Positron emission tomography

18F-Sodium Fluoride Positron Emission Tomography and Computed Tomography in Acute Aortic Syndrome

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Abstract

Objectives

In a proof-of-concept study, this investigation aimed to establish whether 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) combined with computed tomography (CT) angiography could identify aortic medial disease activity in patients with acute aortic syndrome.

Background

Acute aortic syndrome is associated with aortic medial degeneration. 18F-NaF PET detects microscopic tissue calcification as a marker of disease activity.

Methods

Patients with aortic dissection or intramural hematomas and control subjects underwent 18F-NaF PET and CT angiography of the aorta. Aortic 18F-NaF uptake was measured at the most diseased segment, and the maximum value was corrected for background blood pool activity (maximum tissue-to-background ratio [TBRmax]). Radiotracer uptake was compared with change in aortic size and major adverse aortic events (aortic rupture, aorta-related death, or aortic repair) over 45 ± 13 months.

Results

Aortic 18F-NaF uptake co-localized with histologically defined regions of microcalcification and elastin disruption. Compared with control subjects, patients with acute aortic syndrome had increased 18F-NaF uptake (TBRmax: 1.36 ± 0.39 [n = 20] vs 2.02 ± 0.42 [n = 47] respectively; P < 0.001) with enhanced uptake at the site of intimal disruption (+27.5%; P < 0.001). 18F-NaF uptake in the false lumen was associated with aortic growth (+7.1 mm/year; P = 0.011), and uptake in the outer aortic wall was associated with major adverse aortic events (HR: 8.5; 95% CI: 1.4-50.4; P = 0.019).

Conclusions

In patients with acute aortic syndrome, 18F-NaF uptake was enhanced at sites of disease activity and was associated with aortic growth and clinical events. 18F-NaF PET-CT holds promise as a noninvasive marker of disease severity and future risk in patients with acute aortic syndrome.

Radiotracer Enables Real-time Imaging of Innate Immune Activity

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A new radio-labeled molecule capable of selectively reacting with certain high-energy radicals that are characteristic of innate immune activity may allow a non-invasive approach to monitor inflammation in real time by positron emission tomography (PET) imaging. Researchers at The University of Texas MD Anderson Cancer Center utilized new chemistry techniques to synthesize 4-[18F]Fluoro-1-Naphthol ([18F]4FN) as a novel reporter of myeloperoxidase (MPO) activity – a key enzyme active in the innate immune response. The molecule may be able to pinpoint areas of inflammation in a variety of clinical settings, such as inflammatory diseases, infections and immunotherapy-related side effects. The preclinical study was published in Nature Biotechnology.

“There has been a long-standing interest in imaging inflammation and redox in general, but most current approaches generate high levels of background noise from biological processes that generate lower-energy radicals,” said corresponding author David Piwnica-Worms, MD, PhD, chair of Cancer Systems Imaging. “Our molecule is tuned toward inflammation mediated by high-energy radicals, offering the potential to selectively monitor activation of innate immunity.”

The innate immune response is the body’s first line of defense against invading pathogens. In contrast to the adaptive immune response, innate immunity is nonspecific and acts broadly against infections or foreign agents. Innate immunity is largely driven by myeloid cells, including neutrophils, macrophages and natural killer (NK) cells.

Myeloperoxidase is a highly conserved feature of the innate immune response across myeloid cells. This proinflammatory enzyme is activated by hydrogen peroxide to produce a variety of high-energy radicals that are used to eliminate pathogens.

Co-led by Federica Pisaneschi, PhD, assistant professor, and Seth T. Gammon, PhD, associate professor of Cancer Systems Imaging, the research team focused on MPO activity to develop a redox-tuned reporter specific to innate immune activity. Using newly developed chemistry techniques, the team was able to synthesize [18F]4FN as a labeled molecule to selectively bind nearby proteins and cells when [18F]4FN has been oxidized by MPO plus hydrogen peroxide, but not hydrogen peroxide alone.

The researchers evaluated the potential uses of [18F]4FN as an in vivo PET imaging tool in several laboratory models of inflammation. The molecule was able to successfully highlight inflammation from acute toxic shock, arthritis and contact dermatitis, ailments known to be mediated by activation of innate immunity. In addition, their results suggest [18F]4FN is a more specific and robust reporter of inflammation than other clinically utilized PET imaging agents, such as fluorodeoxyglucose ([18F]FDG).

“We need to verify this PET imaging agent in clinical studies, but it certainly has the potential for broad applications that could benefit patients across all kinds of diseases and clinical scenarios,” Dr. Piwnica-Worms said. “A tool like this could be used to identify multi-focal hotspots of inflammation, allowing physicians to intervene before disease progression or to follow the resolution of symptoms during therapy.”

The research team is in discussions with clinical collaborators to test specific applications of [18F]4FN. An initial study, now under Food and Drug Administration review for Investigational New Drug registration and Institutional Review Board approval, will evaluate [18F]4FN as an early biomarker of immune-related adverse events in patients being treated with immune checkpoint inhibitors.

Molecular Imaging Flags Risk of AAA Rupture

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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.”

