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S809 Mini-Review : 18FDG PET in Oncology
S809 Mini-Review
FDG PET in Oncology
Daen de Leon M3852083 August 30th 2003
14 oktober 2010
Daen de Leon
S809 Mini-Review : 18FDG PET in Oncology
5.2 INDICATIONS...........................................................................................................................................9 5.2.1 Screening.......................................................................................................................................9 5.2.2 Diagnosis of Malignancy With a Primitive Tumour..........................................................................9 5.2.3 Localisation of a Primitive Tumour When Metastasis is Discovered...............................................9 5.2.4 Initial Staging of a Known Malignant Tumour................................................................................10 5.2.5 Evaluation of Treatment Response...............................................................................................10 5.2.6 Detection of Recurrence...............................................................................................................10 5.2.7 Differentiation Between Recurrence and Scarring Post-Treatment..............................................10 5.3 USE
5.3.1 Breast Cancer...............................................................................................................................11 5.3.2 Colorectal Cancer.........................................................................................................................13 5.3.3 Head and Neck Cancer.................................................................................................................14 5.3.4 Lung Cancer.................................................................................................................................15 5.3.5 Lymphoma....................................................................................................................................16 5.3.6 Melanoma.....................................................................................................................................17 5.3.7 Esophageal Cancer......................................................................................................................18 5.3.8 Testicular Cancer..........................................................................................................................19 5.3.9 Other Cancer Types.....................................................................................................................19 6 ADVANTAGES AND DISADVANTAGES..................................................................................................20
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S809 Mini-Review : 18FDG PET in Oncology
6.1 ADVANTAGES .......................................................................................................................................20 6.1.1 Long Half-Life Compared to Other Biologically Available Radioisotopes......................................20 6.1.2 Low Toxicity..................................................................................................................................20 6.1.3 No Side Effects.............................................................................................................................20 6.1.4 High Sensitivity.............................................................................................................................20 6.1.5 Shorter Post-Examination Irradiation Period.................................................................................20 6.1.6 No Significant Sterical Changes....................................................................................................21 6.1.7 18F is Lowest Energy First-Row Positron Emitting Element.........................................................21 6.2 DISADVANTAGES ...................................................................................................................................22 6.2.1 Half Life.........................................................................................................................................22 6.2.2 Radioactivity..................................................................................................................................22 6.2.3 Low Specificity..............................................................................................................................22 6.2.4 Cost & Convenience.....................................................................................................................22 6.2.5 Lowered Sensitivity in Diabetics....................................................................................................22 7 COMPLEMENTARY TECHNIQUES...........................................................................................................23 7.1 COMBINED / CO-REGISTERED PET/CT......................................................................................................24 7.2 CO-REGISTERED PET/MRI....................................................................................................................25 7.3 11C METHIONINE.................................................................................................................................25 8 ALTERNATIVES.........................................................................................................................................26 8.1 ALTERNATIVE IMAGING MODALITIES ............................................................................................................27 8.1.1 CT.................................................................................................................................................27 8.1.2 MRI...............................................................................................................................................28 8.1.3 SPECT..........................................................................................................................................28 8.1.4 Mammography/scintimammography.............................................................................................29 8.2 ALTERNATIVE RADIOTRACERS...................................................................................................................30 8.2.1 Non 18F-labeled Radiotraces.......................................................................................................30
188.8.131.52 Tc99m tetrofosmin...................................................................................................................................30 18.104.22.168 11C methionine, 11C thymidine, 11C tyrosine........................................................................................30
8.2.2 18F-labelled Radiotracers.............................................................................................................31
184.108.40.206 18F fluorinated thymidine (FLT)...............................................................................................................31
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S809 Mini-Review : 18FDG PET in Oncology
126.96.36.199 3-O-methyl-6-[18F]fluoro-L-DOPA...........................................................................................................31 18.104.22.168 O-(3-[18F]fluoropropyl)-L-tyrosine (18FPT).............................................................................................31 18.104.22.168 5-[18F]fluorouracil....................................................................................................................................32 220.127.116.11 Other 18F Labeled Radiotracers.............................................................................................................33
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while the others "fermented". and has been in clinical use for almost as long. sourced from academic publications and the internet. 18 FDG enjoys a considerable number of advantages over other tumour imaging modalities and radiotracers (such as a relatively long half life and high sensitivity). This paper aims to draw these strands together through a review of extant scientific literature on 18FDG. and a lack of specific uptake by tumour cells alone.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 1 Introduction Otto Warburg posed the following question in 1924: "If the carcinoma problem is attacked in its relation to the physiology of metabolism. It ends with a brief discussion of the current state of 18FDG PET use in oncology and possible future directions for this life-saving imaging technology. One recently developed radiotracer. 18 F-2-Deoxy-2-fluoro-D-glucose (or 18FDG). the first question is: In what way does the metabolism of growing tissue differ from the metabolism of resting tissue?" (Warburg et al 1924) The answer he found was that only one of thirteen sugar molecules. the USA Food and Drug Administration recently approved 18FDG on the grounds of its exceptional safety and efficacy thus opening the door to more widespread use in oncology treatment. However. has become the most widely in oncology used due to its preferential takeup by cells with a high requirement for glucose. In the last four decades electronic computing. glucose. was oxidised in tumour cells in rats. as observed by Warburg. The ability of some radioactive isotopes to trace biological activity has been known for more than 90 years. including tumour cells. At the same time. alternatives to 18FDG are being researched to overcome at least some of its shortcomings. radionuclide production and detector design technologies have improved sufficiently to permit the widespread adoption of the imaging modality we know today as positron emission tomography (PET) imaging. but it suffers from a few drawbacks. Page 1 of 40 14 oktober 2010 . such as an expensive production procedure.
Nutt 1999) Page 2 of 40 14 oktober 2010 . Brownell and Sweet at Massachusetts General Hospital (MGH) develop a brain scanner for detecting brain tumours Anger invents the eponymous camera which permits visualisation of radiotracer distribution in biological systems Kuhl and Edwards develop image reconstruction techniques for single photon tomography Phelps and Hoffman develop Positron Emission [Transaxial] Tomography (PE[T]T) 18 1958 1960s 1973-75 1976-80 1977-78 1980s 1984-86 1984-85 1990-2001 1991 1997-1998 FDG synthesised by Wolf and Fowler at Brookhaven National Laboratory (BNL) BGO scintillator developed (investigated by Cho and Farukhi. In the same year. and subsequently finds the answer lies with glucose and glycolysis Lawrence invents the cyclotron The Joliot-Curies produce the first artificial radioisotopes Lawrence produces radioactive isotopes of sodium and over the next few years produces another 17 biologically useful radioisotopes Hamilton uses 131 I for diagnostic purposes in patients First nuclear reactor constructed and operated at Oak Ridge Nuclear Lab (ORNL) Radioisotopes produced from reactor at ORNL become available for research Cassen at UCLA invents scintiscanner for measuring radioiodine in the body.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 2 A Brief History of PET Relating To 18FDG Oncology Imaging Date 1859 1896 1911 1923 1924 1931 1934 1935 1939 1942 1946 1951 Event Roentgen accidentally discovers X-rays Becquerel discovers natural radiation of uranium Hevesey uses radioactive lead as a radiotracer in foodstuff Hevesey shows the distribution of radioactive lead in growing bean plants Warburg wonders how to differentiate tumour cells from healthy cells. Toyokuni 1998. Brownell 1999. Hoffman and Phelps FDG approved as radiopharmaceutical by Food and Drug Administration (FDA) Table 1 : Significant events in the history of 18FDG PET (from Warburg 1924. and Derenzo – tomography using BGO made by Thompson at Montreal Neurological Institute) Several researchers study tumour uptake of 18 FDG (eg Di Chiro) First PET medical cyclotron and automated chemistry – commercial production of 18FDG Development of "Block" scintillation detector Development of LSO for use in scintillators 18 18 FDG PET in whole body oncology imaging by Dahlbohm.
was in operation at UCLA (Nutt 1999). the ECAT II. In1976 the first commercial PET scanner. suffered from very low resolution (Brownell 1999). Figure 1 : Coincidence and "unbalance" scans from the first clinical positron imaging detector (from Brownell and Sweet 1953) The technology of positron detectors improved rapidly. producing a string of viable devices. designed by EC&G ORTEC. Page 3 of 40 14 oktober 2010 . and the images thus produced were first called "PET" at that time.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 The first clinical positron imaging device from the 1950s. see Figure 1. Filtered back projection algorithms were developed between 1970 and 1972. Figure 2 : The first commercial PET scanner at UCLA in 1976 (From Nutt 1999 figure 9) Development of ring and cylinder detectors and associated advances in PET detector electronics and computer assisted image acquisition and interpretation have continued over the last 25 years. The first computed tomographic imaging device (PC I) was developed between 1968 and 1971. although clinically useful.
Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 Todays detector assemblies contain tens of thousands of detector elements of high sensitivity LSO. Figure 3 : A modern LSO-based detector PET scanner : Siemens ECAT ACCEL PET system (from Siemens website) Page 4 of 40 14 oktober 2010 . controlled by multi gigahertz processor technologies.
fig 2) The precise energy and coincident nature of these two gamma rays means their origin can be computed when they are detected by a ring of detectors. fig 3) Page 5 of 40 14 oktober 2010 . see Anderson 1932) and an electron totally annihilate each other to produce two coincident 511 keV gamma rays (see Figure 4). the position of the annihilation event and hence location in the body slice can be computed (from Price 2001. By measuring the time of detection of the gamma rays. Figure 5 : Detection of annihilation radiation. where it decays by positron emission. It is these coincident gamma rays that are detected by the PET camera (from Price 2001. The unstable nucleus decays by emission of a positron (a positively charged electron. 18FDG is injected into the patient. β+) which interacts with an adjacent electron (β-) to emit two orthogonal gamma rays (γ) at 511 keV. These are detected by a ring of detectors placed around the part of the body to be observed. The small difference between their arrival times used to calculate the offset within the enclosed slice of the detector array (see Figure 5). Figure 4 : The basic principle of PET. which produce two gamma rays at 180o to each other.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 3 How PET Works PET relies on Einstein's famous equation e = mc2 (Einstein 1905) where a positron (an antielectron.
Page 6 of 40 14 oktober 2010 .10 – 9. investigated 18FDG uptake in tumour cells in the 1980s and found a tumour-tonormal tissue ratio of 2. Other researchers at BNL. or 18FDG) FDG was originally developed in the1970's by Brookhaven National Laboratory (BNL). 4. 18 FDG was suggested as a viable radiotracer after the success of 14C-deoxyglucose studies. made possible due to the great glucose requirement of active brain cells (Ido et al 1977. 15O water and 13N ammonia. bearing in mind Warburg's 1924 findings. but with halflives of less than 20 minutes.5 of 18FDG (Som et al 1980). the University of Pennsylvania and the National Institutes of Health as a radiotracer for imaging brain function in the living human being. these radioisotopes must be produced and used very quickly. Gallagher 1977).Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 4 About 18FDG Original PET images were obtained using 11C-glucose.1 History Figure 6 : The structure of 18 18 F-2-Deoxy-2-fluoro-D-glucose (or fluorodeoxyglucose. Here its history is briefly described along with how it is produced.
k2. It has a halflife of 110 minutes so in practice. FDG is transported and fixed as 18F-FDG-6-phosphate by hexokinase. in injectable form (Bomanji et al 2001). (From Young 1999 figure 1) 18 FDG. 4. These high concentrations of bound radioactive fluorine will lead to a high emission of gamma rays as it decays. Page 7 of 40 14 oktober 2010 . being a glucose analogue. it is effectively "trapped" (Young 1999). as this product is not a substrate for the same enzymatically driven pathways as glucose and the uncatalysed dephosphorylation rate is low. Mannose triflate. a glucose precursor. and. is used to carry out a nucleophilic substitution with the radioactive fluoride and after purification steps 18FDG is obtained in an isotonic medium. k3 and k4 are rate constants.2 Production The radioactive 18F is produced in a cyclotron and is converted into an aqueous medium. is taken into tissues from the bloodstream by the same 18 mechanism as glucose.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 4.3 Mechanism of Action Figure 7 : Pharmacokinetics of 18FDG in vivo : K1. this is just long enough for it to be shipped from a hospital-based cyclotron facility to the imaging facility. which can be detected as "hotspots" by a PET scanner.
the patient is required to fast for a few hours in order to lower serum glucose levels so that 18FDG uptake can be measured once injected. Figure 8 : Coronal whole-body tomograms showing normal distribution of 18FDG in the body. both in terms of techniques. spleen and bone marrow. Page 8 of 40 14 oktober 2010 . From Bomanji (2001) figure 2. 5. This section begins by briefly describing patient preparation.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 5 Current Clinical Use in Oncology 18 FDG has found many uses in oncology imaging. and the normal distribution of 18FDG throughout a healthy body before looking at 18 FDG in oncology imaging. Imaging begins after 60-90 minutes. normal activity in liver. investigation. and excretion of tracer in urinogenitary system. although the exact choice of post-injection imaging varies widely and it is conceded that true optimisation remains a complex issue (Thie 2002).1 General Information and Normal Distribution In clinical oncology usage. types of cancer and in oncology staging. assessment and other indications. Intense uptake in the brain and myocardium.
5. (Talbot et al 2003). take up more glucose than better differentiated ones. Some tumours. metabolically active. (Talbot et al 2003. in fact. 5. 5. It can also indicate whether a tumour which appears necrotic with anatomical imaging modalities is.1 Screening 18 FDG PET is not so useful for systematic oncology screening due to cost and time considerations.3 Localisation of a Primitive Tumour When Metastasis is Discovered 18 FDG PET can highlight tumour sites (including unknown primary tumour sites in a significant proportion of patients – see Lonneux and Reffad 2000 and Lassen et al 1999).2 Diagnosis of Malignancy With a Primitive Tumour 18 FDG PET is potentially useful in detecting malignancy in primitive tumours. but cannot differentiate between primitive and metastatic tissue.2.2.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 5. These are often missed by 18FDG PET. poorly differentiated or aggressive ones. although there are some for which it is not suitable. Jerusalem et al 2003).2 Indications 18 FDG PET has many indications in clinical oncology. such as cancer of the prostrate or kidney. It appears not to work well in evaluating pancreatic masses (Jerusalem et al 2003). such as differentiated thyroid neoplasms or neuroendocrine tumours.2. but currently restricted to high prevalence cancers with otherwise unsatisfactory diagnostic techniques such as isolated pulmonary nodules (Comber et al 2003) and pancreatic cancers. or tumours with a low growth rate. (Talbot et al 2003) Page 9 of 40 14 oktober 2010 .
Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 5. Conversely.2.5 Evaluation of Treatment Response 18 FDG uptake by malignant tissue decreases or disappears after a few cycles of treatment. (Talbot et al 2003) 5. and it is also very efficient at detecting remote metastatic sites through the use of whole-body imaging (Lassen etc al 1999).2. It has been shown that PET provides information of similar accuracy as a whole body technique than a whole battery of other invasive and non-invasive tests together (Czernin 2002).6 Detection of Recurrence 18FDG PET is often used to detect recurrence. continuing 18FDG uptake is symptomatic of the failure of a tumour to respond to therapy.2. especially in non-small cell lung cancer (NSLC) (Jerusalem et al 2003). then 18FDG PET also provides information as to which part of the mass is metabolically active. (Talbot et al 2003) Page 10 of 40 14 oktober 2010 . even before a reduction in tumour size can be measured. colorectal cancers and sarcomas. (Talbot et al 2003) 5.7 Differentiation Between Recurrence and Scarring Post-Treatment 18 FDG has been used for this purpose in lymphomas. head and neck cancers. lung cancer. Many surgeons do not operate for malignant pulmonary masses without first having a PET scan performed.2.4 Initial Staging of a Known Malignant Tumour This is a major indication of 18FDG PET. If recurrence is found. 5. PET has been repeatedly shown to outperform CT in the detection of regional metastases.
