Molecular Imaging Flags Risk of AAA Rupture

Uptake of 18F-sodium fluoride (18F-NaF) can point to active vascular calcification associated with high-risk atherosclerotic plaque and may be a marker of high-risk abdominal aortic aneurysms (AAAs), according to a molecular imaging study.

Uptake of the biomarker on positron emission tomography (PET) and CT was significantly higher in the AAA (aortic diameter exceeding 40 mm) than in nonaneurysmal regions of the same aorta in the 20 patients studied. It was also significantly higher than in aortas of 20 controls in the prospective SoFIA3 study from researchers led by Rachael Forsythe, MD, of University of Edinburgh.

In a 72-person longitudinal cohort, the highest tertile of 18F-NaF uptake had aneurysms expand 3.10 mm per year versus 1.24 mm annually for the lowest tertile (P=0.008). The highest tertile also had triple the risk of AAA repair or rupture (15.3% versus 5.6%, log-rank P=0.043).

In this group with a baseline aneurysm diameter of 48.8 mm, 26.4% had their aneurysm repaired and 4.2% had a rupture and died without repair over 1.5 years of follow-up, Forsythe’s group reported in the Feb. 6 issue of the Journal of the American College of Cardiology.

“Fluorine-18-NaF PET-CT is a novel and promising approach to the identification of disease activity in patients with AAA and is an additive predictor of aneurysm growth and future clinical events,” the SoFIA3study authors concluded from their single-center, proof-of-concept study.

“This is the first study to demonstrate that an imaging biomarker of disease activity can add to the risk prediction of AAA and to suggest that this approach might refine clinical decisions regarding the need for surgery and improve patient outcomes,” they said. “We suggest that 18F-NaF uptake again relates to microcalcification and is particular to the most diseased areas associated with tissue disruption and loss of integrity.”

“Importantly, areas of fluoride uptake did not correspond to regions of macrocalcification on CT, suggesting the importance of dynamic calcification process,” noted an accompanying editorial.

In that commentary, Parmanand Singh, MD, of Weill Cornell Medical College, and Jagat Narula, MD, PhD, of Icahn School of Medicine at Mount Sinai, both in New York City, emphasized that “earlier detection of high-risk aneurysms is important to render appropriate care to the highest risk patients.”

“Despite significant advances in aortic imaging, pharmacotherapy and surgical interventions over the past decade, patients with AAA complications continue to have high rates of mortality,” they wrote. “The identification of aortic features linked to aortic vulnerability is crucial, both in guiding selection of patients for preemptive surgical repair and for optimizing timing of intervention to prevent complications. Noninvasive molecular imaging holds promise to identify markers of aortic instability earlier in the course of disease progression, and could offer a major advance in the diagnosis, surveillance and management of AAA.”

Radiologists Did Most Stroke Thrombectomy In Early Days

But most had neurointerventional training in Medicare data up to mid-2015

As clinical trial evidence turned the corner for mechanical thrombectomy in 2015, what few procedures were done remained solidly the province of radiologists, a study of Medicare data showed.

Looking at a nationally representative 5% sample of Medicare beneficiaries between January 1, 2009, and September 30, 2015, only 555 thrombectomy procedures for acute ischemic stroke were done among nearly 78,000 stroke hospitalizations.

While 61.4% of them were done by radiologists, an equally high proportion of operators had dedicated neurointerventional fellowship training (66.1%), albeit of unknown type or quality, Hooman Kamel, MD, Weill Cornell Medical College in New York City, and colleagues reported here at the International Stroke Conference and online in JAMA Neurology.

Neurologists and neurosurgeons roughly split the rest not done by radiologists — 19.8% and 16.4%, respectively — along with a sliver (2.4%) done by an assortment of other physicians.

“Clinician characteristics did not change significantly after December 17, 2014, when the first trial to show a clinical benefit for thrombectomy was published,” the researchers noted in the paper.

Early in 2015, a subsequent series of trials confirmed that, with advanced imaging-selection of patients, mechanical thrombectomy held a significant outcome benefit for large vessel strokes, kicking off a rapid uptake in the procedure.

