Gerald W. Keister

Complementary methods have helped physicians at M. D. Anderson Cancer Center in Texas improve the success rate of surgical treatments for ectopic parathyroid adenoma. Presurgical SPECT/CT combined with an intraoperative assay for parathyroid hormone is credited with a 97% success rate for the surgical excision of the neoplasms and the near-elimination of failed parathyroidectomy and follow-up surgery.

Dual-phase Tc-99m sestamibi (MIBI) SPECT/CT localizes the adenomas, said Dr. Rodolfo Nunez, an assistant professor of nuclear medicine. Nunez and colleagues adopted an imaging strategy developed by Dr. Raymond Taillefer, a nuclear physician at the Centre Hospital of the University of Montreal in Quebec, Canada, that is based on the differential wash-out of sestamibi from normal thyroid and abnormal parathyroid tissue.

The rate of wash-out from abnormal parathyroid tissue, such as parathyroid adenoma, is much slower than that from normal thyroid tissue, Nunez said. In nearly all cases, sestamibi uptake can still be observed in diseased parathyroid tissue in delayed imaging obtained 90 minutes after tracer administration. The agent will have completely cleared from normal tissue by then.

Technetium-based sestamibi imaging is more than 90% sensitive for localizing parathyroid adenomas in patients with primary hyperparathyroidism, Nunez said. Sensitivity has risen even higher with the adoption SPECT/CT fusion imaging, which more reliably visualizes easy-to-miss ectopic sites in the retroesophageal space and mediastinum.

Ectopic parathyroid glands are a fluke of human embryonic development affecting about one in five U.S. residents. Instead of migrating to a normal position adjacent to the thyroid gland, ectopic parathyroid glands usually settle at the base of the tongue, but their resting place can be anywhere along the path of the initial descent of the thyroid.

Primary hyperparathyroidism (HPT) is characterized by excessive secretion of parathyroid hormone (PTH), leading to excess calcium or low phosphate concentrations in the blood. Parathyroid adenomas cause more than 80% of HPT cases.

A typical Tc-99m MIBI SPECT/CT exam to localize parathyroid adenoma involves early and delayed imaging of the neck and upper thorax and/or mediastinum after an intravenous injection of 20 to 25 mCi of Tc-99m sestamibi. Early imaging is performed about 15 to 20 minutes after the injection. The patient returns to the scanner for delayed imaging completed from 1.5 to two hours after injecting the tracer, depending on the nuclear medicine physician's preference. The SPECT/CT scan is performed between these two planar studies.

"SPECT/CT allows surgeons to plan their surgical approach to the adenoma meticulously," said Dr. Partha Ghosh, clinical marketing manager for molecular imaging at Siemens Medical Solutions. "It also assures that the patient spends less time in surgery because the surgeon knows exactly where to look."

Accurate localization of the relative positions of ectopic parathyroid adenomas and immediately adjacent anatomic structures is crucial to planning minimally invasive surgery, Nunez said.

"Surgeons are now making very small incisions, some as short as one inch in length, so they really appreciate the benefit of SPECT/CT to tell them precisely where the ecotopic adenomas are located," he said.

PTH concentration levels measured from blood samples drawn before surgery and five, 10, and 15 minutes after resection produce a quantifiable measure of surgical success. Surgery is deemed successful when the PTH value of the immunoassay performed 10 minutes after adenoma resection is at least 50% lower than baseline PTH level observed before surgery, Ghosh said.

Smaller changes in PTH level suggest the presence of a second ectopic gland, Ghosh said.

"But when you see a sharp drop in PTH after resection, you're sure the surgery is complete, and the patient will not have a recurrence," he said.

Articles

Complementary methods have helped physicians at M. D. Anderson Cancer Center in Texas improve the success rate of surgical treatments for ectopic parathyroid adenoma.

SPECT/CT plus assay boosts surgical success

Time is not on the side of molecular imaging researchers who hope to expand the use of the carbon-11 tracer into clinical PET practice.

Carbon-11 is popular with MI scientists, but its short 20-minute half-life has raised formidable barriers for its adoption outside of academic healthcare. Most community-based hospitals cannot afford an onsite cyclotron that is essential for its production and swift delivery to radiology departments for diagnostic use. Due to their small numbers, C-11 advocates have been discouraged from seeking federal regulatory clearance and reimbursement. Their inability to take action has contributed to disincentives for clinical use of C-11.