It has also been used to resolve unknown primary tumours and is well suited to imaging dense breasts (Czernin 2001). Figure 9 : Whole-body 18FDG PET identified a primary tumour (marked with an arrow). Indeed. Figure 10 : 18FDG uptake in right-sided ductal carcinoma (marked with an arrow) with no axillary lymph node involvement (from Czernin 2001 figure 1) Page 11 of 40 14 oktober 2010 . 18FDG is the only approved PET radiotracer right now (Zheng et al 2003).Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 5.3.1 Breast Cancer 18 FDG PET has been used in breast cancer for many years in investigating recurrence and metastatic sites (Bomanji et al 2001).3 Use in Imaging Different Cancer Types 5. wheras Bomanji et al (2001) dispute this.(from Czernin 2001 figure 2) Czernin (2001) and Eary (1999) indicate that it is good at determining axillary lymph node staging.
and has had reports of 100% accuracy. However. superior to all other imaging modalities combined. PET's resolution is limited to detecting lesions above 8-10mm and sentinel lymph node biopsy remains superior in this regard (Jerusalem et al 2003). Czernin (2001) also reports that 18FDG PET in detecting metastatic sites in breast cancer has been measured as having sensitivity and specificity of 93% and 78% respectively. Page 12 of 40 14 oktober 2010 .Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 Czernin further indiates 18FDG PET for addressing internal mammary node involvement.
18 in recurrence scans. specificity and accuracy at 95.2 Colorectal Cancer 18 FDG PET has been used to differentiate recurrent tumours from scar tissue (Jerusalem et al 2003). Figure 11 : 18FDG PET image of liver metastasis in patient with history of colon cancer. previously missed by spiral CT but indicated by ultrasound (from Jerusalem et al 2003 figure 2) Page 13 of 40 14 oktober 2010 . FDG PET wins over CT in that CT is often not able to distinguish between soft tissue and tumour.3. 90 and 96% over 192 patients (Coleman 1998). One study put 18FDG PET's sensitivity.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 5.
or radiotherapy.3 Head and Neck Cancer It can be seen from Figure 12 that PET has better sensitivity and specificity for detecting recurrent or residual head and neck tumours after chemo.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 5. Figure 12 : Sensitivity vs specificity for CT/MRI vs PET in head and neck cancer response treatment (from Klabbers et al 2003 figure 1) FDG PET has also been shown to be more sensitive in detecting primary head and neck or involved lymph nodes than CT or MRI. (Coleman 1998) Figure 13 : Coronal (left) and sagittal (right) images of patient with primary tumour at base of tongue (marked by crosshairs) (from Lassen et al 1999 figure 2b) Page 14 of 40 14 oktober 2010 .3. (Klabbers et al 2003).
but that it cannot replace preoperative (invasive) surgical staging due to its inability to detect microscopic structures (Jerusalem et al 2003).3.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 5.4 Lung Cancer 18FDG PET has some value in NSCLC. Figure 14 : Squamous cell carcinoma of right lobe and right paratracheal adenopathy (from Vansteenkiste 2003 figure 4) Page 15 of 40 14 oktober 2010 .
5 Lymphoma 18FDG PET is the best end-of-treatment evaluation procedure for lymphoma patients.3. A negative result from a 18FDG PET scan may well negate the need for further chemo.and radiotherapy treatments (Maisey et al 2000) Figure 15 : Transaxial 18FDG image showing increased pancreatic uptake consistent with lymphomatous involvement (from Delbeke et al 2002 figure 2) Page 16 of 40 14 oktober 2010 . with better results in both positive (100% vs 42%) and comparable negative (83% vs 87%) predictive values against CT (Jerusalem et al 2003).Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 5.
3.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 5. Sensitivity has been reported as 92% and specificity as 77% without clinical information.6 Melanoma 18FDG PET is very sensitive at detecting metastatic disease in melanoma patients (Jerusalem et al 2003). Figure 16 : High risk melanoma patient suffering from lung metastasis (coronal left and transaxial right) (From Jerusalem et al 2003 figure 3) Page 17 of 40 14 oktober 2010 . rising to 100% with clinical information (eg biopsy site locations) (Coleman 1998).
(Block et al 1997) Figure 17 : Primary tumour and myocardial (large arrows) and metastatic (small arrows) uptake of 18FDG in esophageal cancer patient (from Block et al 1997 figure 1) Page 18 of 40 14 oktober 2010 . thus determing selection of patients for operation. It also identifies metastases missed by CT.3. in that it improves the ability to classify patients as having either resectable or unresectable disease. or those which are more amenable to biopsy than those shown by CT.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 5.7 Esophageal Cancer FDG PET has been shown to be of value in staging esophageal cancer.
Figure 18 : Coronal scans of a patient with suspected testicular cancer showing increased uptake in multiple lymph nodes and testis (from Cremerius et al 1999 figure 1) 5.9 Other Cancer Types Musculoskeletal. as with CT. ovarian. (Conti et al 1996.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 5.8 Testicular Cancer FDG PET has been shown to improve the staging of testicular cancer (Cremerius et al 1999) but with some reservations on the limiting resolution.3. Coleman 1998) Page 19 of 40 14 oktober 2010 . pancreatic and thyroid cancers have all been imaged with varying degrees of clinical usefulness by FDG PET.3.
6.4 High Sensitivity The tumour-to-normal tissue ratio of 18FDG has been measured as 2.2 Low Toxicity 18 FDG has low toxicity with toxicity studies showing no adverse affects in animals at 3. (Talbot et al 2003) Page 20 of 40 14 oktober 2010 .1. (Varognolo et al 2000) 6.000 the human dose (Som et al 1980). 6. for example. 18F compounds offer far more practical usage in PET.1. a classical bone scintigraphy.1 Advantages 6.5 (Som et al 1980) 126.96.36.199 Shorter Post-Examination Irradiation Period Patients remain slightly radioactive after examination.1 Long Half-Life Compared to Other Biologically Available Radioisotopes Witth a half-life of 110 minutes. I consider those which are specific to 18FDG (although some pertain other 18F radiotracers) and not to PET in general.1.3 No Side Effects No side effects are known. but this is for a shorter period than with. compare dto 11C of 20 minutes and 15O of 2 minutes. and patients may drive a car after examinations (assuming they could drive one beforehand) (Talbot et al 2003). 6. 18FDG does not cause drowsiness.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 6 Advantages and Disadvantages In considering advantages.10 – 9.
Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 6. Indeed. but once phosphorylated by hexokinase.1.6 No Significant Sterical Changes Introducing a fluorine atom for a hydrogen (H) or alcohol (OH) in metabolic substrates causes no significant sterical changes. although it may cause changes in biological behaviour due to differences in physiochemical properties (Varognolo et al 2000).1.7 18F is Lowest Energy First-Row Positron Emitting Element This means that. 6. imaging can be performed at high resolutions. potentially. it is not a substrate for the phosphoglucose isomerase enzyme driven glycolysis pathway (McMurry 1998). (Varognolo et al 2000) Page 21 of 40 14 oktober 2010 . this is what we see with 18 FDG – it's uptake is more or less through the same pathways as glucose.
6.2 Radioactivity 18 F is a radioactive substance. Some effort has been invested in the USA into tackling the logistics of this by arranging the building of cyclotron facilities at near equidistant points from PET imaging clinics (Varognolo et al 2000) 6. although studies suggest that FDG PET does not present a greater risk than conventional imaging modalities. (Talbot et al 2003) 6. and not all medical facilities can afford them.2. (Talbot 2003) Page 22 of 40 14 oktober 2010 . and hence is subject to regulated usage. preparation and imaging must be done swiftly.1 Half Life The 110 minute half life of 18F means that preparation.2. tumours and areas of inflammation which means that 18FDG PET is susceptible to false positives results. (White et al 2000) 18 6.3 Low Specificity Glycolysis is a universal process throughout the body.2 Disadvantages 6.4 Cost & Convenience The cyclotron facilities required for 18FDG PET are expensive. Those that do not possess a cyclotron need to be located near such a facility so that the 18FDG has not travelled too long and hence "decayed" too much before it is used.5 Lowered Sensitivity in Diabetics Diabetics have a reduced sensitivity to 18FDG.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 184.108.40.206. especially in the brain.
Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 7 Complementary Techniques One of the most interesting recent developments in 18FDG imaging is the ability to generate coregistered images with CT. Figure 19 : The spectrum of medical imaging (from Price 2001 figure 1) Another complementary technique is the use of 11C methionine. Page 23 of 40 14 oktober 2010 . a radiocarbon labeled amino acid. This allows anatomic and metabolic information to be superimposed. allowing the images of gross anatomic structure of CT to guide the radiologist to sites of metabolic. molceular pathway or molecular target/receptor interest.