Serotonin Synthesis and Reuptake in Social Anxiety Disorder: A Positron Emission Tomography Study

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Importance  Serotonin is involved in negative affect, but whether anxiety syndromes, such as social anxiety disorder (SAD), are characterized by an overactive or underactive serotonin system has not been established. Serotonin 1A autoreceptors, which inhibit serotonin synthesis and release, are downregulated in SAD, and serotonin transporter availability might be increased; however, presynaptic serotonin activity has not been evaluated extensively.

Objective  To examine the serotonin synthesis rate and serotonin transporter availability in patients with SAD and healthy control individuals using positron emission tomography (PET) with the radioligands 5-hydroxytryptophan labeled with carbon 11 ([11C]5-HTP) and 11C-labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile [11C]DASB.

Design, Setting, and Participants  We performed a cross-sectional study at an academic clinical research center. Eighteen patients with SAD (9 men and 9 women; mean [SD] age, 32.6 [8.2] years) and 18 sex- and age-matched healthy controls (9 men and 9 women; mean [SD] age, 34.7 [9.2] years) underwent [11C]5-HTP PET imaging. We acquired [11C]DASB PET images for 26 additional patients with SAD (14 men and 12 women; mean [SD] age, 35.2 [10.7] years) and the same 18 sex- and age-matched healthy controls. Participants were recruited through newspaper advertisements. Data were acquired from March 12, 2002, through March 5, 2012, and analyzed from March 28, 2013, through August 29, 2014.

Main Outcomes and Measures  The influx rate of [11C]5-HTP as a measure of serotonin synthesis rate capacity and [11C]DASB binding potential as an index of serotonin transporter availability were acquired during rest. We used the Liebowitz Social Anxiety Scale to measure severity of social anxiety symptoms.

Results  The PET data were not available for analysis in 1 control for each scan. Increased [11C]5-HTP influx rate was observed in the amygdala, raphe nuclei region, caudate nucleus, putamen, hippocampus, and anterior cingulate cortex of patients with SAD compared with healthy controls (P < .05 corrected), supporting an enhanced serotonin synthesis rate. Increased serotonin transporter availability in the patients with SAD relative to healthy controls was reflected by elevated [11C]DASB binding potential in the raphe nuclei region, caudate nucleus, putamen, thalamus, and insula cortex (P < .05 corrected).

Conclusions and Relevance  Neurotransmission in SAD is characterized by an overactive presynaptic serotonin system, with increased serotonin synthesis and transporter availability. Our findings could provide important new insights into the etiology of anxiety disorders.

Scan predicts heart attack risk

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A new way of scanning the heart can identify those who may be at high risk of a heart attack, early tests suggest.

It can identify dangerous plaques in the arteries which nourish the heart. If a fatty plaque ruptures, it can lead to a clot, blocking the flow of blood.

Scientists at the University of Edinburgh said an effective tool for predicting a heart attack would make a “massive difference” to patients.

Experts said it was an exciting start.

More than 100,000 people have a heart attack in the UK each year and disease of the arteries around the heart is the leading cause of death in the world.

Light up

The researchers used a radioactive tracer which can seek out active and dangerous plaques. This was combined with high resolution images of the heart and blood vessels.

The overall effect is a detailed picture of the heart with the danger zones clearly highlighted. The technology is already used to detect tumours in cancer patients.

The first tests of the technique for danger spots in the heart were on 40 patients who had recently had a heart attack.

The scan highlighted the plaque which caused the heart attack in 37 of the patients according to a study published in the Lancet medical journal.

It is the first time a scan has been able to identify danger zones but further tests are needed to see if detecting dangerous plaques before, rather than after, a heart attack has the potential to save lives.

“I suspect not all plaques detected will cause a heart attack, but it could be useful for identifying high risk patients who need aggressive therapy,” cardiologist Dr Marc Dweck told the BBC.

This could include drugs such as statins or aspirin, drastic lifestyle change or even inserting stents into the arteries to keep them open.

Scan
The scan shows a cross-section of the heart and the high risk plaque in orange

‘Massive difference’

The researchers will look at high risk patients, including those about to have surgery, to see if the scan can save lives.

Dr Dweck said if this scan or similar ones proved successful it would make a “massive difference”.

He said: “Heart attacks are the biggest killer in the Western world and there is no prior warning, the first time people know about heart disease is when they have a heart attack.

“If we can treat and stabilise the plaques then we might be able to prevent heart attacks and stop people dying.”

Prof Peter Weissberg, the medical director of the British Heart Foundation, said: “Being able to identify dangerous fatty plaques likely to cause a heart attack is something that conventional heart tests can’t do.

“This research suggests that PET-CT scanning may provide an answer – identifying ‘ticking time bomb’ patients at risk of a heart attack.

“We now need to confirm these findings, and then understand how best to use new tests like this in the clinic to benefit heart patients.”

Prof Andrew Morris, the chief scientist for health in Scotland, said: “These are exciting data – being able to prospectively identify patients at the highest risk of a heart attack and provide treatment to prevent this would be a significant step forward.”

FDA Approves Second Brain Amyloid Imaging Tracer

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The US Food and Drug Administration (FDA) today announced approved of flutemetamol F18 injection (Vizamyl, GE Healthcare), a radioactive diagnostic tracer for use with positron emission tomography (PET) of the brain in adults being evaluated for Alzheimer’s disease (AD) and dementia.

