Applications of PET in medicine and biomedical studies

Transcription

1 Lecture 21 Applications of PET in medicine and biomedical studies PET imaging is a technique for observing biological processes. Because disease is a biological process, molecular imaging is a sensitive and informative means to study and diagnose disease throughout its progression. In addition, molecular imaging provides biological information for the development and assessment of therapies. Neurology Cardiology Oncology Drug development. 1

2 PET studies of glucose metabolism with FDG to map a human brain s activity in performing different tasks. Images are cross sections with the front of the brain at the top. Highest metabolic rates are in red, with lower values from yellow to blue. Arrows indicate the activated regions. Looking at a visual scene activated the visual cortex; listening to a mystery story with language and music activated the left and right auditory cortices; counting backward from 100 by sevens activated the frontal cortex; remembering a previously learned list of objects activated the hippocampus bilaterally; and touching the thumb to the fingers of the right hand activated the left motor cortex and supplementary motor system. 2

3 MicroPET study of whisker stimulation in rat. Whiskers on the right side of the face were stroked after intravenous injection of FDG. The image shows increased metabolic response (arrow) in areas of cortex receiving inputs from whiskers. 3

4 FDG/PET images showing brain function in a normal subject and in a cocaine addict. The cocaine addict has depressed metabolism in frontal regions when compared to the normal subject. Low frontal metabolism may underlie the loss of control in cocaine addiction. 4

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6 Graph of brain dopamine levels normally, after cocaine use, and after GVG followed by cocaine Graph of brain dopamine levels normally, after nicotine use, and after GVG followed by nicotine 6

7 3-D Images of Cocaine in the Brain These images were made by combining and averaging the brain scans of several dozen people who participated in studies at BNL's PET scanner. They show where cocaine concentrates in the brain (red), from several different vantage points. Top side Front Side Bird s Eye View Animation of cocaine spreading through the brain 7

8 In Neurology, PET plays a vital non-invasive role: (1) Pre-surgical assessment of patients with refractory epilepsy. PET has greatly diminished the need for deep electrode monitoring, with all its attendant morbidity. (2) PET is the only clear non-invasive way to distinguish between tumor recurrence and radiation necrosis in the brain of post surgical patients. (3) Provides the earliest positive diagnosis of Alzheimer's Dementia and in differentiating Alzheimer's Dementia from other forms of dementia. All present treatments of Alzheimer's and probably all future ones will require early detection to be effective. 8

9 Image of Human Brain - Stroke Glucose molecule labeled with Fluorine-18. Intravenous administration Dead areas of brain No glucose metabolism 9

10 Metabolic Function of the Normal and Alzheimer s Brain Top row: images near the top of the brain. Bottom row: images midway down the brain. All images are cross sections through the brain, with the front of the brain at the top side of the images. Metabolic function is represented by color, with red the highest. Arrows point to the metabolic dysfunction of Alzheimer s disease. 10

11 Myocardial Viability (PET) Increased uptake at inferolateral wall indicating hibernating, metabolically active myocardium which is still amenable to cardiovascular revasculartization (with stenting or surgical bypass) 11

12 PATIENT 1: These PET scans reveal that both blood flow and metabolism are absent in a large area of the heart. The absence of metabolism indicates that the tissue Blood flow Metabolism is dead, so a cardiac transplantation would be the treatment of choice. Patient 1 transplant PATIENT 2: These PET scans reveal that blood flow is markedly Patient 1I bypass reduced in a large area of the heart, but metabolism is maintained. Because metabolism indicates that the tissue is still alive, cardiac transplantation is not necessary for this patient. However, bypass surgery would improve the function of the heart. 12

13 Five 5-mm-thick longitudinal section images from a whole-body PET scan with FDG of a woman with breast cancer. The whole-body images are used to examine all organ systems for primary and metastatic tumors (arrows). 13

14 Patient with ovarian carcinoma and metastates to retroperitoneum and right iliac lymph nodes, which resulted in right sided kidney obstruction. 14

15 + = Target imaged with short half-life PET probe Different target imaged with short half-life PET probe Combo image from superimposing previous scans 15