18FDG PET (middle) and co-registered images (right) (from Siemens biograph brochure) Page 24 of 40 14 oktober 2010 . Wahl 2003). Figure 20 : Siemens biograph combined PET/CT scanner (from Siemens 2003) The advantage of combined CT and 18FDG PET images is the ability to take the high resolution anatomically detailed images of CT and use the metabolically useful images of 18FDG PET to resolve questions about malignancy. Figure 21 : CT (left). which provides a much more accurate image set. but scanners such as Siemens' biograph allow both procedures to take place in one session.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 7. Co-registered PET/CT images were generated for some time by separate imaging procedures.1 Combined / Co-registered PET/CT This technique has progressed rapidly in the last few years with combined PET/CT scanners now being commercially available from companies such as Siemens. Co-registered images are shown to have higher diagnostic value than either imaging modality alone (Kluetz et al 2000. determine primary tumour sites or indicate the metabolic state of a post-operative mass.
2 for full details). I found mention of it in Coleman (1998) in reference to image interpretation of 18FDG PET scans. However.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 7. The lower uptake of 11C methionine in gray and white matter leads to a clearer indication of metabolic activity in the middle set of images (from Vu and Fischmann 2000) Page 25 of 40 14 oktober 2010 . 7. their diagnostic imaging characteristics are complementary (Vu and Fischman 2000).2 Co-registered PET/MRI Although this technique seems to be less common.2.1. Figure 22 : 18FDG (top). 11C methionine (middle) and fused (bottom) PET images of a cerebral tumour.3 11 11 C Methionine C methionine is often used instead of 18FDG (see Section 8.
myocardial tissue and inflammation . PET using other radiotracers and 18FDG SPECT. Page 26 of 40 14 oktober 2010 . In this section I review these alternatives to 18FDG PET from a variety of extant literature. including CT. and 2) to find a radiotracer with a higher preferential uptake by tumour cells. Many other 18F labeled radiotracers are being investigated. MRI.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 8 Alternatives A number of alternatives exists to 18FDG PET. with a twofold purpose : 1) to find a radiotracer that is not taken up so readily as 18FDG is by other tissues with high glucose requirements such as gray and white matter.
in distinguishing tumour from other soft tissue in the colon and rectum and in detecting lesions in lymph nodes. 8. 18 FDG PET scores over CT in that it can be useful in staging and evaluating response to therapy bronchogenic carcinoma. but this is dependent upon local prevalence of malignancy and FDGPET/surgery costs (Comber et al 2003) Most authors conclude that 18FDG PET will increasingly be used with CT rather than instead of it.1. in testicular cancer (Cremerius et al 1999). However. and 18FDG PET being especially new in particular. Similar conclusions have been made from studies of esophageal cancer (Block et al 1997) and. for the reasons mentioned in Section 7.1 Alternative Imaging Modalities With PET being a relatively new imaging modality in general. Techniques such as Quantitative Contrast-enhanced CT (QECT) may have some benefits in assessing solitary pulmonary nodules. Likewise. with certain caveats on limits of resolution.1. Page 27 of 40 14 oktober 2010 .1 CT CT has for many years been used in all aspects of cancer management. a number of more established imaging modalities are often used to generate images in all aspects of cancer management. head and neck. 18FDG PET can distinguish benign from malignant abnormalities in the lung. It has been shown that 18FDG PET's ability to separate high and low grade brain tumours by their glucose utilization led to more accurate grading than with CT.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 8. (Coleman 1998). 18FDG PET seems to be challenging CT in many areas.
being a planar technique.1. SPECT and MRI co-registered images seem to be more common co-imaging techniques (Maria et al 1998). and if they are tumour remnants. However. but for some reason there do not seem to be much movement towards combined PET/MRI scanners as there has been for PET/CT. and there are a smaller number of them compared to a PET ring detector. There is a reduction in sensitivity also. Many post surgical gross anatomical changes induce contrast enhancement which cannot be distinguished from tumour persistence. Lawson et al 2000). Only metabolic images can determine whether post-operatives masses are tumour remnants or scar tissue. compared to 18FDG PET. which parts are still metabolically active. it suffers from many of the same issues as does CT. 18 FDG SPECT does have the advantage of being able to use existing gamma cameras with some modifications (eg addition of a collimator). However. studies of childhood brain tumours of 18FDG vs 201thallium chloride SPECT indicate that 18FDG SPECT images couldn't beinterpreted without MRI coregistered images to assist (Maria et al 1998) as SPECT does not offer full tomographic images. as gamma camera detectors are typically optimised to scintillate to lower energy photons than gamma rays.1.2 MRI MRI is often used in preference to CT due to its superior soft tissue contrast which can improve tumour localisation and nodal staging.3 SPECT 18 FDG SPECT has been investigated for use in breast cancer imaging for tumours > 2cm. (Lamonica et al 1999) Page 28 of 40 14 oktober 2010 . It seems that co-registration of 18FDG PET and MRI images is a relatively common diagnostic imaging procedure (eg Coleman 1998. 8.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 8. (Ivancevic et al 2000).
Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 8. Page 29 of 40 14 oktober 2010 .4 Mammography/scintimammography These techniques are conventionally used in detection of breast tumours. as has been done in mammography. and is used in screening.1. techniques are being developed for both SPECT and PET to minimise the distance between the camera detector and the tumour in the breast. Conventional mammography presents sub-mm resolution and excellent contrast. However. whereas scintimammography is typically used in staging and detection of primary and recurrent tumours. (Palmedo et al 2002).
1. 11 C thymidine (THY) and 11C tyrosine (TYR) are being investigated in ongoing studies of tumour expression (Bomanji et al).Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 8.1 Non 18F-labeled Radiotraces Several non 18F radiotracers are known. and also for measuring response to treatment (Eary 1999). in much the same was a cisplatin is actively restricted from entering the same types of cell. Klabbers et al (2003) reports that there was no relationship between TYR and tumour proliferation. 11C thymidine. 8.2 Alternative Radiotracers There has been much recent research into investigating other viable radiotracers.1 Tc99m tetrofosmin This is a relatively new radiotracer used in SPECT imaging of breast. especially to overcome 18FDG's lack of specificity.2 11 11 C methionine. lung and thyroid cancer (Ivancevic et al 2000). 8.2. However. MET uptake has been found to correlate with tumour proliferation and response to radiotherapy (although the latter only with limited relevance) (Klabbers et al 2003). However. in tumour cells with overexpression of multi-drug resistance protein (MDR) its uptake is limited. They can also be used for tumour grading. results indicate that uptake may decline more rapidly that 18FDG retention after successful therapy although the fast metabolism and Page 30 of 40 14 oktober 2010 . For THY.2. MET can also be used to determine tumour response to treatment (Eary 1999). 8.1. It is a liphophilic cationic compound which is passively moved across cell membranes. 11C tyrosine C methionine (MET) offers a more specific radiotracer than 18FDG for amino acid metabolism in brain tumours and is less influenced by inflammation.2. but is unfortunately limited by the 20 minute half life of 11C (Jerusalem et al 2003).
Phosphorylated FLT seems to accumulate instead of being incorporated into DNA as thymidine monophosphate is (Klabbers et al 2003). 8. but a seven- fold lower ratio of infected tissue-to-blood in mice with infected tissue.3 O-(3-[18F]fluoropropyl)-L-tyrosine (18FPT) Figure 23 : The structure of 18FPT (from Tang et al 2003 figure 1) Tang et al (2003) have found this amino acid tracer to be more selective for tumour tissue than 18 FDG – almost the same tumour-to-muscle ratio as 18FDG in tumour bearing mice.2 18 F-labelled Radiotracers A number of promising 18F labeled radiotracers are being developed which are proving to be more specific for tumour uptake than 18FDG.2.2. there was a twofold lower ratio of tumour-to-blood takeup in 18FPT injected mice than those injected with 18 FDG. 8.1 18 F fluorinated thymidine (FLT) Attempts to create this 18F labeled analogue of thymidine appear to be more successful than the 11C labeled version due to more favourable metabolite patterns.2.2 3-O-methyl-6-[18F]fluoro-L-DOPA Recent investigation (Bergmann et al 2003) has found this to be an effective tracer for tumour tissue. 184.108.40.206. coupled with formation of metabolites such as 11CO2 make it difficult to monitor the signal (Klabbers et al 2003). Page 31 of 40 14 oktober 2010 . so overall specificity seems to have been improved at the expense of sensitivity.2. However. 8.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 plasma clearance.