How the workforce doing these procedures might have changed since the end of the study period isn’t clear.

Kamel’s group pointed to arguments “that a workforce shortage exists that could be filled by non-neuroscience clinicians with expertise in catheter-based procedures. Neurointerventionalists have countered that they are available to most U.S. patients, but vascular neurologists have nevertheless raised concerns about a shortage.”

“I know in my own institution right now, radiologists aren’t doing the procedures,” commented Ralph Sacco, MD, of the University of Miami, and president of the American Academy of Neurology.

“Radiologists are phenomenally good at working with catheters and often they are part of a team,” he told MedPage Today, “but it’s hard to say, and I’ve never seen differential data regarding outcomes by radiologists, a neurologist, or even interventional neurosurgeon.”

A lot of the future landscape may be up to trainees, Sacco noted. “It’s hard to say what the landscape will look like in the future. But our belief is that more neurologists will become interventional neurologists … Obviously, the demand for more people to do interventional procedures is rapidly rising.”

The researchers suggested that their study may help “inform plans for optimizing systems of acute stroke care across the United States.”

Gold-plated nano-bits find, destroy cancer cells.

Carl Batt

Dickson Kirui


Comparable to nano-scale Navy Seals, Cornell scientists have merged tiny gold and iron oxide particles to work as a team, then added antibody guides to steer the team through the bloodstream toward colorectal cancer cells. And in a nanosecond, the alloyed allies then kill the bad guys – cancer cells – with absorbed infrared heat.

This scenario is not science fiction – welcome to a medical reality.

“It’s a simple concept. It’s colloidal chemistry. By themselves, gold and iron-oxide alloys are benign and inert, and the infrared light is low-power heating,” said Carl Batt, Cornell’s Liberty Hyde Bailey Professor of Food Science and the senior author on the paper. “But put these inert alloys together, attach an antibody to guide it to the right target, zap it with infrared light and the cancer cells die. The cells only need to be heated up a few degrees to die.”

Batt and his colleagues – Dickson K. Kirui, Ph.D. ’11, a postdoctoral fellow at Houston Methodist Research Institute and the paper’s first author; Ildar Khalidov, radiology, Weill Cornell Medical College; and Yi Wang, biomedical engineering, Cornell – published their study in Nanomedicine (print edition, July 2013).

For cancer therapy, current hyperthermic techniques – applying heat to the whole body – heat up cancer cells and healthy tissue, alike. Thus, healthy tissue tends to get damaged. This study shows that by using gold nanoparticles, which amplify the low energy heat source efficiently, cancer cells can be targeted better and heat damage to healthy tissues can be mitigated. By adding the magnetic iron oxide particles to the gold, doctors watching MRI and CT scanners can follow along the trail of this nano-sized crew to its target.

When a near-infrared laser is used, the light penetrates deep into the tissue, heating the nanoparticle to about 120 degrees Fahrenheit – an ample temperature to kill many targeted cancer cells. This results in a threefold increase in killing cancer cells and a substantial tumor reduction within 30 days, according to Kirui. “It’s not a complete reduction in the tumor, but doctors can employ other aggressive strategies with success. It also reduces the dosage of highly toxic chemicals and radiation – leading to a better quality of life,” he explained.

Cornell dots show promise in targeting cancer cells during surgery.

The U.S. Food and Drug Administration (FDA) has approved the first clinical trial of a new technology that uses radiolabeled nanoparticles to brighten cancer cells so they can be detected by a PET-optical imaging camera.

Researchers from Memorial Sloan-Kettering Cancer Center (MSKCC) and Cornell University are collaborating with Hybrid Silica Technologies, a Cornell start-up company, and Dutch optical imaging developer O2view on the project and clinical trial.

The FDA’s investigational new drug (IND) approval for the study represents the first inorganic particle platform of its class to be used for multiple clinical indications, according to co-researcher Dr. Michelle Bradbury, a neuroradiologist at MSKCC and assistant professor of radiology at Weill Cornell Medical College.

The trial will explore the applications of cancer targeting and future therapeutic diagnostics, as well as cancer disease staging and tumor burden assessment through lymph node mapping.