This is the second brain imaging drug to get FDA approval. The first, florbetapir F18 injection (Amyvid, Eli Lilly and Company), was approved last year.

Both drugs are radioactive diagnostic agents that are injected into the bloodstream, where they cross the blood-brain barrier and selectively bind to amyloid plaques. A positive scan does not establish a diagnosis of AD or other dementia. However, a negative scan means that there is little or no β-amyloid accumulation in the brain and that the cause of the dementia is probably not due to AD.

“Many Americans are evaluated every year to determine the cause of diminishing neurologic functions, such as memory and judgment, that raise the possibility of Alzheimer’s disease,” said Shaw Chen, MD, deputy director, Office of Drug Evaluation IV, FDA Center for Drug Evaluation and Research, in an FDA press release announcing the new approval. “Imaging drugs like Vizamyl provide physicians with important tools to help evaluate patients for AD and dementia.” 

According to the FDA statement, flutemetamol’s effectiveness was established in 2 clinical studies that included 384 participants with a range of cognitive function who were injected with the tracer and then scanned. The images were interpreted by 5 independent readers masked to all clinical information. Some scan results were also confirmed by autopsy.

The study results demonstrate that flutemetamol correctly detects β-amyloid in the brain, the FDA statement notes. The results also confirm that the scans are reproducible and that trained readers can accurately interpret them. Flutemetamol’s safety was established in a total of 761 participants.

This agent is not indicated to predict the development of AD or to monitor how patients respond to treatment, the FDA notes. PET images using this agent should be interpreted only by healthcare professionals who successfully complete training in an image interpretation program. Drug labeling includes information on image interpretation.

Safety risks associated with flutemetamol include hypersensitivity reactions and the risks associated with image misinterpretation and radiation exposure. Common adverse effects include flushing, headache, increased blood pressure, nausea, and dizziness.

Last year, Eli Lilly requested that the Centers for Medicare & Medicaid Services (CMS) provide coverage for the use of PET amyloid imaging as a diagnostic test to estimate amyloid neuritic plaque density in adults with documented cognitive impairment who are being evaluated for AD.

Florbetapir Approved: Now How Do We Use It?

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April 19, 2012 — Florbetapir (Amyvid, Eli Lilly/Avid Radiopharmaceuticals), a new agent to detect beta-amyloid plaques in living patients with possible Alzheimer’s disease (AD), has just been approved by the US Food and Drug Administration (FDA). The question now is how this imaging option will be used in practice.

Although they are for the most part enthusiastically awaiting access to this new agent, expected to be available by June, many neurologists are also striking a cautionary note. Cost, availability, the need for expert interpretation of scans using the florbetapir tracer, and what it really means for a diagnosis of AD are a few of the concerns being raised.

Medscape Medical News polled experts in the field of AD to see how they view the approval and how they see this diagnostic tool may fit into their clinical practice.

Diagnostic Dilemmas

Florbetapir is a diagnostic agent tagged with a radioisotope, fluorine-18. Used with positron emission tomography (PET), it binds to amyloid plaques in the brain. Approved by the FDA on April 9, florbetapir is 1 of 3 imaging agents in various stages of development; others are florbetaben (Bayer/Piramal Imaging SA) and flutemetamol (GE Healthcare). All are reported to detect amyloid deposition in the living brain.

 
 

Although the presence of amyloid on the scan doesn’t necessarily mean the patient has AD, a scan showing little amyloid deposition, “is inconsistent with a neuropathological diagnosis,” of AD, a press release from the company at the time of approval notes. The statement added that the safety and effectiveness of florbetapir have not been established for predicting development of dementia or other neurologic conditions, or for monitoring responses to therapies.

Still, the use of florbetapir may clear up some diagnostic dilemmas, said Sandra Black, MD, professor, Department of Medicine, Division of Neurology, University of Toronto, Ontario, Canada. “It might help in situations where you’re not quite sure what’s going on — when you don’t know whether this is aphasia due to AD or a frontal temporal dementia-type thing.”

Pedro Rosa-Neto, MD, assistant professor, neurology, neurosurgery and psychiatry, McGill University, Montreal, Quebec, Canada, felt that the new tracer could be informative in the investigation of patients with early onset or atypical presentations of dementia to rule out AD, and in cases of rapidly progressive dementia.

“Rapidly progressive Alzheimer’s disease is a highly neglected condition, frequently misdiagnosed as Creutzfeldt-Jakob disease,” Dr. Rosa-Neto noted. For these selected cases, he sees PET using florbetapir adding to the information gained from the clinical history, various magnetic resonance imaging (MRI) modalities, including fluid-attenuated inversion recovery and diffusion-weighted imaging, cerebrospinal fluid sampling, and neuropsychological and genetic evaluations.

Although the tracer could be of assistance in patients with dementia in whom it’s unclear whether amyloid is a cause of cognitive deterioration, it would not be as useful an addition in cases where all clinical, cognitive, and imaging findings strongly point to the presence of AD, said Liana Apostolova, MD, Alzheimer’s Disease Research Center, University of California, Los Angeles.