2.4 5-[18F]fluorouracil Figure 24 : The structure of [18F]fluorouracil (from Varagnolo et al 2000 figure 10) 5-[18F]fluorouracil is a chemically identical form of 5-fluorouracil.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 8. which is a conventional chemotherapeutic treatment for liver metastases in colorectal cancer treatment.2. (Varagnolo 2000) Page 32 of 40 14 oktober 2010 .
σ receptors are present in larger numbers on certain tumours of the colon. and on malignant melanoma cells. • • hypoxic cell binding agents – eg [18F]fluoromisonidazole (also reported in Eary 1999) tissue-specific tumour imaging agents – eg 3'-deoxy-3'-[18F]fluorothymidine (18FLT).2.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 8.2. brain. breast and kidney.5 Other 18F Labeled Radiotracers Figure 25 : The structure of [18F]α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol (from Varagnolo et al 2000 figure 1) Varognolo et al (2000) have reported on a large number of 18F labeled radiopharmaceuticals including: • • proteins and peptides – eg N-succinimydyl 4-([18F]fluoromethyl)-benzene σ receptor binders – eg [18F]α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1piperazine-butanol. which is incorporated into newly synthesized DNA • • radiolabelled monoclonal antibodies for use in melanoma imaging radiolabelled amino acids for imaging brain tumours – eg L-[218F]fluorophenylalanine and L-[3-18F]α-methyltyrosine (18FMT) • radiolabelled estrogen and progesterone for imaging breast cancer – eg [18F]fluoro-17βestradiol • radiolabelled androgens for imaging prostate cancer – eg 11β-[18F]fluoro-5αdihydrotestosterone (18F-DHT) Page 33 of 40 14 oktober 2010 . lung.
In vivoimaging of gene expression and gene therapy (Price 2001).Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 9 Future Developments There are many possible future uses for 18FDG PET. Gupta et al 2002) Expanded use in tumour biology (Eary 1999) In vivoimaging of pharmacodynamic endpoints (Price 2001) In vivoimaging of pharmacokinetics of drugs (Price 2001). In vivo determination of mechanism of action (Price 2001). Some of these include: • • • • • • • Phase I/II assays for selecting new anti-cancer drugs (Talbot 2001. Page 34 of 40 14 oktober 2010 . In vivo imaging of molecular pathways and mechanisms (Price 2001).
given the limiting resolution inherent in PET and the current problems of specificity with 18 FDG. 18FDG is the only approved PET radiotracer for breast cancer. Page 35 of 40 14 oktober 2010 .Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 10 Conclusion 18 FDG PET has. developments in both combined PET/CT systems and alternative 18F and non-18F labeled radiotracers continue. it is true to say that 18FDG has opened up a whole new set of possibilities for PET imaging. and much work is being done in clinical areas to quantify the benefits of this remarkable PET radiotracer in other cancer treatments. Currently. monitoring treatment response and checking for post-treatment recurrence. But for the time being. become the "gold standard" in staging. for many cancers. However. allowing patients to be more accurately diagnosed and treated – and so saving many hundreds of lives.
ucla. UCLA (http://www.crump. figure 3 From Crump InstituteWebsite.htm) From Brownell (1999).html) From Young (1999) figure 1 From Bomanji et al (2001) figure 2 From Czernin (2001) figure 2 From Czernin (2001) figure 1 From Jerusalem et al (2003) figure 2 From Klabbers et al (2003) figure 1 From Lassen et al (1999) figure 2b From Vansteenkiste (2003) figure 4 From Delbeke et al (2002) figure 2 From Jerusalem et al (2003) figure 3 From Block et al (1997) figure 1 From Cremerius et al (1999) figure 1 From Price (2001) figure 1 From Siemens' website (www.com) From Price (2001).gov/pet/FDG.com) From Siemens' website (www. From Siemens' website (www.siemens.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 A.edu:8801/NMMediabook/tracers/fdg.com) From Vu and Fischmann (2000) From Tang et al(2003) figure 1 From Varagnolo et al (2000) figure 10 From Varagnolo et al (2000) figure 1 Page 36 of 40 14 oktober 2010 . Figure and Table List Cover Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure 18 Figure 19 Figure 20 Figure 21 Figure 22 Figure 23 Figure 24 Figure 25 From Brookhaven National Laboratory website (http://www.bnl. figure 9.siemens. figure 2 From Nutt (1999).siemens. figure 2 From Price (2001).
891-921 1905 BM Gallagher. Nucleonics 1953. John P. Molecular Imaging and Biology Vol. R. Czernin J.. 1. Grafton and James R. Issue 6. T Ido. The Lancet Oncology March 2001. Keith CJ. Greer. Kimberly Hawley. Radiopharmaceuticals XXVII: 18Flabeled 2-deoxy-2-fluoro-D-glucose as a radiopharmaceutical for measuring regional myocardial Page 37 of 40 14 oktober 2010 . "The Apparent Existence of Easily Deflectable Positives. Carl D. Cooper. Clinical PET in Oncology. Conti. No. 1.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 B.L.William H. Irene Feurer. Barry A. Marsha C. No. Marci S. Brownell G. Molecular Imaging and Biology Vol. "Localization of brain tumors with positron emitters". No.54:900-904. 1998 Comber LA. Eric Kovalsky. Clinical Positron Imaging Vol. 2002 Dominique Delbeke. Nuclear medicine in cancer diagnosis. RR MacGregor. Sweet. 1. David L. Pages 717-735 Cremerius U. Bailey. 2-Deoxy-2-[F-18]Fluoro-D-Glucose Imaging with Positron Emission Tomography for Initial Staging of Hodgkin's Disease and Lymphoma. References Anderson. 1932). 17. Ell. 4. M Reivich (1977). Günther RW and Buell U. Kinney. Ann Thorac Surg 1997. David S. DE Kuhl. 2002 Janet F Eary. Siegel. Annalen der Physik. Bading. Nuclear Medicine and Biology. Clinical Radiology (2003) 58: 706– 711 Peter S. 238 (September 9. JS Fowler. Zimny M. Jennifer Keppler. October 15th 1999 Coleman RE. Miles KA. FDG-PET in Breast Cancer: A Different View of its Clinical Usefulness. 1. Block. Morgan. Martin. 105–114. Scott T." Science 76. August 1996. Lilien. G. Fidelma L. Urology. Improvement in Staging of Esophageal Cancer With the Addition of Positron Emission Tomography. G. 354: 853-57 Einstein A. Volume 23. Mark I. PET and [18F]-FDG in Oncology: A Clinical Update. Flanagan. Presentation to Massachusetts General Hospital on author's 50th anniversary. Alexander Patterson. Borchers H.L. A Ansari. V Casella. DR Christman. Lancet 1999. 1999. Sudhir Sundaresan. Ted Arrowsmith. C-N Wan. Farrokh Dehdashti. "A History of Positron Imaging". Costa DC. 35–45. AP Wolf.H.Wildberger JE. 15–30. Does positron emission tomography using 18-fluoro-2-deoxyglucose improve clinical staging of testicular cancer? Results of a study in 50 patients. P Som. Jakse G. and Joel D. Solitary Pulmonary Nodules: Impact of Quantitative Contrast-enhanced CT on the Cost-effectiveness of FDG-PET. 4. 11:40-45. "Clinical role of positron emission tomography in oncology". W. On Electrodynamics of moving bodies or Zur Electrodynamik bewegter Korper. 2:157-164 Brownell.64:770 –7 Bomanji JB.Griffiths M. H Atkins.