The migration of molecular probes from bench to bedside would be swifter and cheaper if C-11 were as easily accessible as fluorine-18, which can be produced and distributed from regional radiopharmacies because of its six-hour half-life.

Basic scientists often use C-11 because the high-energy positron-emitting isotope is easily bonded to most chemical compounds that show diagnostic or therapeutic promise. It does not alter the structure, reaction time, or mechanisms of action used by biological agents, and it labels molecules without changing their biological specificity, maximizing the probability of successful migration from the laboratory to animal and human testing.

C-11's 20-minute half-life can be advantageous, said Dr. Juri Gelovani, director of experimental diagnostic imaging at M.D. Anderson Cancer Center in Houston. It minimizes radiation exposure and enables repeat measurements without interference from previous studies.

Most F-18-based radiopharmaceuticals were first paired with C-11 in the laboratory. F-18 thymidine, for example, evolved from studies of C-11 thymidine that demonstrated its ability to measure cell proliferation.

Other investigational agents include C-11 PIB for Alzheimer's disease, C-11 methionine for tumor recurrence, C-11 choline for prostate cancer, and C-11 raclopride for neurological disorders. Designing chemical compounds bonding the base molecule of these agents with F-18 can be difficult, expensive, and time-consuming.

Experimental applications of C-11 probes have begun in humans at academic institutions equipped with cyclotrons and could potentially migrate quickly to community-based hospitals that acquire a baby cyclotron or linear accelerator designed to make C-11 generation more affordable. Systems from AccSys Technology, GE Healthcare, and Siemens Medical Solutions cost about $2 million.

But potential purchasers are biding their time because of regulatory and reimbursement problems, according to Ward Digby, director of biomarker product management at Siemens.

"It's a Catch-22, because since these carbon-based radioisotopes are not approved or reimbursable, they are not being used in local hospitals," he said. "Thus, community hospitals have no incentive to invest in a baby cyclotron. There is little interest, therefore, in conducting large, expensive clinical studies to get C-11 tracers approved."

MIO Briefing

Carbon-11 tracer's 20-minute half life makes it too expensive for most community hospitals, but it can minimize radiation exposure and enable repeat measurements without interference from previous studies.

Short half-life handicaps clinical adoption of carbon-11 radioisotope

In the quantitative world of molecular imaging, the standardized uptake value (SUV) looms large as a key measure of tumor aggressiveness and therapeutic response.

An SUV is a simple semiquantitative index of glucose metabolism that measures the concentration and activity of fluorine-18 FDG in a tumor during a PET scan. Data are acquired 45 to 60 minutes after injection and then normalized for the injected dose and the patient's weight and height. The SUV is obtained by locating a region of interest (ROI) over a lesion, then dividing that by the injected dose and the patient's body weight. It is expressed by the formula:

AT = activity in ROI, V = volume of ROI, Kg = patient weight, A = injected activity (injected FDG dose)

Two parameters can be obtained from that formula: the SUVmax, which is the maximum pixel count in the region, or the average pixel count, the SUVaverage.

Several variables go into the SUV that potentially make it less useful. These discourage many radiologists from relying on this calculation. Body composition and habitus are a source of variability because the conventional SUV normalizes for body weight. Fat, however, has a much lower uptake of FDG than do other tissues, meaning the SUV for many tissues shows a strong positive correlation with weight.

Variations in the time from tracer injection to time of PET scanning (uptake period) have an extreme effect on the SUV. Dr. Dominique Delbeke, a professor of radiology at Vanderbilt University, points out that disruptions or delays in the workflow in a radiology department can affect the uptake period and change the SUV by 15% to 20%.

Plasma glucose level at the time of study also has a major effect on the SUV. Because the uptake of FDG by a tumor relates to the amount of glucose in the blood, there will be less FDG if the serum glucose level is higher.

Other factors that can affect the SUV include lesion blurring due to patient motion, FDG dose infiltration, and partial volume effects that depend on scanner resolution.

"Most of us do not use SUVs for our diagnostic clinical PET imaging," said Dr. Edward Coleman, director of nuclear medicine at Duke University. "We use visual interpretation. SUVs are not used much clinically. The one area in which the SUV has been shown to provide a great deal of prognostic information is when it is used at the time of diagnosis of lung nodules in patients who have lung cancer."

Both Delbeke and Coleman stress that SUVs are very valuable in following the effect of therapy on cancer, as an index of response to therapy. But Delbeke opposes use of SUVs in clinical situations because of their technical complexity and the risk of misleading referring physicians.

