were evaluated by stepwise logistic regression analysis.
Ninety-five percent confidence interval (CI) and odds ratio (OR) per SD increase were presented together. Interobserver and intraobserver variability for SYNTAX scores

  • was done by Bland-Altman analysis.

An exploratory evaluation of additional cut points was performed using the receiver operating characteristic (ROC) curve analysis.
All the P values were 2-sided, and a P < 0.05 was considered as statistically significant.
RESULTS
Baseline Characteristics
In total, 181 patients (50.2 ± 6.5 years, 52.5% were composed of males) were included in the study. Baseline clinical, angiographic, and laboratory characteristics of the patients
relative to SYNTAX score groups are shown in Table 2. Age, sex, HT, DM, BMI, and medication were not different between the groups. Baseline clinical and laboratory characteristics
of patients according to PTX-3 quartiles are shown in Table 3. The Bland-Altman analysis revealed that the degrees of intraobserver and interobserver variability for SYNTAX score
and Gensini score readings were 5% and 6% for SYNTAX and 8% and 9% for Gensini,
respectively.
Table 2   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.TT2.jpeg
Table 3   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.TT3.jpeg

The PTX-3 levels demonstrated an increase from the low SYNTAX group to the high SYNTAX group (r = 0.87, P < 0.001).
The low SYNTAX group had statistically significantly higher PTX-3 levels when compared with the control group (0.50 ± 0.01 vs 0.24 ± 0.01 ng/mL, P < 0.001); similarly,
the PTX-3 levels were higher in the high SYNTAX group than in both

  • the intermediate SYNTAX group (0.84 ± 0.08 vs 0.55 ± 0.01 ng/mL, P < 0.001) and
  • the low SYNTAX group (0.84 ± 0.08 vs 0.50 ± 0.01 ng/mL, P < 0.001).
  • there was no difference in levels of PTX-3 between the low and the intermediate SYNTAX group (0.50 ± 0.01 vs 0.55 ± 0.01 ng/mL, P = 0.09).

On the other hand, there was no difference in levels of hs-CRP between the control and the low SYNTAX group (0.81 ± 0.42 vs 0.86 ± 0.53 mg/dL, P = 0.96).
The intermediate SYNTAX group had statistically significantly higher hs-CRP levels

  • compared with the low SYNTAX group (1.3 ± 0.66 vs 0.86 ± 0.53 mg/dL, P = 0.002);
  • the hs-CRP levels were not different between the high SYNTAX group
    • and the intermediate SYNTAX group. (1.3 ± 0.66 vs 1.3 ± 0.43 mg/dL, P = 0.99).

Univariate correlation analysis revealed a positive correlation between serum PTX-3 levels and hs-CRP levels with

  • the SYNTAX and Gensini scores
    • for SYNTAX: r = 0.87 [P < 0.001] and r = 0.36 [P = 0.01];
    • for Gensini: r = 0.75 [P < 0.001] and r = 0.27 [P = 0.002],  (Fig. 1).

In addition to that, the Gensini and SYNTAX scores are found to be well correlated with each other (r = 0.80, P < 0.001).
When the SYNTAX score was taken as continuous variable, multivariate linear regression analysis revealed that

  • the SYNTAX score was correlated with PTX-3 and hs-CRP (for PTX-3: β = 0.84 [P < 0.001]; hs-CRP: β =0.08 [P = 0.032]).

Figure 1   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.FF1.jpeg

For determining the predictors of intermediate and high SYNTAX scores and only-high SYNTAX scores,

  • 2 different sets of univariate and multivariate analyses were performed among the patients who underwent coronary angiography.

For predicting the intermediate and high SYNTAX scores, the SYNTAX score was dichotomized into

  • high (score ≥22) and
  • low (<22) groups,

whereas for predicting the only-high SYNTAX scores, the SYNTAX score was dichotomized into

  • 2 groups with a score of 33 or greater and a score of less than 33.

In the first multivariate analysis (where SYNTAX cutoff was 22), the parameters showing significance in the univariate analysis

  • age,
  • sex,
  • HT,
  • DM,
  • low-density lipoprotein cholesterol [LDL-C],
  • hs-CRP,
  • PTX-3

were evaluated by multivariate analysis to determine the

  • independent predictors of intermediate and high SYNTAX scores.

In the univariate analysis, higher values of

  • age (OR, 1.5 [95% CI, 1.1–2.0]; P = 0.01),
  • LDL-C (OR, 1.3 [95% CI, 0.98–1.8]; P = 0.068),
  • hs-CRP (OR, 2.6 [95% CI, 1.8–3.8]; P < 0.001), and
  • PTX-3 (OR, 13.6 [95% CI, 6.4–28.9]; P < 0.001)
    • were associated with higher SYNTAX scores,
  • HT (OR, 0.44 [95% CI, 0.24–0.80]; P = 0.008) and
  • DM (OR, 0.48 [95% CI, 0.25–0.91]; P = 0.02)
    • were associated with lower SYNTAX scores.

In the multivariate analysis – age, DM, LDL-C, hs-CRP, and PTX-3 – were found to be

  • independent predictors of “intermediate to high” SYNTAX score (Table 4).

Increased

  • age (OR, 2.5 [95% CI, 1.3–4.8]; P = 0.007),
  • LDL-C (OR, 2.8 [95% CI, 1.5–5.2]; P = 0.001),
  • hs-CRP (OR, 3.3 [95% CI, 1.8–6.1]; P < 0.001), and
  • PTX-3 (OR, 35.4 [95% CI, 10.1–123.6]; P < 0.001)
    • were associated with increased SYNTAX scores,

whereas DM (OR, 0.08 [95% CI, 0.02–0.33]; P < 0.001) was associated with lower SYNTAX score (Table 4).

In the second univariate and multivariate analyses (where SYNTAX cutoff was 33),

  • the parameters that showed significance in the univariate analysis were age, LDL-C, glucose, hs-CRP, and PTX-3.
  • In the univariate analysis, increased
    • age (OR, 1.5 [95% CI, 1.0–2.3]; P = 0.05),
    • LDL-C (OR, 1.5 [95% CI, 0.97–2.2]; P = 0.07),
    • hs-CRP (OR, 1.4 [95% CI, 0.97–2.1]; P = 0.072), and
    • PTX-3 (OR, 18.5 [95% CI, 6.6–51.8]; P < 0.001)
      • were found to be associated with increased SYNTAX scores.

When these parameters were evaluated with multivariate analysis, only PTX-3 (OR, 18.4 [95% CI, 6.2–54.2]; P < 0.001)

    • was found to be an independent predictor for high SYNTAX score (Table 4).