Bandy. Fazzari M. Clin Positron Imaging. Gupta. K. Ifat A. PET for in vivo pharmacokinetic and pharmacodynamic measurements. A. European Journal of Cancer 39 (2003) 1525–1534 Bianca M. Sandra J. Wang H. No. 3. Beguin. pp. Jerusalem. Labeled 2-deoxyD-glucose analogs. Erdi Y. Martinelli MA. Frost. 2000 G. Humm JL.3(6):223-230. . Müller. J Nucl Med 18: 990-996. Abdel-Malek Reffad. Damgaard and L. Slotman. Finn RD. 7. C-N Wan. Adriaan A. 2003 Kluetz PG. 137–141. Dieter L. G. Udaya M. 3. 2000 Nov. Three Cases of Primary Hyperparathyroidism (PHP) with Prior Failed Surgery Where Culprit Lesions Were Identified by 11C-Methionine Positron Emission Tomography (PET) and Accurately Localized with PET-MRI Coregistration. The Value of Positron Emission Tomography for Monitoring Response to Radiotherapy in Head and Neck Cancer. Clinical Positron Imaging Vol. Ginsberg R. Intraindividual Comparison of F-18-Fluorodeoxyglucose and Tc-99mTetrofosmin in Planar Scintimammography and SPECT. 4.2(3):159-171. Yeung HW. Karpeh M. Lassen. Targovnik. Goodwin. Macapinlac HA. Kinahan PE. Mullen. A Comparative Study of 511 keV SPECT and PET Using Separate 370 MBq F-18-FDG Doses on Different Days. Nabi HA. N. Felicetta. 31–36. P. Mazumdar M. Daugaard. R. 1999 May. Shah.M. Hans-Ulrich Aldinger. Jerome H. 1999 Michael A. Kewei Chen. Combined PET/CT Imaging in Oncology. Tumor Treatment Response Based on Visual and Quantitative Changes in Global Tumor Glycolysis Using PET-FDG Imaging. 2-deoxy-2-fluoro-D-mannose and C14 2-deoxy-2-fluoro-D-glucose. M Reivich and D Kuhl (1978). Andreas Wolter. European Journal of Cancer 38 (2002) 2094–2107 T Ido. Velimir Ivancevic. Eigtved. 1. Akhurst T. J Labeled Compounds and Radiopharm. Friberg. Klaus-Jürgen Winzer. Clin Positron Imaging. Daniel J. F-18 labeled 2-deoxy-2-fluoro-D-glucose. Price. James V. European Journal of Cancer. Jennifer T. Chander S. 1. E. Aboagye. 1978. Lamonica D. Hustinx. Impact on Patient Management. 257–270. Joachim M. No. 17–29. Clinical Positron Imaging Vol. Srivastava N. JS Fowler. No. Guillem J. Downey R. Meltzer CC. 5. Casilla C. Grossman Z. Y. The Visual Response Score and the Change in Total Lesion Glycolysis. Fillet. 4.O. Molecular Imaging and Biology Vol. 18F-FDG Whole Body Positron Emission Tomography (PET) in Patients with Unknown Primary Tumours (UPT). 35. AP Wolf. U. Villemagne VL. V Casella. Kabadi. No. Klippenstein D. Cohen AE. 1076-1082. Clin Positron Imaging. Munz. Clinical Positron Imaging Vol. Townsend DW. No. Metastases from Unknown Primary Tumor: PET-FDG as Initial Diagnostic Procedure?. 14: 175-184. 2000 Max Lonneux. Lawson. Vilani J. Ben J.2(2):81-91. Leslie B. 2000 Page 38 of 40 14 oktober 2010 . Vol. Klabbers. Lammertsma. Larson SM. 3. PET scan imaging in oncology. G. 1977. 1999 Mar.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 glucose metabolism in vivo: tissue distribution and imaging studies in animals.
Dirk Von Mallek. Talbot. Synthesis and evaluation of O-(3-[18F]fluoropropyl)-L-tyrosine as an oncologic PET tracer. Schackert. Norman. Molecular Imaging & Biology. D. Bishop. UCLA Department of Molecular and Medical Pharmacology (http://laxmi. June 2001. Nuclear Medicine and Biology 29 (2002) 809–815 Price P. ZH Oster. Fundamentals of Organic Chemistry 4th ed. Hubner. Thie.R.html) Johan F. and Luis A. Jimenez. Steinmeier.. Gary T. Xiaolan Tang. L. Nuclear Medicine and Biology 30 (2003) 733–739 Joseph A. Issue 1. J Nucl Med 21. R.N. D. M. Mingfang Wang. Are 18Fluorodeoxyglucose positron emission tomography and magnetic resonance imaging useful in the prediction of relapse in lymphoma residual masses? European Journal of Cancer 36 (2000) 200-206 Bernard L. .nuc. Breast cancer imaging with PET and SPECT agents: an in vivo comparison. Kerrou. Walter E. B. TRENDS in Molecular Medicine. Vansteenkiste.edu:8248/M248_98/synprob/part2/hist_rad. Montravers. Younsi. Petegnief. Manquan Gan. G. Flux. K. Alexander Matthies. PET as a potential tool for imaging molecular mechanisms of oncology in man. Lei Luo. HL Atkins. Pediatr Neurol 1998. 2fluoro-2-deoxy-D-glucose (18F): Nontoxic tracer for rapid tumor detection. D Bandoypadhyay. Nuclear Instruments and Methods in Physics Research A 504 (2003) 129–138 Ganghua Tang. F. January-February 2002. Padhani. A. Suzanne T. Mucha and G. Beuthien-Baumann. 670675 (1980). Pages 261-267 P Som. Ott. N. Chemistry of Imaging Probes I.E. Karl F. Michael Reinhardt. JS. Maisey. Pages 11-26 Holger Palmedo. C-N Wan.19:351-357. B. A P Wolf and S Zabinski. Positron emission tomography with [18F]-FDG in oncology. Maria. Pharmacology 248 : An Introduction to Biological Imaging (Winter 1998 presentation). 1-11 (Article in press) Page 39 of 40 14 oktober 2010 . Evaluation of automatic multimodality fusion technique of PET and MRI/CT images for computer assisted brain tumor surgery. 238–244. PET scan in the staging of non-small cell lung cancer. The History of Positron Emission Tomography. H Turner.ucla. HansJu¨rgen Biersack. 4. Sobottka. CY Shiue. pp 442-446 S. A. Smith. D. 3. Volume 1230. A fluorinated glucose analog.D. Hill. Comparative Value of Thallium and Glucose SPECT Imaging in Childhood Brain Tumors. October 2001. Optimizing Imaging Time for Improved Performance in Oncology PET Studies. Volume 4.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 N. McMurry J. J. RR MacGregor. Grahek. KÊMatsui. 2002 T Toyokuni 1998. No. Drane. 7:10. Jenne Hensel. Brooks/Cole Publishing.Fowler. International Congress Series. Molecular Imaging and Biology Vol. Mastin. Webb. . DF Sacker.J. R. Y. Cunningham. 1998 R Nutt. Lung Cancer (2003) xxx. A.
A. Anatomolecular Imaging with 2-Deoxy-2-[18F]Fluoro-D-Glucose: Bench to Outpatient Center. Clinical Positron Imaging Vol. 127–129. J. Val Johnston. 27. Stephen White. 3. Biochem.edu/JPNM/TF00_01/Sept26/WriteUp. Combined F-18 FDG and C-11 Methionine PET for Cerebral Tumors. European Journal of Cancer. K. Nuclear Medicine and Biology 30 (2003) 405– 415 Thanks to Johanne (again!) for her patience and support during the last 8 months – Love Daen Page 40 of 40 14 oktober 2010 . 1773-1782. No. Cremerius. Baum. 18F-labeled Radiopharmaceuticals for PET in Oncology. 13. Mazzi and E. Gary D. Pauwels. Measurement of Clinical and Subclinical Tumour Response Using [18F]-¯uorodeoxyglucose and Positron Emission Tomography: Review and 1999 EORTC Recommendations.html) Accessed October 4/5th 2003 Richard L. E. 49–56. K. 35. Hutchins. M. 1924. Fischman. J. K. Lammertsma.harvard. 103–112. Ohannesian. Zeitschr. Xiangshu Fei. Varagnolo. David W. pp.. O. Leonard C. Megan Fawcett. Synthesis and preliminary biological evaluation of radiolabeled benzylguanine derivatives. pp. Negelein. Herholz. 1999 Qi-Huang Zheng. The metabolism of cancer cells. Hoekstra. Posener. Erickson. No.. Pruim and P. Wahl. Occupational Exposure in Nuclear Medicine and PET. 2003 Warburg. David Binns. 5. 3. Vol. No. Molecular Imaging and Biology Vol.Daen de Leon S809 Mini-Review : 18FDG PET in Oncology M3852083 L. R. Xuan Liu. M. 2.. U. Excluding FDG.med. K. Nuclear Medicine & Biology. Stokkel. Young. Vol. 2000 Tung Vu. Alan J. September 26 2000 (http://www. 152:129–169. Ji-Quan Wang. P. 2000 H. new potential PET imaging agents DNA repair protein O6alkylguanine-DNA alkyltransferase breast cancer. Joint Program in Nuclear Medicine web page. O. VIII. Price.A. Harvard Medical School. Lee Stone. U.