“While the test could be useful to confirm that presumption, dementia specialists can already diagnose AD under these circumstances with high sensitivity,” she said. “This is when I might say, ‘I’m pretty certain what’s going on at this point; I don’t need to subject the patient to this expensive diagnostic procedure.”

Role in Mild Cognitive Impairment?

Some clinicians agreed that there is a place for the new biomarker in patients with mild cognitive impairment (MCI). Ronald Petersen, MD, PhD, director, Alzheimer’s Disease Research Center, Mayo Clinic, Rochester, Minnesota, credited with developing the concept of MCI, said the tracer “will be helpful” to see whether amyloid can explain memory problems experienced by these patients. “It will not make the diagnosis, but it will help the clinician sort out the cause of the symptoms.”

Dr. Petersen pointed out that many patients with MCI — perhaps up to 40% — don’t have AD as the underlying cause of their cognitive problems.

For Steven T. DeKosky, MD, vice president and dean, University of Virginia School of Medicine, Charlottesville, the new biomarker “seems like a reasonably accurate detector” of whether MCI is AD in development or whether it relates to some other cause.

Other physicians said they wanted to avoid using the new tracer in cases of MCI.

“Although I think a positive amyloid imaging study would increase the likelihood that the person will decline, that is not known for certain,” said David Knopman, MD, Department of Neurology, also at Mayo Clinic Rochester, Minnesota. “So, I would definitely not do an amyloid scan routinely.”

Doctors stressed that a positive scan does not necessarily mean an asymptomatic patient will develop AD. “Many cognitively normal elderly will show amyloid deposition in their brains as the disease is believed to have an asymptomatic stage that lasts up to 20 years,” pointed out Dr. Apostolova.

“I don’t think we know enough about the prognostic factors of a positive amyloid scan,” said Adam S. Fleisher MD, director of brain imaging, Banner Alzheimer Institute, Phoenix, Arizona, during a Web-based debate on the role of neuroimaging in the diagnosis of AD earlier this year.

On the other hand, a negative scan may not mean a patient is out of the woods because there could be another explanation for their cognitive problems, such as vascular dementia.

“We will have to be very careful using amyloid imaging and making sure patients understand that a negative scan is not necessarily a cause to celebrate,” said James B. Brewer, MD, PhD, associate professor, radiology and neurosciences, Human Memory Laboratory, University of California at San Diego, who also participated in the Webinar.

Possible other causes of cognitive decline could include stroke, thyroid problems, drug interactions, chronic alcoholism, and vitamin deficiencies. Psychiatric disorders such as depression can masquerade as dementia as well.

The Alzheimer’s Association acknowledged that FDA approval of florbetapir is a “double-edged sword,” although it supports the move.

…the fact that all of the potential uses of this product are not crystal clear tempers our enthusiasm.

In a statement, the Association said that although the approval will expand the clinical and research opportunities for amyloid imaging, “the fact that all of the potential uses of this product are not crystal clear tempers our enthusiasm.” Additional research is needed to clarify the role of florbetapir-PET imaging in Alzheimer’s, it added.

Worried Well

Physicians weighing in agreed that amyloid measurements alone are not enough — that other imaging tests, including MRI, should also be part of the diagnostic equation. Many talked about the “multi-modal use” of this and other emerging amyloid biomarkers.

And, as Dr. Brewer pointed out, the new amyloid tracer does not measure tau, which some experts believe plays a crucial role in AD. Another agent under development by researchers at the University of California, Los Angeles, called FDDNP, images both tau and amyloid on PET.

All doctors also emphasized the importance of patient counseling before ordering an amyloid test.

“You have to have a good understanding of how that’s going to influence discussions with the patient, and your treatment and prognostic decision-making,” said Dr. Fleisher. He added that the test results could be quite anxiety provoking for a patient.

Doctors who spoke to Medscape Medical News also expressed a concern about “direct to patient” advertising and about “worried well” patients asking for this test. Many called for caution about using this new biomarker in cognitively normal patients who are anxious about their amyloid status.

The Alzheimer’s Association, too, warns of “less than scrupulous” imaging operators who make unrealistic promises to such patients about the value of florbetapir imaging. It recommends that the test be accessible only in the context of a complete evaluation of medical/neurologic status and with appropriate expert consultation.

Cost Issues

Cost may be a significant issue in determining whom to scan using this new biomarker, doctors agreed. The price tag for the radioactive compound alone appears to be in the neighborhood of $1600, said Dr. Apostolova.

“Then there will be the added cost of getting the PET scan which in most places will be between $1000 and $1500. So I think we are looking at a cost of about $2500 to $3000 per scan here.”

Because the tracer will be costly, “we have to use it with caution and only when it’s really necessary,’ said Dr. Apostolova, “Is it going to tell me anything beyond what I already know?”

As for insurance coverage, Dr. Petersen said that it’s unclear at this time who will pay for this new agent when it becomes available in June. Dr. Knopman commented that that “to start with, no insurer will pay for it.” The agent is also not currently eligible for coverage by the Centers for Medicare and Medicaid Services (CMS) because of its specific policy on reimbursement for PET procedures.

During a press conference after approval of the agent, Stephanie Prodouz, manager of Eli Lilly Bio-Medicines Communications, said that, “Although Amyvid will not be eligible for coverage, it’s important to note that Lilly is working with a broad group of stakeholders to explore and collaborate with CMS to find a new policy for PET coverage.”