Table 4   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.TT4.jpeg

The ROC curve analysis further revealed that the PTX-3 level was a strong indicator of high SYNTAX score with

  • an area under the curve (AUC) of 0.91 (95% CI, 0.86–0.96) (Fig. 2).

The optimal cutoff of PTX-3 for the high SYNTAX score was 0.75 ng/mL.
Sensitivity, specificity, positive predictive value, and negative predictive value to identify high SYNTAX score for the PTX-3 level

  • were 90%, 84%, 97%, and 60%, respectively.
  • the ROC curve analysis of PTX-3 for intermediate-high SYNTAX score revealed that the AUC value was 0.82 (95% CI, 0.75–0.89).

The optimal threshold of PTX-3 level that

  • maximized the combined specificity and sensitivity to predict
    • intermediate to high SYNTAX score was 0.73 ng/mL.

For the cutoff value of 0.73 ng/mL, sensitivity, specificity, positive predictive value, and negative predictive value

  • to identify intermediate-high SYNTAX score were 56%, 98%, 97%, and 56%, respectively.

Figure 2   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.FF2.jpeg

In the ROC analysis of hs-CRP for high SYNTAX scores, the AUC value was found to be 0.68 (95% CI, 0.59–0.77; P < 0.001).
The optimal threshold of hs-CRP that maximized the combined specificity and sensitivity to predict for high SYNTAX scores was 0.89 mg/dL.
Similarly, the ROC analysis of hs-CRP for the intermediate-high SYNTAX scores revealed an AUC of 0.74 (95% CI, 0.65–0.83; P = 0.001).
The cutoff value of hs-CRP to predict the intermediate-high SYNTAX scores with a maximized sensitivity and specificity was 0.66 mg/dL.
DISCUSSION
In this particular study, we investigated the relationship between the serum PTX-3 level and the severity of CAD

  • assessed by SYNTAX and Gensini scores in patients with SAP.

The PTX-3, was significantly higher than control group in the patients with CAD, and the serum PTX-3 levels

  • were associated with the SYNTAX and Gensini scores.

When compared with the hs-CRP, the PTX-3 was found to be more tightly associated with the complexity and severity of CAD in the patients with SAP.
Pentraxin 3, an acute-phase reactant that is functionally and structurally similar to CRP,1 is produced both by different kinds of cells such as

  • macrophages, dendritic cells, neutrophils, fibroblasts, and vascular endothelial cells.2
  • Pentraxin 3 is released following the inflammatory stimuli19; therefore, it may reflect the local inflammatory status in tissues.20

Serum PTX-3 levels were shown to be elevated in patients with

  • vasculitis,6 acute myocardial infarction,7,8 and systemic inflammation or sepsis,9 psoriasis, unstable angina pectoris, and heart failure.10–13

Higher PTX3 levels were reported to be associated with worse cardiovascular outcomes

  1. after acute coronary syndromes,8,21
  2. in the elderly people without known cardiovascular disease22 and
  3. associated with overall mortality in patients with stable coronary disease,
  4. independent of systemic inflammation.14

There are 2 reports investigating the association of PTX-3 level and the atherosclerotic burden.15,16 In one of these reports,

  • Knoflach et al.15 took B-mode ultrasonography as the atherosclerosis index.

They did not provide any information about coronary anatomy, and in the other report, Soeki et al.16 evaluated 40 patients who

  • underwent coronary angiography and measured their Gensini scores.

However, in none of the studies were the SYNTAX score and Gensini score used together to assess the degree of coronary atherosclerotic burden.
To our knowledge, this is the first report that showed the association of PTX-3 levels with the complexity and severity of CAD assessed by

  • SYNTAX and Gensini scores in patients with stable coronary disease.

Chronic low-grade inflammation has been thought to play a major role in the pathogenesis of atherosclerosis.23,24 Previous studies have reported that

  • levels of inflammatory markers such as hs-CRP, interleukin 6, and so on were increased in atherosclerosis.25

In the present study, both the SYNTAX and the Gensini scores were found to be correlated with serum PTX-3 and hs-CRP levels,

  • which in turn might reflect the degree of inflammation.

The SYNTAX score is an important tool in the classification of complex CAD26 and can give predictive information about short- and long-term outcomes

  • in patients with stable CAD who undergo percutaneous coronary intervention.27–30

Although the SYNTAX score is currently used for assessing the angiographic complexity of CAD rather than the severity of coronary atherosclerotic burden,

  • because more complex lesions tend to have more atherosclerotic burden,
  • the SYNTAX scores may also reflect the severity of coronary atherosclerotic burden.

The Gensini score, a well-known and widely used scoring system to evaluate the severity of CAD,18 was measured and

  • found to be well correlated with the SYNTAX score,
    • which supports the idea that angiographically more complex lesions tend to have more atherosclerotic burden.

When compared with the hs-CRP,

  • the PTX-3 seems to be more tightly associated with coronary disease burden (r = 0.36 vs r = 0.87).

We found out that the serum PTX-3 levels were higher than those in the control group, even in the low SYNTAX group.
On the other side, the serum hs-CRP levels were not different in the control and the low SYNTAX groups.
It was reported that the leukocytes mainly found in the coronary artery lumen are the neutrophils.31
It is also known that PTX-3 is stored in specific granules of neutrophils and released in response to inflammatory signals.32
The reason why serum PTX-3 levels seem more tightly associated with the coronary disease burden

  • when compared with serum hs-CRP levels may be the association of the
  • on-site presence of neutrophils and local inflammatory signal–triggered release of  PTX-3.

On the other hand, some human studies revealed that PTX-3 was produced more in areas of atherosclerosis and may contribute to its pathogenesis.31
Some other studies suggested that PTX-3 may be part of a protective mechanism in

  • vascular repair via inhibiting fibroblast growth factor 2 or some other growth factors responsible for smooth muscle proliferation.33,34

But still, the exact role of PTX-3 in the pathophysiology of atherosclerosis seems to be obscure for the time being. It is well established that atherosclerosis
has an inflammatory background in most of the cases. In addition to that, high blood CRP level is known as an indicator of future cardiovascular disease risk
even in healthy individuals.35 According to the results of univariate and multivariate analyses, for intermediate and high SYNTAX scores,

  1. age, DM, LDL-C, hs-CRP, and PTX-3 were found to be independent predictors, whereas for the presence of
  2. high SYNTAX score, only PTX-3 was found to be an independent predictor.

Because of the tighter association with atherosclerotic burden and the on-site vascular presence,

    • PTX-3 may be a promising candidate marker for vascular inflammation and future cardiovascular events.

LIMITATIONS
The major limitation of the current study is the number of patients included. It would be better to include more patients to increase the statistical power.