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Rio Grande Games offers 3 exciting new additions
Courtesy Rio Grande Games
Rio Grande Games is one of the premiere board game publishers in the United States. Its games have won the coveted German Game of the Year award multiple times. If you have a chance to play one of its games, it's almost always guaranteed to be good.
Presented here are three different games that are all fun to play.
This game places you in the role of a tribal leader in the year 2097. The earth has entered another ice age, and 90 percent of the population is gone. Your tribe must survive by using scarce resources, acquiring new items and recruiting more tribe members. The player with the largest tribe at the end of the game is declared the winner.
Arctic Scavengers is a deck-building game with player-vs.-player battles. It offers a surprising array of options, and the theme is fresh. Each player receives a deck of the same 10 cards. After a thorough shuffle, each player draws five cards. The cards represent members or equipment of a player's tribe. Cards allow a player to take actions during a turn.
The actions a player can do center around collecting more cards for building the size of a deck. New members can be purchased, new equipment can be dug out of the junkyard and players commit tribe members to battle over a single contested resource card at the end of each turn.
A unique aspect to this game is the player battles. The tribe that dedicates the most powerful cards to the battle will win the contested resource and add it to its own deck.
When the last contested resource card is won, the game is over. Each card in a player's deck representing a member of the tribe has a point value. Each player adds these points, and the player with the highest total point value wins. A bunch of expansions in the box allow for varied game play.
This card drafting game features excellent claymation-style art and competitive game play. Players manage a tribe of cavemen and compete against each other to gather food, hunt dinosaurs, recruit tribesmen and discover inventions The first tribe of cavemen to discover fire wins the game.
Players begin with cards representing a cave and two tribe members. Each tribe member has a set of abilities that assists the tribe in various actions. Players also begin with cardboard tokens representing food and teeth. Food is used to feed your tribe and teeth are used to bid for a conch that gives a player first play in the round.
At the start of a turn, a pool of face-up cards is created and made available for purchase by all players. The pool of cards are things each tribe needs: new cavemen, inventions that grant powers, dinosaurs that can be hunted for food and teeth, and new caves, which allow bigger tribes.
Next the players bid their teeth tokens for a conch to see who will be the starting player. The starting player gets first pick from the pool of cards. The starting player also gets a second turn, which the other players do not get, but a starting player must feed the tribe.
Eventually one of the cards placed in the pool is the invention of fire. The first player to get the starting player conch and supply enough invention points may discover fire and win the game.
The five villages is a bright and cheery game about delivering and selling produce in Italy. Players act as farmers who gather eight different kinds of produce and then sell them at five cities along the Italian Riviera.
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text: Eyewitness Eyewitness: Scotland Photographs from the Guardian Eyewitness series Dez Johnston, 31, theology student and security guard, from Lenzie, near Glasgow, with Pixie: 'Strangely, no one in my family has ginger hair. I grew up in the Highlands, in Speyside, so maybe it's from the whisky?'Illustration: Photograph: Kieran Dodds/Panos Thursday 28 August 2014 12.49 EDT Share on Facebook Share on Twitter Share via Email Share on Pinterest Share on Google+ Share on WhatsApp Share on Messenger Reuse this content


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Dingle Peninsula, Dingle
31 Reviews
31 Reviews
While I do not think it is as dangerous as some of the other reviews, you DO have to watch out for sheep in the road (right around that next corner!) so drive slowly and you should be fine. Got a pic of the map before starting out----also had a very nice lunch in Dingle proper at a local pub.
Address: Dingle Peninsula
Do drive the winding road around the Penninsula that goes up and down the mountain. It is breath-taking. As always, the road are EXTREMELY narrow which is nerve wracking to say the least when driving on the edge of a mountain with only water below you! Sends shivers up my spine just thinking about it. It is worth it though. There is not much traffic and whenever another car around the bend, we just pulled over into the bushes if need be. Praise the good Lord, we did not encounter any tour buses on these roads.
Look for the 'sleeping giant' - an island that you can see from one of the mountain roads that looks almost exactly like a sleeping giant. There are a number of islands to see. Near the islands, you will also encounter a very large and very white crusifix facing the setting sun and the islands. It is amazing!
On Slea Head Drive, look for the Bee Hive Huts. The cost of admission is 3 euros and then you have to hike a bit up the hill to them but they are absolutely fascinating and the scenery is breath-taking.
There is also a fort on the same road (I think) that is situated on the edge of a mountain as are a lot of things in Ireland. I imagine it was for protection. It is also breath-taking as the water is just below.
Also look for the famine huts on the same road. Interesting but get there early as it closes early in the day.
Along the drive, you will find a relatively new restaurant (just opened in June 2009) that is actually very good. We stopped in when looking for the fort and had some coffee and dessert.
Address: Slea Head Drive
Directions: Dingle PenninsulaRelated to:
The clear and clean Atlantic seas wash against the rugged coastline of Ireland providing the perfect arena for watersports, angling, and sailing. Check out http://www.dodingle.com for loads of holiday activities.
Address: The Dingle Peninsula
Website: http://www.dodingle.com/
If you have only one day in this part of Ireland, I would definately recommend the Dingle Peninsula over the Ring of Kerry. The roads are not nearly as crowded and the views are just as good, if not better in some areas. The peninsula also has plenty of things to see and places to stop. We actually had worse weather for this drive then the Ring, and still enjoyed it more.
Hop on a bike and get ready to push down on the peddles a few hundred times. If you have the will bike the entire Dingle Peninsula. It took me about 4 hours to do, and I was exhausted when I got back, but I would recommend it to anyone who likes scenic coastal biking.
Make sure to leave yourself some extra time to be able to see the bee hive huts and some of the old church building along the way.
**Disclaimer: cars will whiz by you only inches from your handle bars. At times you may think you are going to die, don't worry everyone has the same feeling and from talking to locally it seems that people are rarely clipped.
Address: Dingle Peninsula
Directions: From either of the bike shops in Dingle get a trail map. The people in the store know the route well and will explain it to you. There are also one or two points that you can shorten your trip. Make sure they point these out to you.
Pack a lunch at the local grocery store (if you like egg salad pack it, the Irish make great egg salad) and hike out to the mouth of the bay. It is only a 1 mile hike out of town and is almost totally flat. After you get to the mouth of the bay I recommend you hike up to the lighthouse on your left. Not far at all. From the take a look around, snap some photos, and hike as far down the coast as you can. I personally recommend you hike about 3 miles down the coast (if you up for it). You will gain some elevation in the first mile and get some great views off the cliffs. From there it is peaceful, beautiful exercise.
Eat your lunch on top of one of the cliffs on the way back and see if you can find the dolphin swimming out in the ocean.
Address: Dingle Bay Lighthouse
Directions: Basically walk out of down toward the mouth of the bay. Stay on the left hand side of the bay, you can't miss it.
Many people like to bike around the Dingle Peninsula. I hear it's wonderful, but since we didn't do it, I won't write about what it's like. Instead, we took a fairly long (about 6 miles round trip) walk to the village of Ventry (or Ceann Trá in Irish). You will be treated to great views the entire way as you transition from Dingle harbor to Ventry Harbor.
Simply follow the main road west out of town and follow the signs to Ceann Trá. You will turn left at a roundabout and cross a bridge shortly after you leave town. Be sure to wear highly visible clothing and be alert for cars, as the road is quite narrow in places. You'll be rewarded with excellent views and a peek into the Irish-Language-Only culture in Ceann Trá.
Address: Ceann Tra, County Kerry, Ireland
Directions: Head west out of town and follow Road R559. Be sure to turn left at the roundabout just outside of town, and follow the signs to Ceann Tra and Slea Head.
Website: http://www.dingle-peninsula.ie/walking.html
A fun thing to do, especially if you're jet-lagged (as we were), is to take a walk along Dingle Harbor. You can't go wrong traveling either way -- past Ventry Manor to Eask Tower, or to the Lighthouse. We chose to do the latter. Despite the heavy rain when we did it, the views were magnificent. Supposedly, it's also a way to see Fungi the Dolphin for free, but it was too stormy for us to tell dolphin splashes from whitecaps. Be sure to bring Gore-Tex coats and good boots, as rain can start at any time, and the trail is likely to be muddy.