Treatment Lacking

Although there is palpable excitement among some neurologists about the diagnostic possibilities of this new tracer, their enthusiasm is also tempered by the lack of available AD treatments.

“From a scientific viewpoint, the development of amyloid imaging was huge [but] the commercial availability is less so, unless it can be tied to finding better therapeutics,” said Dr. Knopman. “Until there are better therapeutics for AD, amyloid imaging does not change the landscape in clinical practice.”

Until there are better therapeutics for AD, amyloid imaging does not change the landscape in clinical practice.

But new treatments are on the horizon, according to Marwan Sabbagh, MD, director, Banner Sun Health Research institute, Sun City, Arizona. “Later this year, you will see 2 large immunotherapy studies — bapineuzumab and solanezumab — reporting their data to the world on their phase 3 trials, so the game changing elements here are perfectly timed in anticipation of these potential disease modifying agents.”

Bapineuzumab and solanezumab are both monoclonal antibodies that bind to and clear beta amyloid. Dr. Sabbagh is an investigator on both trials and serves on the steering committee for the bapineuzumab study.

Still, it’s unclear what role the amyloid plays and whether clearing it will result in any change in cognitive status. However, if safe and effective treatments become available, “that changes the whole ball game,” commented Dr. Brewer.

Dr. Apostolova agreed. “If we can find an agent that can halt the disease progression, before symptoms occur, this [florbetapir] will become the single most useful diagnostic and prognostic test out there,” she added.

For his part, Dr. DeKosky said that if an effective AD drug were available, the amyloid test could be used not necessarily to rule out AD but to determine that the cognitive impairment a patient experiences is indeed AD, so that drug could be administered.

Still, even in the absence of more effective amyloid treatments, many doctors felt that the test could nevertheless be useful. For example, said Dr. Brewer, it provides physicians with an opportunity to educate patients, help them manage risk factors and perhaps get them enrolled in a clinical trial.

As well, said Dr. Apostolova, the test results may spur patients to make necessary work-related arrangements or put their personal affairs in order. “Knowledge is power,” she said.

Clinical Studies

According to Eli Lilly, the information on scans using the new tracer correlates highly with what is seen on autopsy. In a study that used the majority interpretation of 5 readers, there were 96% sensitivity and 100% specificity in patients who underwent scanning within a year of death.

Dr. Black called this autopsy correlation research “elegant.” “It showed that indeed they were really picking up the amyloid” prior to death in these patients, she said.

The clinical studies also showed that the new diagnostic tracer appears to be very safe. The most common adverse reactions reported in these trials were headache (1.8%), musculoskeletal pain (0.8%), fatigue (0.6%), nausea (0.6%), anxiety (0.4%), back pain (0.4%), increased blood pressure (0.4%), claustrophobia (0.4%), feeling cold (0.4%), insomnia (0.4%), and neck pain (0.4%).

The studies are outlined in more detail in the product prescribing information.

But although the new imaging agent is safe and promises to be helpful diagnostically, training of interpreters will be key. Florbetapir was approved only with the proviso that Eli Lilly improve education initiatives for readers of the images. In January 2011, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted 13 to 3 against recommending approval for the tracer, but in a second unofficial vote, the committee voted 16 to 0 in favor of approval if the company would agree to structured training for those reading the scans.

“There was a fear that radiologists would not know how to interpret the scans, as well as a concern about what would be an appropriate use of this agent,” said Dr. Black.

After working with the FDA and nuclear medicine experts, Eli Lilly developed both an online and an in-person training program for physicians. According to the company, images should be interpreted only by readers who have successfully completed a training course. The company cautions that errors may occur in the estimation of plaque density during image interpretation.

“This is a new kid on the block; it’s a new technique” that requires training, commented Dr. Apostolova, who carries out imaging research. “It’s not the case that one day, all of a sudden, one’s brain’s tissue becomes full of amyloid. It’s a slow protracted continuous build up.”

Patients will fall on a continuum, with some having minimal amyloid binding and others moderate or severe amounts, she added. “The last ones would be the easiest to call, but there will be many intermediate cases where we have to decide on a threshold that we will be using to call a scan positive versus calling it negative.”

Not Straightforward

The lack of familiarity in reading scans could pose “a big problem” for clinicians since “it’s not straightforward,” commented Dr. Petersen.

Dr. Knopman agreed, saying he’s “very concerned” about the scan interpretation issues. “I am dubious that radiologists who don’t do a lot of them will misinterpret them,” he said. “Even after nuclear medicine physicians have taken the course provided by Lilly, if they have low instances of contact with the test, they are likely to make mistakes in interpretation.”

He added that he’s particularly worried about the risk for overdiagnosis of Alzheimer’s, especially when the amyloid imaging is not interpreted in light of the clinical history.

“For example, up to 30% of cognitively normal people over age 70 years are expected to have a ‘positive’ scan,” he said. “I’m worried that a normalperson will hear that their amyloid scan shows ‘Alzheimer’s disease’ and will conclude that they have the disease and are at imminent risk of losing their memories. In fact, an abnormal amyloid scan should be interpreted as showing amyloidosis, not Alzheimer’s.”