Besides, the SYNTAX and Gensini scores give us an idea about the complexity and severity of coronary atherosclerosis; however,
with coronary angiography alone, it is not possible to understand the extent of coronary plaque. In addition to that, the coronary anatomy of the
control group was not known, which was another limitation. Our selected population was free of other confounders of systemic inflammation, and
we did not have data about inflammatory markers other than hs-CRP, such as interleukin 6, tumor necrosis factor α, and so on, which may be accepted
as a limitation. Another limitation of the current study is that because there was no long-term follow-up of the patients, it did not provide any prognostic
data in terms of future cardiovascular events.
CONCLUSIONS
Pentraxin 3, a novel inflammatory marker, is associated with the complexity and severity of the CAD assessed by the SYNTAX and the Gensini scores in patients with SAP and seems to be more tightly associated with coronary atherosclerotic burden than hs-CRP.

REFERENCES

1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.
2. Brown DW, Giles WH, Croft JB. White blood cell count: an independent predictor of coronary heart disease mortality among a national cohort. J Clin Epidemiol. 2001; 54: 316–322.
3. Kannel WB, Anderson K, Wilson PW. White blood cell count and cardiovascular disease. Insights from the Framingham Study. JAMA. 1992; 267: 1253–1256.
4. Muscari A, Bozzoli C, Puddu GM, et al.. Association of serum C3 levels with the risk of myocardial infarction. Am J Med. 1995; 98: 357–364.
5. Ridker PM, Cushman M, Stampfer MJ, et al.. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336: 973–979.
6. Fazzini F, Peri G, Doni A, et al.. PTX3 in small-vessel vasculitides: an independent indicator of disease activity produced at sites of inflammation. Arthritis Rheum. 2001; 44: 2841–2850.
7. Peri G, Introna M, Corradi D, et al.. PTX3, A prototypical long pentraxin, is an early indicator of acute myocardial infarction in humans. Circulation. 2000; 102: 636–641.
8. Latini R, Maggioni AP, Peri G, et al.. Prognostic significance of the long pentraxin PTX3 in acute myocardial infarction. Circulation. 2004; 110: 2349–2354.
9. Muller B, Peri G, Doni A, et al.. Circulating levels of the long pentraxin PTX3 correlate with severity of infection in critically ill patients. Crit Care Med. 2001; 29: 1404–1407.
10. Bevelacqua V, Libra M, Mazzarino MC, et al.. Long pentraxin 3: a marker of inflammation in untreated psoriatic patients. Int J Mol Med. 2006; 18: 415–423.
11. Inoue K, Sugiyama A, Reid PC, et al.. Establishment of a high sensitivity plasma assay for human pentraxin3 as a marker for unstable angina pectoris. Arterioscler Thromb Vasc Biol. 2007; 27: 161–167.
12. Suzuki S, Takeishi Y, Niizeki T, et al.. Pentraxin 3, a new marker for vascular inflammation, predicts adverse clinical outcomes in patients with heart failure. Am Heart J. 2008; 155: 75–81.
13. Matsubara J, Sugiyama S, Nozaki T, et al.. Pentraxin 3 is a new inflammatory marker correlated with left ventricular diastolic dysfunction and heart failure with normal ejection fraction. J Am Coll Cardiol. 2011; 57: 861–869.
14. Dubin R, Li Y, Ix JH, et al.. Associations of pentraxin-3 with cardiovascular events, incident heart failure, and mortality among persons with coronary heart disease: data from the Heart and Soul Study. Am Heart J. 2012; 163: 274–279.
16. Soeki T, Niki T, Kusunose K, et al.. Elevated concentrations of pentraxin 3 are associated with coronary plaque vulnerability. J Cardiol. 2011; 58: 151–157.
17. SYNTAX working group. SYNTAX score calculator. Available at http://www.syntaxscore.com. Accessed May 20, 2012.
18. Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol. 1983; 51: 606.
20. Mantovani A, Garlanda C, Bottazzi B, et al.. The long pentraxin PTX3 in vascular pathology. Vascul Pharmacol. 2006; 45: 326–330.
21. Matsui S, Ishii J, Kitagawa F, et al.. Pentraxin 3 in unstable angina and non-ST-segment elevation myocardial infarction. Atherosclerosis. 2010; 210: 220–225.
22. Jenny NS, Arnold AM, Kuller LH, et al.. Associations of pentraxin 3 with cardiovascular disease and all-cause death: the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol. 2009; 29: 594–599.
26. Serruys PW, Morice MC, Kappetein AP, et al.. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009; 360: 961–972.
27. van Gaal WJ, Ponnuthurai FA, Selvanayagam J, et al.. The SYNTAX score predicts peri-procedural myocardial necrosis during percutaneous coronary intervention. Int J Cardiol. 2009; 135: 60–65.
28. Lemesle G, Bonello L, de Labriolle A, et al.. Prognostic value of the SYNTAX score in patients undergoing coronary artery bypass grafting for three-vessel coronary artery disease. Catheter Cardiovasc Interv. 2009; 73: 612–617.
29. Capodanno D, Di Salvo ME, Cincotta G, et al.. Usefulness of the SYNTAX score for predicting clinical outcome after percutaneous coronary intervention of unprotected left main coronary artery disease. Circ Cardiovasc Interv. 2009; 2: 302–308.
30. Kim YH, Park DW, Kim WJ, et al.. Validation of SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score for prediction of outcomes after unprotected left main coronary revascularization. JACC Cardiovasc Interv. 2010; 3: 612–623.
32. Jaillon S, Peri G, Delneste Y, et al.. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J Exp Med. 2007; 204: 793–804.
33. Inforzato A, Baldock C, Jowitt TA, et al.. The angiogenic inhibitor long pentraxin PTX3 forms an asymmetric octamer with two binding sites for FGF2. J Biol Chem. 2010; 285: 17681–17692.
34. Camozzi M, Zacchigna S, Rusnati M, et al.. Pentraxin 3 inhibits fibroblast growth factor 2–dependent activation of smooth muscle cells in vitro and neointima formation in vivo. Arterioscler Thromb Vasc Biol. 2005; 25: 1837–1842.
35. Koenig W, Sund M, Frohlich M, et al.. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999; 99: 237–242.
Keywords:  pentraxin 3; coronary artery disease; SYNTAX score; hs-CRP; inflammation

This is not the only recent finding that adds to the ability to evaluate these patients.  An as yet unpublished paper, expected to be published soon reports on

QRS fragmentation as a Prognostic test in Acute Coronary Syndrome,  and this reviewer expects the work to have a high impact.  The authors state that
QRS complex fragmentation is a promising bed-side test for assessment of prognosis in those patients.  Presence of fragmented QRS in surface ECG during ACS

  • represents myocardial scar or fibrosis and reflect severity of coronary lesions and a correlation between fQRS and depression of Lv function is established.