SUV quantification as an automated feature has been available on PET scanners for the past five to seven years, according to Jonathan Frey, director of product marketing for the molecular imaging division of Siemens Medical Solutions.

SUVs earn cheers for research but jeers for routine clinical use

Technical advances continue to make PET/CT and SPECT/CT suitable as platforms for molecular imaging. Pharmaceutical companies and specialty laboratories are developing and refining new radiopharmaceuticals. Imaging equipment manufacturers are incorporating more powerful and sensitive technology into their equipment and sophisticated reconstruction software is producing clearer images.

"Essentially, the driving force in molecular imaging today is the development of new biomarkers and, most important, radiolabeled tracers," said Jonathan Frey, director of marketing in the molecular imaging division of Siemens Medical Solutions.

Two important trends are influencing radiolabeled tracer development. The first is the development of more sensitive tracers that can target and identify diseases earlier than the current generation of clinical agents. The second is the evolution of more specific tracers that result in less noise and greater conspicuity. Specificity has driven design because in addition to requiring a well-defined image, clinicians also need anatomic information that shows exactly where the observed entity is located in the body.

Quantification assesses changes in the activity of a tumor or other tissue over time, including physiologic changes and response to therapeutic agents. To further explore quantification, Philips Medical Systems is researching compartmental modeling, a technique that takes information from animal studies and determines where a particular agent goes and in what proportion.

"It is necessary to do pharmacokinetic modeling of every agent to determine which critical organs, in addition to the target, may also pick up the therapeutic dose," said Dr. David Rollo, chief medical officer and program manager of nuclear medicine and molecular imaging at Philips. "There won't be a 'one size fits all' like there is currently with chemotherapy."

Probably the biggest limitation in quantification has been attenuation, Frey said. This is compensated by attenuation correction and is best performed with CT. The evolution of hybrid systems, along with CT attenuation techniques, has made quantification a reality for SPECT. Although attenuation correction and quantification have long been available for PET, SPECT has never been quantifiable before.

Technological advances in both detectors and reconstruction software are making PET/CT and SPECT/CT better platforms for molecular imaging. In the SPECT arena, noteworthy advances include solid-state detectors and improvements in the doping material in sodium iodide crystals, Rollo said.

"By improving detector characteristics, energy resolution can be improved, which contributes to better overall spatial resolution," he said.

Just as important are advances in reconstruction software. Philips has developed ASTONISH, a proprietary 3D reconstruction and resolution recovery software. It features advanced reconstruction algorithms for SPECT and planar imaging that improve resolution by modeling collimator characteristics and imaging depth. It also corrects for loss due to scatter and attenuation. Typical measurement capability of a nuclear medicine camera is about 1.2 cm of spatial resolution, Rollo said. With ASTONISH, that spatial resolution drops to 4.4 mm.

Improved detector material and enhanced reconstruction software are also driving enhancements in PET/

CT. PET detectors have traditionally used bismuth germinate oxide (BGO) scintillation crystals, but newer detectors use lutetium oxyorthosilicate doped with cesium (LSO) and gadolinium oxyorthosilicate doped with cesium (GSO).

"LSO has turned out to be the perfect crystal material for PET," Frey said. "It is highly suitable for capturing coincident 511-kev photons, an attribute that has taken the industry by storm. This is clearly the detector of choice and has made a big difference in improved spatial resolution and throughput."

Philips recently introduced the GEMINI TF, the first PET system to use atomic particle time measurements to deliver increased image quality and consistency. The device uses lutetium yttrium orthosilicate (LYSO) scintillator, curved photomultipliers, and Philips' proprietary TruFlight technology.

A major advance in PET/CT scanning is retrospective respiratory gating, a technology that allows physicians to use 4D imaging over time, according to Karthik Kuppusamy, general manager of molecular imaging and radiopharmacy at GE Healthcare. GE's Discovery-STE PET/CT system employs a technology called Dimension, an advanced retrospective gating CT application that analyzes and characterizes the respiration-induced motion of anatomy.

"Dimension is not about diagnosis but about driving the right therapy for the patient," Kuppusamy said.

Gerald W. Keister

Articles

SPECT/CT plus assay boosts surgical success

MIO Briefing

SPECT/CT plus assay boosts surgical success

Short half-life handicaps clinical adoption of carbon-11 radioisotope

MIO Briefing

SUVs earn cheers for research but jeers for routine clinical use

New scanners gear up for molecular imaging