Dr. Black said her “hunch” is that florbetapir will be more likely to be used in specialty memory clinics that have access to experts who can properly interpret the scans than in general family practices.

Longer Half-Life

One of the advantages of the new agent is its versatility. Florbetapir has a half-life of almost 2 hours, compared to a half-life of 20 minutes for the currently available amyloid imaging agent, carbon 11–labeled Pittsburgh compound B (C-PiB).

The discovery of PiB was truly ground-breaking and set the stage for the current series of amyloid tracers now hitting the market, said Dr. DeKosky, who led the clinical trials of PiB.

“PiB was 7 years ahead of all these others,” he said. “We were able to find a way to non-invasively detect amyloid in living people harmlessly, and then several people found a way to develop different compounds. They are all to be congratulated, but the first one is always the one for which there’s romance,” he says wryly.

But because even florbetapir still loses over half of its radioactivity every 2 hours, it must be distributed in a timely fashion from a radiopharmacy to an imaging center. To address this problem, Siemens PETNET Solutions, a subsidiary of Siemens Medical Solutions USA Inc, announced last week a manufacturing and distribution agreement with Eli Lilly.

Beginning in June, Siemens will supply florbetapir to imaging centers in limited US markets. By the end of the year, the company anticipates having 25 manufacturing centers and co-located radiopharmacies offering the compound.

Dr. Apostolova pointed out that to administer florbetapir, a center must also have a PET scanner. In addition to the manufacturing and distribution of florbetapir, Siemens announced its new Biograph mCT PET/CT (computed tomography) scanner, and related software.

Many neurologists said they have faith that the distribution network used by Lilly/Avid will make the agent widely available to clinicians.

“Now we have PET scanners everywhere, which we didn’t have maybe 7 or 8 years ago,” Dr. Black noted. “And now we have an 18-fluorine compound and there are others that should be emerging soon.”

This widening and promising landscape, she said, “is very exciting.”

 

Early Detection of Recurrent Disease by FDG-PET/CT Leads to Management Changes in Patients With Squamous Cell Cancer of the Head and Neck.

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Abstract

Objective. The objective of this study was to compare the efficacy of surveillance high-resolution computed tomography (HRCT) and physical examination/endoscopy (PE/E) with the efficacy of fluorodeoxyglucose (FDG)-positron emission tomography (PET)/HRCT for the detection of relapse in head and neck squamous cell carcinoma (HNSCC) after primary treatment.

Methods. This is a retrospective analysis of contemporaneously performed FDG-PET/HRCT, neck HRCT, and PE/E in 99 curatively treated patients with HNSCC during post-therapy surveillance to compare performance test characteristics in the detection of early recurrence or second primary cancer.

Results. Relapse occurred in 19 of 99 patients (20%) during a median follow-up of 21 months (range: 9–52 months). Median time to first PET/HRCT was 3.5 months. The median time to radiological recurrence was 6 months (range: 2.3–32 months). FDG-PET/HRCT detected more disease recurrences or second primary cancers and did so earlier than HRCT or PE/E. The sensitivity, specificity, and positive and negative predictive values for detecting locoregional and distant recurrence or second primary cancer were 100%, 87.3%, 56.5%, and 100%, respectively, for PET/HRCT versus 61.5%, 94.9%, 66.7%, and 93.8%, respectively, for HRCT versus 23.1%, 98.7%, 75%, and 88.6%, respectively, for PE/E. In 19 patients with true positive PET/HRCT findings, a significant change in the management of disease occurred, prompting either salvage or systemic therapy. Of the 14 curatively treated patients, 11 were alive with without disease at a median follow-up of 31.5 months.

Conclusion. FDG-PET/HRCT has a high sensitivity in the early detection of relapse or second primary cancer in patients with HNSCC, with significant management implications. Given improvements in therapy and changes in HNSCC biology, appropriate modifications in current post-therapy surveillance may be required to determine effective salvage or definitive therapies.

Source: The Oncologist.

Alzheimer’s brain scan advances

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Pioneering brain imaging that can detect the build-up of destructive proteins linked to Alzheimer’s has been developed by Japanese scientists.

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It could lead to new ways of diagnosing the condition and of testing the effectiveness of new drugs.

The technology, reported in the journal Neuron, can identify inside a living brain clumps of a protein called tau that is closely linked to the disease.

Alzheimer’s Research UK said it was promising work.

Alzheimer’s disease is a problem for researchers trying to come up with a cure. The brain starts to die years before any symptoms are detected, which means drugs are probably given too late.

A diagnosis of Alzheimer’s cannot be made with absolute certainty until a patient has died and their brain is examined. It is also not 100% clear what is the cause of the dementia and what are just symptoms.

One protein, called tau, is very closely linked to the disease, with tangles of tau thought to be one way in which brain cells are killed.

The team, lead by the National Institute of Radiological Sciences in Chiba, used positron emission tomography to build a 3D picture of tau in the brain.

They developed a chemical that could bind to tau and then be detected during a brain scan.

Brain scan Finding tau in the brain

Tests on mice and people with suspected Alzheimer’s showed the technology could detect tau.