There are still other indicators that need to be considered, such as the mean arterial blood pressure.

There has been review and revisions of the guidelines for treatment of UA/NSTEMI within the last year, with differences being resolved among the Europeans and US.

Guidelines Updated for Unstable Angina/Non-ST Elevation Myocardial Infarction
According to the current study by Jneid and colleagues, new evidence is available on the management of unstable angina. This report replaces the 2007 American College of Cardiology Foundation/American Heart Association (ACC/AHA) Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (UA/NSTEMI) that were updated by the 2011 guidelines.

This guideline was reviewed by

  • 2 official reviewers each nominated by the ACCF and the AHA, as well as
  • 1 or 2 reviewers each from the American College of Emergency Physicians; the Society for Cardiovascular Angiography and Interventions; and the Society of Thoracic Surgeons; and
  • 29 individual content reviewers, including members of the ACCF Interventional Scientific Council.

The recommendations in this focused update are considered current

  • until they are superseded in another focused update or the full-text guideline is revised, and are official policy of both the ACCF and the AHA.

STUDY SYNOPSIS AND PERSPECTIVE
American cardiology societies have caught up with the European Society of Cardiology by

  • issuing their second update to the UA/NSTEMI guidelines in 18 months,
  • with the 2012 focused update replacing the 2011 guidelines [1].

The new recommendations include ticagrelor (Brilinta) as one of the options for antiplatelet therapy alongside prasugrel (Effient) and clopidogrel, bringing them in line with European.
The European guidance, however, gave precedence to the new antiplatelets over clopidogrel, whereas the American update “places ticagrelor on an equal footing with the other two antiplatelets available–
this is the main reason for the update,” lead author Dr Hani Jneid (Baylor College of Medicine, Houston, TX), told heartwire . “Doctors now have a choice for second-line therapy after aspirin, depending on

  • the patient’s clinical scenario,
  • physician preference, and cost,”
    • now that clopidogrel is available generically.

The US decision to recommend

  • first prasugrel–in its 2011 update to the UA/NSTEMI guidelines–and
  • now ticagrelor as equivalent antiplatelet therapy choices to clopidogrel after aspirin
    • puts it somewhat at odds with the Europeans,
    • who reserve clopidogrel use for those who cannot take the newer agents.

The reason for the Americans differing stance is that because while they are faster acting and more potent–

  • the cost-effectiveness of the new agents is not known.
  • it isn’t clear how the efficacy observed in pivotal clinical trials of these agents is going to translate into real-world benefit,
  • and issues such as bleeding with prasugrel and compliance with a twice-daily drug such as ticagrelor remain concerns.

Bulk of 2012 Update on How to Use Ticagrelor
The 2012 ACCF/AHA focused update for the management of UA/NSTEMI stresses that

  • all patients at medium/high risk should receive dual antiplatelet therapy on admission,
  • with aspirin being first-line, indefinite therapy.

The bulk of the update centers on how to use ticagrelor which–

  • like prasugrel or clopidogrel–
  • can be added to aspirin for up to 12 months (or longer, at the discretion of the treating clinician).

Jneid notes it’s important to remember that prasugrel can only be used in the cath lab

  • in patients undergoing percutaneous coronary intervention (PCI),
  • whereas ticagrelor, like clopidogrel, can be used in medically managed or PCI patients.

And he emphasizes that, in line with the FDA’s black-box warning on ticagrelor,

The 81-mg aspirin dose is also considered a reasonable option in preference to a higher maintenance dose of 325 mg in

  • any acute coronary syndrome (ACS) patient following PCI, he adds, as
  • this strategy is believed to result in equal efficacy and lower bleeding risk.

With regard to how long antiplatelet therapy should be stopped before planned cardiac surgery, the recommendation is

  • five days for ticagrelor–the same as that advised for clopidogrel.
  • and seven days prior to surgery for prasugrel.

Jneid also highlights other important recommendations from the 2011 focused update carried over to 2012:

It is “reasonable” to proceed with cardiac catheterization and revascularization within

  • 12–24 hours of admission in initially stable, very high-risk patients with ACS.

An invasive strategy is “reasonable” in patients with

  • mild and moderate chronic kidney disease.

In those with diabetes hospitalized with ACS, insulin use should target glucose levels <180 mg/dL,

  • a less-intensive reduction than previously recommended.

Platelet function or genotype testing for clopidogrel resistance are both considered “reasonable”

  • if clinicians think the results will alter management,
  • but Jneid acknowledged that “there is not much evidence to support these assays” .

Committee Encourages Participation in Registries
Jneid observes that unstable angina and NSTEMI are “very common” conditions that carry a high risk of death and recurrent heart attacks,

  • which is why “the AHA and ACCF constantly update their guidelines so that physicians can provide patients with
  • the most appropriate, aggressive therapy with the goal of improving health and survival.”

To this end, he notes that the writing panel encourages

  • clinicians and hospitals to participate in quality-of-care registries designed
  • to track and measure outcomes, complications, and
  • adherence to evidence-based medicines.

Conflicts of interest for the writing committee are listed in the paper.

References

Jneid H, Anderson JL, Wright SR, et al. 2012 ACCF/AHA focused update on the guideline for the management of patients with unstable angina/non-ST elevation myocardial infarction (Updating the 2007 guideline and replacing the 2011 focused update): A report of the ACCF/AHA.
Circulation 2012;      Available at: http://circ.ahajournals.org/  http://dx.doi.org/10.1161/CIR0b013e3182566fleo
source   http://www.medscape.org

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Imaging-biomarkers is Imaging-based tissue characterization

Author – Writer: Dror Nir, PhD

For everyone who is skeptical about the future role of imaging-based tissue chracterisation in the management of cancer, the following “Statement paper” ESR statement on the stepwise development of imaging biomarkers published online: 9 February 2013, by the European Society of Radiology (ESR), should provide substantial reassurance that this kind of technology will become a must! In support of this claim I quote the following information:

“The European Society of Radiology and its related European Institute for Biomedical Imaging Research (EIBIR) should have a relevant role in coordinating future developments of biomarkers and in the assessment and validation of imaging biomarkers as surrogate end points.