16 Image of the chest and abdomen reveals a solitary focus of cancer within the liver. PET is effectively able to exclude that cancer has spread elsewhere in the body. PET Scan showing diffuse spread of prostate cancer to bone. PET has the advantage over traditional bone scanning in its ability to differentiate active from dormant disease. 16

17 Comparison of a digital X-ray mammogram (left) with a positron emission mammography image (right) of an infiltrating carcinoma visualized in a dense breast. (Courtesy of Lee P Adler, Fox Chase Cancer Center,Philadelphia.) 17

18 Computer fused CT CT && PET PET Image fusion n readily localized tumor tumor location in in the the spleen (arrow) in in this this patient with lymphoma (green arrowheads indicate normal physiologic activity in the bowel and kidney). [CT data above left, PET data above right. Image fusion below.] CC 19 18

19 Monitoring Radio/chemotherapy FDG PET is useful for monitoring the therapeutic response of tumor tissues in lung cancer. Radiotherapy results in injury to DNA, RNA, protein and membranes of cancer cells, so that altered metabolism and cell death are reflected in a reduction in methionine and thymidine uptake, which procedes the autolysis of cells observed as necrosis. In monitoring radiotherapy, changes in FDG uptake correlate with the number of viable cancer cells, and the reduction of viable tumor tissue is reflected by decreased FDG uptake. No visible reduction of tumor volume is evident until a large part of the necrotic tissue has been removed. FDG PET enables functional evaluation of tumor viability to assess the therapeutic effects on tumor tissue, earlier than morphologic evaluation of tumor volume reduction by CT scan. 19

20 Lung cancer: response to therapy (Hanna, Nahmias) Week 1 Week 7 Week 1 Week Responder Patient alive 20 months after end of chemotherapy Non-responder Patient survived 2 months after end of chemotherapy Courtesy of David Townsend, Ph.D. University of Tennessee Medical Center!20 Bernard Bendriem, Ph.D., Siemens Medical Solutions

21 Fast scan --> possible to do scans during the treatment First cycle of chemotherapy Second cycle of chemotherapy Week 0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Cancer Imaging and Tracer Development Week Responder Non-responder Tumor SUV max Tumor SUV max SUV- standard uptake value

22 recent study PET-guided chemo linked to better Hodgkin lymphoma outcomes A study in the Journal of Clinical Oncology tested the use of PET scans to guide treatment of stage III and IV Hodgkin lymphoma, allowing patients with negative scans to finish with a less aggressive type of chemotherapy than those whose scans were positive. The research found that 82% of patients with clear scans who finished ABVD treatment were in remission and cancer-free at two years, while 64% of patients with positive scans who switched to an aggressive ebeacopp regimen were also cancer-free after two years, far more than would be expected under standard care. The findings, based on imaging from 33 patients, may enable doctors to provide tailored treatment and "a new standard of care," said researcher Oliver Press. 22

23 Imaging Gene Therapy Next slide illustrates PET imaging to assess viability of gene therapy for restoring dopamine synthesis in a monkey with a MPTP lesion in the striatum on one side of the brain which models Parkinson s. An adeno-associated virus containing the aromatic amino acid decarboxylase gene to produce the corresponding enzyme for synthesizing dopamine from L-dopa was stereo- tactically injected into MPTP-lesioned striatum. (MPTP (1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine) causes selective destruction of dopaminergic neurons of the nigrostriatal pathway in humans and other primates. ) The PET study of dopamine synthesis demonstrates that the virus has transferred the decarboxylase gene and that the enzyme has been transcribed and translated into an active state and is synthesizing dopamine. Dopamine synthesis was imaged with aromatic amino acid decarboxylase substrate, meta-[18f] fluorotyrosine. 23

24 Dopamine synthesis in striatum Unilateral dopamine MPTPinduced deficit (arrow) Restoration of dopamine synthesis (arrow) after gene therapy using a virus that contained the aromatic amino acid decarboylase gene. 24