Dr Makoto Higuchi, from the National Institute of Radiological Sciences in Japan, said: “Positron emission tomography images of tau accumulation… provide robust information on brain regions developing or at risk for tau-induced neuronal death.”

The research is at an early stage, but it could eventually lead to an actual test for Alzheimer’s disease.

It might also allow researchers to closely follow the impact drugs that affect tau have on the brain.

Another protein – beta amyloid – is also linked to Alzheimer’s and can be detected in similar tests.

Dr Eric Karran, director of research at Alzheimer’s Research UK, said: “This promising early study highlights a potential new method for detecting tau – a key player in both Alzheimer’s and frontotemporal dementia – in the living brain.

“With new drugs in development designed to target tau, scans capable of visualising the protein inside the brain could be important for assessing whether treatments in clinical trials are hitting their target.

“If this method is shown to be effective, such a scan could also be a useful aid for providing people with an accurate diagnosis, as well as for monitoring disease progression.”

Physician Gave Chemo to Patients Without Cancer..

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Hematologist-oncologist Farid Fata, MD, in suburban Detroit, Michigan, was arrested August 6 and charged with Medicare fraud in a federal case that stands out from dozens of others recently brought against healthcare providers.

For one thing, the dollar amount of alleged fraud — $35 million — is higher than most for individual providers charged by the government. The potential physical harm to patients described by prosecutors also is far more substantial. In a criminal complaint filed in a federal district court in Detroit, prosecutors said that the 48-year-old Dr. Fata ordered toxic chemotherapy for patients who did not have cancer or whose cancer was in remission. Doing this “is simply poisoning the patient,” prosecutors said in a later court filing.

And something else happened in Dr. Fata’s case that is unusual: Rather than keeping their heads down, some employees at Dr. Fata’s high-profile practice challenged his actions before he was arrested, according to the government.

One employed oncologist, for example, told agents from the FBI and the Department of Health and Human Services that he discovered that Dr. Fata had ordered chemotherapy for a patient whose cancer was in remission. The oncologist said he advised the patient to get a second opinion and not return to Dr. Fata’s practice.

This oncologist and other employees also reported that Dr. Fata ordered intravenous immunoglobulin (IVIG) for patients whose antibody levels did not warrant the therapy. One nurse practitioner (NP) told federal agents that she pulled the charts for 40 patients scheduled for IVIG therapy and saw that 38 had neither low antibody levels nor a recurrent infection, which is another indication for the treatment. The NP consulted 2 other employees about the issue, and the 3 of them canceled the IVIG therapy for the 38 patients.

Dr. Fata’s employees had internally challenged other practices they considered unethical, such as fabricating cancer diagnoses in patient records to justify insurance claims for chemotherapy and positron emission tomography (PET) scans, according to interviews conducted by federal agents. Some employees quit over these issues. The employed oncologist, who had considered quitting, described working with Dr. Fata as “living with this hell.”

Dr. Fata has not yet had his day in court to refute these charges. “He vehemently denies all the allegations,” said Christopher Andreoff, the physician’s attorney, in an interview with Medscape Medical News.

Andreoff faulted federal prosecutors for failing to review patient files “to determine the propriety of diagnoses and subsequent treatment.” He also said that the federal charges do not identify the current and former employees of Dr. Fata cited in the criminal complaint. They may be “disgruntled,” he said.

“People shouldn’t race to make a judgment,” said Andreoff. “There’s still the presumption of innocence.”

On Thursday, US Magistrate Judge David Grand ruled that Dr. Fata could get out of jail once he posted a $170,000 bond. Prosecutors appealed the judge’s decision but lost, according to newspaper accounts of yesterday’s court proceedings. Grand said that Dr. Fata must not practice medicine or bill anyone for the time being as conditions of his release.

Federal prosecutors wanted Dr. Fata behind bars while he awaits trial. They argued in a court filing that he poses a flight risk and possesses the means to return to his native Lebanon because the taxable estate for him and his wife exceeds $40 million. Although the government has begun to seize some of his assets, others are at Dr. Fata’s disposal, prosecutors said. Andreoff countered that his client is a naturalized American citizen who has traveled only once to Lebanon since 2001.

Prosecutors also emphasized the severity of the charges against Dr. Fata in their arguments to keep him locked up. They said that if convicted, Dr. Fata faces substantial time in prison, especially if unwarranted chemotherapy has injured or killed any patients. They noted that some of his patients already have complained to a local newspaper that they suffered mistreatment. The Oakland Press quoted the father of one deceased patient as saying that his son had been “tortured” with needless chemotherapy.

An Otherwise Shiny Career

Regardless of whether Dr. Fata is found innocent or guilty, his arrest on August 6 stands in jolting juxtaposition to an otherwise shiny career.

Dr. Fata completed a hematology-oncology fellowship at Memorial Sloan-Kettering Cancer Center in New York City. In 2005, he founded Michigan Hematology Oncology (MHO), which now has 60 employees and 7 locations throughout suburban Detroit. According to the MHO Web site, Dr. Fata’s research has been published in peer-reviewed journals such as Cancer, the Journal of Clinical Oncology, and the Annals of Internal Medicine. A search of medical literature through PubMED unearthed 20 articles in which Dr. Fata is a coauthor and sometimes the lead author. The MHO Web site also states that Dr. Fata often lectures at hospitals in southeast Michigan and functions as principal investigator on cancer protocols funded by the National Institutes of Health.