Acknowledgements

This paper was kindly prepared by the ESR Subcommittee on Imaging Biomarkers (Chairperson: Bernard Van Beers. Research Committee Chairperson: Luis Martí-Bonmatí. Members: Marco Essig, Thomas Helbich, Celso Matos, Wiro Niessen, Anwar Padhani, Harriet C. Thoeny, Siegfried Trattnig, Jean-Paul Vallée. Co-opted members: Peter Brader, Nicolas Grenier) on behalf of the European Society of Radiology (ESR) and with the help of Sabrina Doblas, INSERM U773, Paris, France.

It was approved by the ESR Executive Council in December 2012..”

According to ESR: “There is increasing interest in developing the quantitative imaging of biomarkers in personalised medicine”. In this perspective, “Biomarkers” are tissue properties that can be quantitatively and reproducibly measured by imaging devices. One example for a major unmet need, which I found to be most interesting is the imaging-based detection of tumor invasiveness.

Quoting from the paper: ” Biomarkers are defined as “characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathological processes, or pharmaceutical responses to a therapeutic intervention” [1]. Broadly, biomarkers fall into two categories: bio-specimen biomarkers, including molecular biomarkers and genetic biomarkers, and bio-signal biomarkers or imaging biomarkers. Bio-specimen biomarkers are obtained by removing a sample from a patient. Examples of these molecular biomarkers are genes and proteins detected from fluids or tissue samples. Bio-signal biomarkers remove no material from the patient, but rather detect and analyse an electromagnetic, photonic or acoustic signal emitted by the patient [2]. These imaging biomarkers have the advantage of being non-invasive, spatially resolved and repeatable [3]. They are of particular interest if they can overcome the limitations of the established histological “gold standards”. Indeed, invasive reference examinations, such as biopsy, can be inconclusive, are non-representative of the whole tissue (which is a tremendous limitation when assessing malignant tumours, which are known to be heterogeneous) and possess non-negligible levels of mortality and morbidity.

Genetic biomarkers indicate whether a disease may occur, but they are usually inefficient to assess the presence and stage of a disease. Similar to molecular biomarkers, imaging biomarkers can be used for early detection of diseases, staging and grading, and predicting or assessing the response to treatment [3]. Accordingly, because of their relative lower cost compared with imaging, molecular biomarkers may be more appropriate for disease screening and early detection than imaging biomarkers. With their high sensitivity, molecular biomarkers could also detect subclinical stages of disease before any morphological or functional change is detectable on imaging. In contrast, imaging biomarkers are often more useful than molecular biomarkers for disease staging, and also grading and for assessing tumour response, because localised information is crucial.”

The main messages ESR wishes to deliver in this paper are that:

• Using imaging-biomarkers to streamline drug discovery and disease progression will drive a huge advancement in healthcare.

• The clinical qualification and validation of imaging biomarkers technology pose challenges, mainly in establishing the accuracy and reproducibility of such techniques. In that respect, agreements on standards and evaluation methods (e.g. clinical studies design) is imperative.

• There should be high motivation to pursue the development of imaging-biomarkers as the “clinical value of new biomarkers is of the highest priority in terms of patient management, assessing risk factors and disease prognosis.”

The paper deals to a great extent with the requirements on accuracy, reproducibility, standardization and quality control from the process of developing imaging-biomarkers:

“Accuracy: Before being routinely used in the clinic, imaging biomarkers must be validated. Determining the accuracy implies calculating the sensitivity and specificity of the biomarker when compared with a biological process, such as tumour necrosis, which can be assessed at histopathological examination… [6–9]  [10, 11]

Reproducibility: Repeatability (measurements at short intervals on the same subjects using the same equipment in the same centres) and reproducibility (measurements at short intervals on the same subjects using different facilities in the same and different centres) studies must be conducted for image acquisition and image analysis…. Reproducibility studies are now very often included in scientific papers, as advised by the “standards for reporting of diagnostic accuracy” (STARD) criteria and should ideally include Bland-Altman plots and results of coefficients of repeatability [16, 17].

Standardisation: Standardisation relates to the establishment of norms or requirements about technical aspects. In the development of imaging biomarkers, two main aspects should be considered: Standardisation of image acquisition and Standardisation of image analysis…  [18] [19–21]  [22] [27, 28] [31–33]

Quality control: Adequate phantoms could be used to validate, on a day-to-day basis, that the biomarker stays robust and to avoid any drift in the machine, acquisition or processing protocol….  [34] [30, 35] [36] [37] [23].”

The proposed development workflow:

“Similar to new drugs, the development of biomarkers has to pass along a pipeline going from discovery, through verification in different laboratories, validation and qualification before they can be used in clinical routine. Validation includes the determination of the accuracy and the precision (reproducibility) of the biomarker and standardisation concerns both acquisition and analysis. Qualification, defined as a “graded, fit-for-purpose evidentiary process linking a biomarker with biological processes and clinical end-points”, is a validation process in large cohorts of patients involving multiple centres, similar to phase III clinical trials, to obtain regulatory approval as surrogate endpoints [4]. A more extensive path to biomarker development has been reported [5]. The first step is the proof of concept, which defines any specific change relevant to the disease that can be studied using the available imaging and computational techniques. The relationship between this change and the presence, grading and response to treatment of the disease constitutes the proof of mechanism. The images needed to extract the biomarker must be appropriate (in terms of resolution, signal and contrast behaviour). Preparation of images relates to improving the data before the analysis (such as segmentation, filtering, interpolation or registration). The analysis and modelling of the signal by computational numerical adjustment of a mathematical model allow extracting the needed information (such as structural, physical, chemical, biological and functional properties). After this voxel-by-voxel computation, the spatial distribution of the biomarker can be depicted by parametric images, defined as derived secondary images which pixels represent the distribution values of a given parameter. Multivariate parametric images obtained by statistical modelling of the relevant parameters allow the reduction of data and a clear definition of the defined disease target. The abnormal values should be defined and measured through histogram analysis. A pilot test on a small sample of subjects, with and without the disease, has to be performed to validate the process—also called proof of principle—and to evaluate the influence of potential variations related to age, sex or any other source of biases. Finally, proofs of efficacy and effectiveness on larger and well-defined series of patients will show the ability of a biomarker to measure the clinical endpoint (Fig. 1).”

Steps for the development of imaging biomarkers (adapted from [5])

Steps for the development of imaging biomarkers (adapted from [5])

The authors admit that the requirement posed on development of imaging-biomarkers represents a huge challenge and they try to offer ideas, mainly taken from the “MRI experience” to overcome certain hurdles. There is one important point on which they do not discuss: the definition of appropriate reference test. It is my own experience, based on many study protocols I developed in the past decade, that without reaching an agreement on that point, the development of imaging-biomarkers will just move in circles. Note, that today’s most “acceptable” reference test is histopathology, which everyone admits (as well mentioned in this paper); suffers many limitations. When it comes to validating imaging-biomarkers, the need to accurately match imaging products with histopathology is an additional major hurdle.