25 COMBINING THE DESIGN OF MOLECULAR IMAGING PROBES AND DRUGS Diagnostic radiopharmaceuticals (i.e., molecular imaging probes) and therapeutic pharmaceuticals have been coupled together by combining the goals of molecular diagnostics and molecular therapeutics. These relationships involve PET technology and the biological and physical sciences in the academic setting, and the pharmaceutical, radiopharmaceutical, and imaging industries in the commercial one. The combination approaches seek to use common molecules or analogs as molecular imaging probes to image and modify the function of a disease target, and as drugs to alter or terminate the target. Molecular imaging probes and drugs are then further screened and evaluated with approaches, like the one shown in next slide, that use mouse models of human disease evaluated with micropet, along with traditional pharmacologic, biochemical, and behavioral measures. After a relatively small number of studies in mice, initial studies in patients are performed with molecular imaging probes and labeled drugs to assess whether the findings in mice, to a first approximation, are similar to those in patients, or how they differ. 25

26 Model approach for the discovery and evaluation of molecular imaging probes and drugs. (A) A small number of animals with genetically manipulated cells to mimic human disease are evaluated with micropet and molecular probes, along with behavioral assessments and direct biological assays of tissue. If results are encouraging, a small number of studies are performed in patients to assess correspondence between the animal model and humans. In this case, a clinical PET scanner is used to perform the same assays in humans that were performed with micropet in animals. (B) If the correspondence is reasonable, larger numbers of animals are studied to better define the properties of the imaging probe or drug. (C) More studies with clinical PET in patients are performed to more extensively evaluate the probe or drug in humans. 26

27 PET has multiple roles in this process: It provides in vivo biological characterization of the imaging probe or drug. It is used to titrate a drug to a disease target in tissue for accurate dosing by administering a labeled form of the drug. It provides pharmacodynamic and pharmacokinetic characterization of drugs and probes. It can determine whether the drug properly modified or terminated the biological process of disease or restored a normal process affected by disease. 27

28 MERGING PET AND CT INTO A SINGLE DEVICE Initial approach -- a software solution (briefly discussed before). CT Fused PET Software routine access to image archives carefully-controlled patient positioning different scanner bed profiles internal organ movement disease progression in time limited registration accuracy inconvenience for patient (two scans) labor intensive registration algorithms 28 Hardware images immediately available single patient positioning same bed for both scans little internal organ movement scans acquired close in time improved registration accuracy single, integrated scan no further alignment required

29 The biograph PET/CT system developed by Townsend while in Univ. Pittsburg combines highest performance PET and highperformance CT technology in a single, combined gantry. A fixed fulcrum, fully cantilevered patient handling system allows efficient patient positioning in the scanner, and avoids any relative deflection and misregistration between the CT and the PET acquisition. The combined tunnel diameter matches the CT gantry opening to allow for easier patient handling and increased patient comfort. 29

30 PERCENTAGE ANNUAL SALES Current PET/CT scanner designs Aquiduo LSO 4 x 4 x 20 mm 3 3D only (no septa) 16 slice CT 70 cm port 4.5 ns coincidence gantry on rails PET PET/CT

31 Non-Hodgkin s lymphoma Patient with history of non-hodgkin s lymphoma in in remission. Recent R complaint of pelvic pain. Focal uptake of FDG initially thought to be within bone structures. The CT was normal. PET/CT localizes lesions to soft tissue and not bone. 31

32 biograph-based IMRT in cervical cancer 14 mm increase in axial extent of para-aortic nodes. Additional IMRT plan post- treatment 32

33 Dramatic progress in PET acquisition times allows now to use PET during the treatment 33

34 18F-fluoride bone scan LSO PET/CT Cancer Imaging and Tracer Development Metastatic breast cancer CT: 157 mas, 120 kv, 5 mm slices PET: 11.8 mci 18 F-fluoride, 110 min p.i, 4 min/bed, 9 beds

35 New development Cherenkov Luminescence Endoscopy (CLE) combines endoscopy with the phenomenon responsible for the blue glow in the cooling water nuclear power reactor cores. Cherenkov radiation can be observed from a range of positron-, β-, and α-emitting radionuclides using standard optical imaging devices. CLI could dramatically improve the resolution of PET scans, enabling PET scanners to detect smaller objects than previously possible. Cherenkov luminescence was especially exciting because the light used to reveal diseased tissue is visible light that can be detected with simple optical sensors. It also is compatible with commercially available optical imaging instruments and a wide selection of the nuclear imaging agents that doctors use to make structures in the body visible. 35