Dr. Fata also has made a name for himself as the founder of Swan for Life, a nonprofit organization that provides “support, education and resources to cancer patients and their families,” according to the group’s Web site. Swan for Life programs range from support groups and educational workshops for patients to fee-based medical services such as acupuncture and clinical massage. The nonprofit has raised money through fashion shows, a gala ball, and an annual 5k run, the most recent one on August 4.

Dr. Fata was listed as president of the foundation, and his wife Samar Fata as treasurer, on the group’s tax return for 2011, the latest on file with GuideStar, an online database on nonprofits. The tax return put 2011 revenues at $595,904 and expenditures and disbursements at $267,836. Revenue included a $300,675 contribution from a tax-exempt trust called Fata 2011 Grantor Charitable Lead Annuity with the same address as Dr. Fata’s home in Oakland Charter Township, Michigan. Total assets for Swan for Life at the end of 2011 were valued at $950,954.

Head-Injured Patient Had to Receive Chemo Before ED Trip

The criminal complaint filed against Dr. Fata on Tuesday said that his practice, MHO, billed Medicare $35 million over the course of 2 years. Of that amount, roughly $25 million was billed specifically by Dr. Fata. Almost all of that $25 million was for drug infusions, the highest amount billed for those services by any hematologist-oncologist in Michigan.

It is not clear how long federal authorities have scrutinized Dr. Fata. One court document filed by prosecutors called the investigation “very brief.” The complaint suggests that the government has moved with extreme urgency. The allegations against Dr. Fata come from 8 current or former employees, all of whom were interviewed earlier this month. Only 7 such individuals, all unnamed, are mentioned in the complaint, however. Of these, 6 were interviewed the day before Dr. Fata was arrested as federal agents raided his home and office.

“Our first priority is patient care,” said US District Attorney Barbara McQuade in a news release. “The agents and attorneys acted with a great attention to detail to stop these allegedly dangerous practices as quickly as possible.”

Many of the allegations center on Dr. Fata’s use of chemotherapy, and in particular, administering it to patients who did not need it. One NP told federal agents that “Dr. Fata falsified cancer diagnoses to justify cancer treatment” and that blood cancers were easier to falsify than tumors because physicians have more discretion to interpret blood tests. This NP and other employees also said that patients whose cancer was in remission were put on “maintenance” doses of chemotherapy. A medical assistant quoted Dr. Fata as telling patients that once they had chemotherapy, “they had to have it for the rest of their lives.”

Dr. Fata also ordered chemotherapy for all patients with advanced cancer who would not benefit from it, according to the employed oncologist interviewed by federal agents. “No other physician would do this and would let the patients die in peace,” the complaint quotes the oncologist as saying. In April 2012, the American Society of Clinical Oncology said that administering chemotherapy to patients with advanced cancer who would not benefit from it is 1 of 5 practices that oncologists must abandon.

The current and former employees paint a picture of a physician who was obsessed with administering chemotherapy, no matter the circumstances. “A male patient fell down and hit his head when he came to MHO,” the complaint alleged. “Dr. Fata directed [an NP] that he must receive his chemotherapy before he could be taken to the emergency room.” Dr. Fata’s order was carried out. The man eventually died from the head injury.

In another alleged incident, a patient with extremely low and potentially fatal levels of sodium was given chemotherapy before he could go the emergency department, as ordered by Dr. Fata.

Doses of chemotherapy were excessive as well, according to the employed oncologist at MHO. For example, Dr. Fata would order 56 doses of rituximab (Rituxan, Genentech) over the course of 2 years for a patient with non-Hodgkin’s lymphoma compared with 12 doses that a “normal oncologist” might order.

Dr. Fata Owned Firm That Did PET Scans, Complaint Says

Current and former employees of Dr. Fata describe other practice patterns that are hallmarks of Medicare fraud cases:

  • Unusually high patient volume: One employee said Dr. Fata saw 30 to 60 patients per day. Three other employees put the count at 50 to 70. Several said that Dr. Fata could sustain this pace because he used unlicensed foreign physicians to conduct examinations that typically lasted several hours. Then Dr. Fata would pop in at the end.
  • Upcoding: One NP told federal agents that Dr. Fata “bills every patient at the highest possible code, even though he only spends 3 to 5 minutes with them.”
  • Interlocking services: The criminal complaint states that Dr. Fata incorporated a company called United Diagnostics in November 2012. According to a business office employee interviewed by federal agents, all the PET scans ordered by Dr. Fata were performed at United Diagnostics. Another employee said that the percentage of Dr. Fata’s patients who received PET scans increased from 30% to 70% once United Diagnostics opened for business. Likewise, Dr. Fata started a pharmacy in 2012, and he instructed MHO employees to make it their sole source for oral chemotherapy drugs.

In addition, the complaint alleges problems that could be classified as simply careless medicine.

  • Dr. Fata performed bone marrow biopsies assisted by medical assistants who were not wearing gloves.
  • Patients sometimes received the wrong medicine, or medicines out of sequence, because of poor record-keeping.
  • At one time, patients received chemotherapy without a physician present.

Source: http://www.medscape.com