This is why, I see as a necessary step, to develop “real-time” imaging based tissue characterization combined with in-situ imaging-based histology.

 

References

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Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69(3):89–95CrossRef

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Waterton JC, Pylkkanen L (2012) Qualification of imaging biomarkers for oncology drug development. Eur J Cancer 48(4):409–415PubMedCrossRef

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European Society of Radiology (2010) White paper on imaging biomarkers. Insights Imaging 1(2):42–45CrossRef

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Wagner JA, Williams SA, Webster CJ (2007) Biomarkers and surrogate end points for fit-for-purpose development and regulatory evaluation of new drugs. Clin Pharmacol Ther 81(1):104–107PubMedCrossRef

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Marti Bonmati L, Alberich-Bayarri A, Garcia-Marti G, Sanz Requena R, Pérez Castillo C, Carot Sierra JM, Herrera M (2012) Imaging biomarkers, quantitative imaging, and bioengineering. Radiol 54(3):269–278CrossRef

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Lewin M, Poujol-Robert A, Boelle PY et al (2007) Diffusion-weighted magnetic resonance imaging for the assessment of fibrosis in chronic hepatitis C. Hepatology 46(3):658–665PubMedCrossRef

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Luciani A, Vignaud A, Cavet M et al (2008) Liver cirrhosis: intravoxel incoherent motion MR imaging–pilot study. Radiology 249(3):891–899PubMedCrossRef

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Bonekamp S, Torbenson MS, Kamel IR (2011) Diffusion-weighted magnetic resonance imaging for the staging of liver fibrosis. J Clin Gastroenterol 45(10):885–892PubMedCrossRef

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Nanotechnology and Heart Disease

Author and Curator:  Tilda Barliya PhD

Cardiovascular disease is the most common cause of death worldwide and will become even more prevalent as the population ages. New therapeutic targets are being identified as a result of emerging insights into disease mechanisms, and new strategies are also being tested, possibly leading to new treatment options. Improving diagnosis is also crucial, because by detecting disease early, the focus could be shifted from treatment to prevention (1).

Mortality rates for cardiovascular disease have improved, but there are inequalities across the UK

The World Health Organization estimates that more than 17 million people died from cardiovascular diseases in 2008. In the U.S., about 785,000 people will have new heart attacks this year and 470,000 will suffer recurrent ones. While more patients are surviving such events, about two-thirds don’t make complete recoveries and are vulnerable to heart failure (2).

Heart and vascular disease is the number one killer in most industrialized nations, and costs countries billions in health care, and lost wages. Nanotechnology, biotechnology, robotics, and stem cells are reinvigorating the development of artificial components of the cardiovascular system. We’ve seen hearts grown from stem cells in labs, artificial mechanical hearts, companies spending millions to develop artificial blood, and now even artificial vascular tubes which act more like the real thing. Combined with upcoming advances in robotic and micro-surgery, medicine could be on the path to conquering its public enemy number one.

Nanotechnology offers several tools and advantages in cardiovascular science which are in the areas of diagnosis, imaging, and tissue engineering.

including:

  • treating defective heart valves
  • detecting and treat arterial plaque
  • understanding at a sub-cellular level how heart tissue functions in both healthy  and damaged organs, which can help researchers design better treatments

Examples:

Robert Langer, Omid Farokhzad and colleagues have developed nanoparticles that can cling to artery walls and slowly release medicine, an advance that potentially provides an alternative to drug-releasing stents in some patients with cardiovascular disease. The particles, dubbed “nanoburrs” because they are coated with tiny protein fragments that allow them to stick to target proteins, can be designed to release their drug payload over several days (3, 4). The nanoburrs are targeted to a specific structure, known as the basement membrane, which lines the arterial walls and is only exposed when those walls are damaged. Therefore, the nanoburrs could be used to deliver drugs to treat atherosclerosis and other inflammatory cardiovascular diseases. In the current study, the team used paclitaxel, a drug that inhibits cell division and helps prevent the growth of scar tissue that can clog arteries

Prof. Erkki Ruoslahti and other researchers from UC Santa Barbara have developed a nanoparticle that can attack plaque –– a major cause of cardiovascular disease (5).  These lipid-based micelles target the p32 receptors known to overexpress in plaques. To accomplish the research, the team induced atherosclerotic plaques in mice by keeping them on a high-fat diet. They then intravenously injected these mice with the micelles, which were allowed to circulate for three hours.

Clinical Trials:

“Nanotechnology creates artificial artery for clinical trials”

Researchers at London Royal Free Hospital are hoping to save limbs and lives with the creation of their new artificial artery. Unlike current artery replacements, this grafting substance was created using nanotechnology and can pulse with the natural movements of the body. That pulsing will allow the polymer tube to be used in very small grafts (<8mm), giving hope that damaged arteries which would normally lead to amputations or heart attacks can now be treated (6). The clinical study should have started by the end of 2010. No further information is currently available on this clinical trial.

The new artificial artery material was developed by Professors George Hamilton (vascular surgery) and Alexander Seifalian (nanotechnology and tissue repair). The substance is a polymer which has been embedded with different types of special molecules. Some of these molecules aid circulation, others encourage stem cells to coat its walls. That coating is very important and may allow the artificial tissue to bond better with the body and promote long term health. Most importantly though, the design of the artificial vascular tissue is resistant to clotting and can pulse.

Summary:

Research of heart disease is progressing on several levels simultaniously. It is believed that nanotechnology may offer several advantages in detecting and treating several heart conditions, however, they have yet to progressed into the clinical trials.

Quoting Dr. Tal Dvir: ” Many current experimental approaches to heart attack involve supplying growth factors, drugs, stem cells and other therapeutic agents to the scarred, dying tissue. Some of these compounds, such as periostin and neuregulin, have been shown in animal models to enhance heart regeneration and improve cardiac function. But the existing delivery approaches are all invasive, involving direct injections into the heart, catheter procedures, or surgical placement of implants that release the necessary factors.