Multiple applications

“Cancer has largely been the heavy hitter for nanoparticle probes, and I think there are overlaps with other diseases where institutions could make use of such types of particles,” Bradbury “We are developing the [therapeutic diagnostic] probes and using them for surgical applications, mainly lymph node mapping.”

The so-called “Cornell dots” are silica spheres approximately 6 nm in diameter that enclose several dye molecules. The silica shell, which is essentially glass, is chemically inert and small enough to pass through the body and exit in the urine. For clinical applications, the dots are coated with neutral molecules — polyethylene glycol (PEG) — so the body will not recognize them as foreign substances and activate a patient’s immune system to reject them.

To make the nanoparticles adhere to tumor cells, organic molecules that bind to tumor surfaces or specific locations within tumors can be attached to the PEG shell. When exposed to near-infrared light, the dots become brighter and help identify the targeted cancer cells.

Nanoparticle half-life

Nanoparticles in general can linger in the bloodstream for many hours and even days, depending on their size. Given their 6-nm size, the nanoparticles have a half-life of approximately six hours in the bloodstream before evacuation through the kidneys. “Within a 24-hour period,” Bradbury said, “50% may be cleared through the kidneys.”

Among the researchers’ goals in this trial is to validate the pharmacokinetics and dosimetry of the nanoparticles and PET-optical imaging technology for safe use in humans. Researchers also will collect blood and urine samples to see how different parts of the body, besides organs, react to the nanoparticles.

The study will include five metastatic melanoma patients as its first enrollees. “If all goes well with a few patients, we hope to proceed with a targeted study,” Bradbury said.

Surgical information

The technology, the researchers believe, could be particularly beneficial during surgical treatment, allowing surgeons to see the invasive or metastatic spread to lymph nodes and distant organs and illustrating the extent of treatment response.

Initially, the surgical applications will include cancer within the complex area of the head and neck. With the help of the nanoparticles and PET-optical imaging camera, surgeons will be able to detect the activity of the lymph nodes.

Currently, Bradbury explained, physicians have little or nothing to refer to during surgery other than a preclinical scan — and compared to the scan, the patient is now in a totally different position on the table.

“How would they know where they are in the neck?” she asked. “They just don’t [know], so they want tools so they can see what they are doing and see the nodes in relation to vital structures, such as nerves. They don’t want to pick up activity from a lymph node plus an adjacent tumor, which would be easy to do, if you don’t know where you are exactly.”

Nanoparticles in mice

Researchers have already had some success with the nanoparticles and the PET-optical imaging technology in a preclinical study in mice. Among the conclusions is that the nanoparticles have been “optimized for efficient renal clearance” and “concurrently achieved specific tumor targeting” (Journal of Clinical Investigation, July 2011, Vol. 121:7, pp. 2768-2780).

In addition, the multimodal silica nanoparticles exhibit “what we believe to be a unique combination of structural, optical, and biological properties,” wrote lead study authors Dr. Miriam Benezra and Dr. Oula Penate-Medina and colleagues.

To be clinically successful, the group added, the “next generation of nanoparticle agents should be tumor selective, nontoxic, and exhibit favorable targeting and clearance profiles. Developing probes meeting these criteria is challenging, requiring comprehensive in vivo evaluations.”


Targeted drugs to tackle hepatitis C.

But experts debate US screening recommendations.

John strains to recall the gap between learning that he had hepatitis C and deciding to get treated: it was either four years or five. His thinking is clouded by the combination of three drugs that he is taking to clear the infection. After the treatments’ other side effects set in — severe flu-like symptoms, depression and exhaustion — he took leave from his job as a chef in New York. John, whose name has been changed to protect his privacy, was at high risk of catching the virus, having once been addicted to crystal methamphetamine. But as a 51-year-old, he is also a baby boomer — a member of the generation born between 1945 and 1965 — millions of whom will face the disease and its sometimes harrowing treatment.

Better drugs are on the way. But the possibility of improved treatment is intensifying a debate about whether to screen a broad swathe of the US population for hepatitis C.