The ultimate goal is to have the particles release compounds that promote regeneration. One approach is to release factors that attract the patient’s own stem cells, avoiding the need for tissue-engineered patches. But to date, no one’s gotten stem cells to differentiate efficiently into cardiomyocytes”

REFERENCES

1. http://www.nature.com/nature/supplements/insights/cardiovascular/index.html

2. Novel Cure for Ailing Hearts. http://online.wsj.com/article/SB10000872396390443537404577577002440205144.html

3. Chan JM., Zhang L., Tong R., Ghosh D., Gao W., Liao G., Yuet KP., Gray D., Rhee JW., Cheng J., Golomb G., Libby P, Langer R and Farokhzad OC. Spatiotemporal controlled delivery of nanoparticles to injured vasculature. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2213-8.  http://www.pnas.org/content/107/5/2213.long

4. Chan JM., Rhee JW., Drum CL., Bronson RT., Golomb G., Langer R and Farokhzad OC. In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid-polymeric nanoparticles. Proc Natl Acad Sci U S A. 2011 Nov 29;108(48):19347-52.

http://www.pnas.org/content/108/48/19347.long

5. Hamzah J., Kotamraju VR., Seo JW., Agemy L., Fogel V., Mahakian LM., Peters D., Roth L., Gagnon MK., Ferrara KW and Ruoslahti E. Specific penetration and accumulation of a homing peptide within atherosclerotic plaques of apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7154-9. http://www.pnas.org/content/108/17/7154.long

6. Written By: : http://singularityhub.com/2010/01/05/nanotechnology-creates-artificial-artery-for-clinical-trials/

7. Ikaria® Commences Global Registration Trial for Bioabsorbable Cardiac Matrix. http://www.prnewswire.com/news-releases/ikaria-commences-global-registration-trial-for-bioabsorbable-cardiac-matrix-136581753.html.

8. Posted by: Prof. Lev-Ari :”Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel” http://pharmaceuticalintelligence.com/2013/02/27/arteriogenesis-and-cardiac-repair-two-biomaterials-injectable-thymosin-beta4-and-myocardial-matrix-hydrogel/

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Virtual Biopsy – is it possible?

Author and Curator: Dror Nir, PhD

In a remark made to my last post: New envelopment in measuring mechanical properties of tissue, Dr. Aviva Lev-Ari, PhD, RN, Director and Founder of our Open Access Online Scientific Journal:  Leaders of Pharmaceutical Business Intelligence, asked whether OCT can be used for the purpose of performing biopsy. My answer to her question was “YES”. I thought that it will be worthwhile explaining why I am so “optimistic” about this:

A conventional biopsy is a process where a tissue sample is being cut out of the body and after being subjected to all kind of chemical processes a thin-film of tissue is trimmed and read under the microscope by a trained pathologist. Can imaging provide histological assessment of “thin-film” of tissue without cutting it out of the body? The answer would be positive if the imaging will result with high resolution reconstruction of a tissue sample identical in quality to a “live-sample” that is put under the microscope.

I was happy to find support to my optimism regarding the feasibility of constructing such device in the following article: Virtual skin biopsy by optical coherence tomography: the first quantitative imaging biomarker for scleroderma published on February 20th 2013 in Ann Rheum Dis doi:10.1136/annrheumdis-2012-202682

 This article reports an original, first study to perform histological comparison and explore Optical coherence tomography (“OCT”) as a potential imaging technique for the clinical assessment of patients presenting with systemic sclerosis (“SSc”). In their study the investigators used a device emitting low-intensity infrared laser beam, capable of producing high-contrast images of skin up to 2 mm deep with resolutions of 4–10 μm.

[START ORIGINAL PAPER]

ABSTRACT

Background

Skin involvement is of major prognostic value in systemic sclerosis (SSc) and often the primary outcome in clinical trials. Nevertheless, an objective, validated biomarker of skin fibrosis is lacking. Optical coherence tomography (OCT) is an imaging technology providing high-contrast images with 4 μm resolution, comparable with microscopy (‘virtual biopsy’). The present study evaluated OCT to detect and quantify skin fibrosis in SSc.

Methods

We performed 458 OCT scans of hands and forearms on 21 SSc patients and 22 healthy controls. We compared the findings with histology from three skin biopsies and by correlation with clinical assessment of the skin. We calculated the optical density (OD) of the OCT images employing Matlab software and performed statistical analysis of the results, including intraobserver/ interobserver reliability, employing SPSS software.

 Results

Comparison of OCT images with skin histology indicated a progressive loss of visualisation of the dermal–epidermal junction associated with dermal fibrosis. Furthermore, SSc affected skin showed a consistent decrease of OD in the papillary dermis, progressively worse in patients with worse modified Rodnan skin score (p<0.0001). Additionally, clinically unaffected skin was also distinguishable from healthy skin for its specific pattern of OD decrease in the reticular dermis (p<0.001). The technique showed an excellent intraobserver and interobserver reliability (intraclass correlation coefficient >0.8).

Conclusions

OCT of the skin could offer a feasible and reliable quantitative outcome measure in SSc. Studies determining OCT sensitivity to change over time and its role in defining skin vasculopathy may pave the way to defining OCT as a valuable imaging biomarker in SSc.

Virtual skin biopsy by OCT

The OCT images acquisition allowed the reconstruction of a virtual skin biopsy measuring 4×0.4×2 mm. The main structure of the healthy skin was easily recognisable by OCT (figure 1).

Virtual biopsy of forearm skin by optical coherence tomography. Representative 3D reconstruction from the tomography of healthy and systemic sclerosis (SSc) (site modified Rodnan skin score=3) skin scans. The keratin of the skin appears as a white line on the surface (k). The epidermis (ED) is quite visible in the healthy skin by the contrast with the increased optical density of the papillary dermis (PD). The dermal– epidermal junction (DEJ) is quite visible in the healthy skin between the ED and PD. On the contrary, neither clear distinction of ED and PD or DEJ is appreciable in the SSc skin. The vessels (*) are numerous and very well recognisable in healthy skin, whereas they appear less numerous and less distinct in the OCT image of SSc skin. Total depth of 3D reconstruction=1.2 mm. Scale bars are calculated by ImageJ.

Virtual biopsy of forearm skin by optical coherence tomography. Representative 3D reconstruction from the tomography of healthy and systemic sclerosis (SSc) (site modified Rodnan skin score=3) skin scans. The keratin of the skin appears as a white line on the surface (k). The epidermis (ED) is quite visible in the healthy skin by the contrast with the increased optical density of the papillary dermis (PD). The dermal– epidermal junction (DEJ) is quite visible in the healthy skin between the ED and PD. On the contrary, neither clear distinction of ED and PD or DEJ is appreciable in the SSc skin. The vessels (*) are numerous and very well recognisable in healthy skin, whereas they appear less numerous and less distinct in the OCT image of SSc skin. Total depth of 3D reconstruction=1.2 mm. Scale bars are calculated by ImageJ.

Some quantitative results  – in images:

Validation of optical coherence tomography (OCT) images by histology. (A and B) H&E staining (A) and corresponding OCT scan (B) from a healthy control (HC). The green line is the mean A-scan of the entire OCT image (100 scans) overlaid by matching the scale bars of OCT and histology. The green arrow indicates the nadir of the valley in the mean A-scan, which corresponds to the dermal–epidermal junction clearly visible on both images. The green arrowhead indicates the second peak of the mean OCT A-Scan which corresponds by the overlay to the most superficial region of the papillary dermis. (C and D) H&E staining (C) and corresponding OCT scan (D) from a systemic sclerosis (SSc) patient (site modified Rodnan skin score =3). The red line is the mean A-scan of the OCT image, overlaid by matching the scale bars in the two panels. The red arrow indicates the nadir in the valley of the mean A-scan, which in this case does not correspond to the dermal–epidermal junction. The red arrowhead corresponds to the second peak in mean A-Scan. (E) Overlay of HC and SSc. Scale bar=240 μm.

Validation of optical coherence tomography (OCT) images by histology. (A and B) H&E staining (A) and corresponding OCT scan (B) from a healthy control (HC). The green line is the mean A-scan of the entire OCT image (100 scans) overlaid by matching the scale bars of OCT and histology. The green arrow indicates the nadir of the valley in the mean A-scan, which corresponds to the dermal–epidermal junction clearly visible on both images. The green arrowhead indicates the second peak of the mean OCT A-Scan which corresponds by the overlay to the most superficial region of the papillary dermis. (C and D) H&E staining (C) and corresponding OCT scan (D) from a systemic sclerosis (SSc) patient (site modified Rodnan skin score =3). The red line is the mean A-scan of the OCT image, overlaid by matching the scale bars in the two panels. The red arrow indicates the nadir in the valley of the mean A-scan, which in this case does not correspond to the dermal–epidermal junction. The red arrowhead corresponds to the second peak in mean A-Scan. (E) Overlay of HC and SSc. Scale bar=240 μm.

Optical coherence tomography (OCT) of affected and not affected skin in plaque morphea. (A) OCT of not affected skin. Vertical scale represents depth in micrometre from the surface. The dermal–epidermal junction (DEJ) level is indicated by the white dotted line. Mean A-scan curve is overlaid and displayed in green. (B) OCT of affected skin in morphea patient. Mean A-scan curve is overlaid and displayed in red. Note the poorly visible DEJ and the valley of the curve below the DEJ (arrowhead). (C) Overlay of mean A-scan curves from the analysis of affected and unaffected skin in a morphea patient. Note that in the curves overlay graph both the difference depth of the first valley is clearly appreciable (arrowheads). Similarly the second mean A-scan peak (arrow) is subtle in the affected skin, similar to scleroderma affected skin.

Optical coherence tomography (OCT) of affected and not affected skin in plaque morphea. (A) OCT of not affected skin. Vertical scale represents depth in micrometre from the surface. The dermal–epidermal junction (DEJ) level is indicated by the white dotted line. Mean A-scan curve is overlaid and displayed in green. (B) OCT of affected skin in morphea patient. Mean A-scan curve is overlaid and displayed in red. Note the poorly visible DEJ and the valley of the curve below the DEJ (arrowhead). (C) Overlay of mean A-scan curves from the analysis of affected and unaffected skin in a morphea patient. Note that in the curves overlay graph both the difference depth of the first valley is clearly appreciable (arrowheads). Similarly the second mean A-scan peak (arrow) is subtle in the affected skin, similar to scleroderma affected skin.

DISCUSSION

The current gold standard for semiquantitative assessment of skin fibrosis, the mRSS, suffers from several shortcomings ranging from the subjectivity of skin palpation assessments and the high level of skill required from the clinical investigator. Even more importantly, a meta-analysis of three independent studies determined an overall within patient interobserver SD of five units independently of the mean skin score,[6 21] which represents an SE ranging from 20% to 26%. A primary outcome measure with 25% of SE entails the recruitment of a large number of patients to attain statistical validity in minimally significant changes, a task often difficult to accomplish given the comparatively low incidence of SSc.

A robust imaging biomarker for the assessment of skin fibrosis in SSc has not previously been reported. Herein we report the first study aimed to validate OCT for the quantitative assessment of skin involvement in SSc.

To date, the limited data on surrogate outcome measures for skin involvement are largely composed of histopathological or molecular changes in affected skin.[22 23] Despite conceptually very valuable, these studies, involving skin biopsies, are invasive and limited because of a site bias, referring to only one precise body area. Moreover, they are difficult to repeat in longitudinal manner and showed no sensitivity to change over time.[24] In this study, we evaluated OCT skin scanning as a reliable and quanti­tative tool that could be used as a surrogate marker of skin fibrosis. The technique requires minimal operator training, less than 10s per site examined, and offers the great advantage of saving image files for further or centralised operator independ­ent analysis. This latter is a particularly useful tool limiting the ‘hands on’ time in the clinic office and allowing a centralised, blinded assessment of results in clinical trials.

We observed an excellent correlation of OCT mean A-Scan curves and mRSS score at the site of analysis. More importantly, the corroboration of our OCT findings with pathological changes at the DEJ provides a robust construct validity for the technique. Of interest, we found that the changes of the OD of the dermis in SSc are similar to the ones observed in a case of plaque morphea, corroborating even further the potential value of OCT in measuring skin fibrosis.

Additional Comment

HFUS (High Frequensy Ultrasound) has been recently suggested to offer a quantitative assessment of skin thickness in SSc by several studies.8–10 In contrast with ultrasound, OCT does not require any use of gels, is able to give a higher resolution images and the analysis algo­rithm is automatic, not involving any operator interpretation. Nevertheless, since the penetration of OCT is limited to the first millimetre of skin, OCT and HFUS may be explored as comple­mentary imaging biomarkers in SSc.

REFERENCES

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correlate of outcome in systemic sclerosis: high-dose versus low-dose penicillamine trial. Arthritis Rheum 2000;43:2445–54.

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associated with improved survival. Arthritis Rheum 2001;44:2828–35.

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Clements PJ, Lachenbruch PA, Seibold JR, et al. Skin thickness score in systemic

sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 1993;20:1892–6.

   8     Akesson A, Hesselstrand R, Scheja A, et al. Longitudinal development of skin
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   9     Moore TL, Lunt M, McManus B, et al. L. Seventeen-point dermal ultrasound scoring
system—a reliable measure of skin thickness in patients with systemic sclerosis. Rheumatology (Oxford) 2003;42:1559–63.

10     Kaloudi O, Bandinelli F, Filippucci E, et al. High frequency ultrasound

measurement of digital dermal thickness in systemic sclerosis. Ann Rheum Dis 2010;69:1140–3.

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22     Farina G, Lafyatis D, Lemaire R, et al. A four-gene biomarker predicts skin disease
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diffuse cutaneou

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