Last month, the pharmaceutical company Gilead, based in Foster City, California, submitted its hepatitis-C drug sofosbuvir to the US Food and Drug Administration for approval, after phase II trials showed a 100% success rate in a few patient groups when it was used in combination with existing drugs. Last week, the first phase III results showed similarly promising results (E. Lawitz et al. N. Engl. J. Med.; 2013).

The drug is one of at least ten in phase III trials in the United States that promise to improve results or reduce side effects. The first of these drugs could reach the market as early as 2014, and a recommendation from the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, to screen an entire generation for the disease could create vast demand for them.

John is a part of a demographic time bomb. Up to 4 million Americans are infected with hepatitis C, which can irreparably damage the liver and lead to liver cancer, but because it inflicts injury slowly over decades, as many as 85% of carriers do not know that they have it. Baby boomers account for about 27% of the US population, but up to 75% of those infected with hepatitis C, possibly because injecting drugs — one infection route — was more common during their youth than in other eras. Last August, the CDC recommended screening the entire generation of people born between 1945 and 1965, as well as people in high-risk populations such as intravenous-drug users. The CDC predicts that generational screening would find an extra 800,000 cases and prevent at least 120,000 deaths. “We have an opportunity to make a real dent in the impact of the disease,” says Kimberly Page, an epidemiologist at the University of California, San Francisco.


John’s doctor, infectious-disease specialist Kristen Marks of Weill Cornell Medical College in New York, says that screening is especially important for baby boomers because early symptoms of hepatitis C, such as fatigue and malaise, are difficult to distinguish from signs of ageing. People dismiss symptoms, says Marks, and some might not remember trying intravenous drugs in their youth. Even if they do, she adds, “they might not tell their doctor”. A peak in cases of liver scarring from untreated hepatitis C is expected in the next few years (see ‘An approaching burden’). But with the new drugs on the horizon, now is an optimistic time for treatment, says Marks. “Historically, not having good treatments was a disincentive for screening,” she says. “Now, I think there’s a renewed interest.”

But last November, the US Preventive Services Task Force (USPSTF), a panel of experts assembled by the US Department of Health and Human Services, released a draft statement giving the screening recommendation a ‘grade C’. That means that doctors should consider birth year when deciding whether to offer screening, but should take other factors into account. The mediocre grade could discourage many health-care providers — including Medicaid, the provider for people with low incomes — from pushing screenings.

As with its controversial recommendations in 2009 and 2012 to limit screening for breast and prostrate cancer, the USPSTF has tried to balance the benefits of screening against the risk of unnecessary treatment. The combination therapies used to combat hepatitis C can cost US$1,100 per week and last for up to a year, with severe side effects. Other treatments cost $4,100 per week. (Gilead declined to comment on the future price of sofosbuvir-based treatments.)

“We have an opportunity to make a real dent in the impact of the disease.”

Roger Chou, an internal-medicine specialist at Oregon Health and Science University in Portland and a scientific reviewer for the USPSTF, adds that in most patients, the disease is imperceptible: only 20% of people develop liver scarring in the first 20 years of infection, according to the CDC. Of the few baby boomers that might be caught through additional screening, says Chou, some will not need to be treated.

But new drugs, however expensive, could change the calculus for doctors and patients, says Mark Eckman, a physician at the University of Cincinnati in Ohio, who has calculated that even screening the entire US population would be cost effective given the financial and personal burdens of living with liver diseases (M. H. Eckman et al. Clin. Infect. Dis. 56, 1382–1393; 2013).

For example, sofosbuvir, which is one of a set of new antiviral drugs that specifically target hepatitis C rather than viruses in general, can achieve success rates above 90% in combination treatments of just three months. The drug inhibits the virus’s RNA polymerase, preventing viral replication. It is also being tested without the classic combination drug of pegylated interferon, which boosts the immune system but causes harsh side effects.

The USPSTF is still reviewing its draft recommendations, but it is likely to make a final decision in the next few months, well before approval of sofosbuvir or other new drugs could alter the calculations.

That is too bad, says David Thomas, a viral-hepatitis specialist at Johns Hopkins University in Baltimore, Maryland, who argues that the next generation of drugs helps to justify wide-scale screening. “It makes a pretty easy case for doing something different,” he says.

Source: Nature