From the main road, turn right just past Bambury's Guesthouse and just before the town limits. Continue past Skellig's Hotel and on to the Coast Guard Station. Turn left. You should be where Sara is standing in the photo above. Walk past the wall and continue along the path to the tower, and on to the lighthouse. Give our regards to the cows and sheep you encounter along the way. Enjoy!
Address: Start at the Dingle Coast Guard Station
Directions: From the town center, follow the main road east (toward Tralee). Turn right at Bambury's, past Skellig's Hotel, and on to the Coast Guard Station. Walking path is on the left.
Website: http://www.dingle-peninsula.ie/walking.html
When you are lucky, you may get into a "Dingle-trafic-jam" with local sheep - it will even make a great picture, in case that you are able to find a perfect place to stand with your camera.
Simply try to be quicker in finding a great place to take the picture, than I did ! I simply was 2 minutes too late to climb up one of these side-walls, but I was lucky anyway somehow...
Believe me, if you want to arrange such a picture by waiting at a crossing for some sheep, it SIMPLY WILL NOT WORK, it might be the best to arrange such a picture with the help of the local farmers, who will of course expect some tip !
Directions: I took this picture in one of the side-roads in Dingle-island. Speak to the local farmers and ask them, at what he will pass by...
Not far from Gallarus Oratory you may see Kilmalkedar ( Cill Maolcheadair ) with its small graveyard and a famous "Ogham-stone" and this famous early celtic cross.
The celtic cross on the left was made of 1 piece of stone and the ogham-stone on the right of my picture is that small needle-like stone, that even has a small hole drilled in on the top. Such ogham-stones were taken as a calender maybe, but scientists are not really sure about it. Another ogham stone of Kilmalkedar cemetery might have been used as a callender, BUT nobody knows for sure - see my last picture.
Directions: Kilmalkedar is in a distance of 4km from Gallarus Oratory, at the north-west cost of Dingle peninsula.
This old stone-age village is to be found not far from Gallarus Oratory . It consists of several houses, also called clochans . These buildings are quite usual in that area and they were built by heaping up stones and rocks of all sizes, forming a flat and narrow house, only the roofs are missing today, obviously they had roofs made of straw.
Nowadays there is a fence around these buildings, BUT of course you may climb over it and take a closer look at this great remains !
Directions: You have to keep your eyes open, when driving through Dingle Island in order to find these treasures of Irish history. This village is about halfway between gallarus Oratory and Kilmalkedar.
Dunbeg Fort ( An Dun Beag ) is the best-preserved of the Irish Forts dating back to the Iron-time. Dunbeg Fort ( An Dun Beag ) is about 6 km west of Dingle-town, when you drive on road R559 ( the Slea Head Drive).
On my picture you may see one of the small doors leading from one of the rooms into another, the stones are just heaped upon each other, but in a perfect and absolutely wind-proof way. At some places these walls are 1 meter thick.
Directions: You will get to Dunbeg Fort, when you drive on Slea Head Drive (R559) , the scenic circle-road west of Dingle-town. Dunbeg Fort will be on the right of the road, next to the cliffs !
Dingle-town is the main village of Dingle-peninsula, and mostly the island and also the village are simply called "Dingle". Dingle has only 1300 inhabitants but recently it became quite popular among young tourists - certainly not only for Funghi, the dolpin, but also for the many pubs offering live-music sessions every night in summer. Dingle is also a good place to go shopping for things that you are used to from home, but cannot get at most places in Ireland. I mean things like special camera-accesories and camping-articles. Many shops have specialized and offer such things for the tourists.
In summer, between May and October there is a good bus-service to Dingle, taking you directely to Dingle-Main-street.
Directions: Dingle Peninsula is the nothernmost of the 5 fingers reaching out into the Atlantic ocean at the south-westcoast of Ireland.
The scenery and country side are just outstanding on the drive west from Dingle. You'll want to pull over many times to OOHH and AAHH when possible. The road is narrow and many times allows only one car at a time so caution and concentration is required for the driver. Lots of sheep wandering the roads. At Slea Head is much to see, including the over look of the Blasket Islands, historic beehive huts from 2000BC, the Blasket Island interpretive center.
From Slea Head the road winds north through the tiny village of Dunquin and their great ceramic shop. At Clogher Head the road turns east to Ballyferriter. Just take your time and wander the side roads and enjoy the Ireland you have always imagined - far from the crowds and tourist shops.
The scenery and country side are just outstanding on the drive west from Dingle. You'll want to pull over many times to OOHH and AAHH when possible. The road is narrow and many times allows only one car at a time so caution and concentration is required for the driver. Lots of sheep wandering the roads. At Slea Head is much to see, including the over look of the Blasket Islands, historic beehive huts from 2000BC, the Blasket Island interpretive center.
From Slea Head the road winds north through the tiny village of Dunquin and their great ceramic shop. At Clogher Head the road turns east to Ballyferriter. Just take your time and wander the side roads and enjoy the Ireland you have always imagined - far from the crowds and tourist shops.
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A Calumet County man accused of driving his car into a group of motorcycle riders last year reached a plea deal Tuesday.
Clinton Lovelace, 26, was driving on Highway 151 in Fond du Lac County when he drove over the center line and into a dozen motorcyclists from Michigan.
Ten cycle riders were struck. Two riders, 43-year-old Douglas Yonkers and 59-year-old Daniel Winsemius, were killed in the crash.
Lovelace pleaded guilty to reduced charges of negligent homicide and reckless injury, reducing his recommended sentence to 20 years.
Many of the riders involved in the crash traveled to Wisconsin on Tuesday to be observe the proceedings.
Rick VanDam was the most seriously injured biker to survive the crash. He felt a strong urge to be in court.
"I think he's just reluctantly taking a way out that's safe rather than gambling on another term," VanDam said. "I haven't heard that he's got a lot of remorse. I don't know what he's owning up to."
VanDam said he has more surgeries ahead, but plans on being back in Wisconsin next February for Lovelace's sentencing.
Man who struck motorcycle group, killing 2, reaches plea deal
A Calumet County man accused of driving his car into a group of motorcycle riders last year reached a plea deal Tuesday.
Copyright 2013 by WISN.com All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
Aaron Rodgers mum on relationship with brother Jordan Rodgers
Man charged with homicide in crash that killed woman, 60
Appeals court rules accused Slender Man attackers will stay in adult court
Police rescue missing autistic boy, pull him from river
Two critically injured in Fond du Lac plane crash


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Azul, LLC Overview
Azul, LLC filed as a Domestic in the State of California and is no longer active. This corporate entity was filed approximately eleven years ago on Friday, February 25, 2005 , according to public records filed with California Secretary of State.
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- Coilover KitsHonda Fit
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- Off-Road BumpersSkid Plates Provide The Ultimate In Off-Road ProtectionIf you take your 4x4 off-roading, you have likely gained an appreciation of how unforgiving trails can be when it comes to your vehicle's underside. Deep ruts with rough edges can appear out of nowhere, sturdy-looking rocks can shift unexpectedly, and tranquil bodies of water can hide everything from sinkholes to fallen tree trunks. Before you know it, the underside of your truck has bounced off something hard enough to damage moving suspension components or puncture housings containing engine oil, gasoline, transmission fluid, or differential gear oil.
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- Automotive ToolsWhat Special Tools Are Available For Suspension Repair?Seasoned professional automotive technicians often say if you're using too much physical effort during a repair, you're simply not using the right tool. This is true, and a perfect example is repairing and replacing suspension components. If you've ever done this type of work or attempted to do it, you know it can be trickier than merely loosening and tightening bolts.
- Performance Suspension PartsCoil, Leaf, & Torsion Bar | Describing The 3 Different Kinds of SpringsThe springs in your vehicle probably aren't something you think about until there's a problem or you've decided to upgrade suspension parts in the interest of sportier handling. But what specifically do springs do? In short, they play a major role in the safe handling and ride comfort of your vehicle. Not only do they keep a vehicle at a designated standing height, they provide recoil necessary to bounce back after suspension components move up and down over uneven road surfaces. By themselves, springs will continue to bounce up and down for a long time unless a motion damper such as a shock absorber is present to keep things stable. Springs can be soft and extremely bouncy, or they can be stiffer and less bounce-prone.
- Performance Suspension PartsHow Do Shock Absorbers Work?Shock absorbers (also known as "shocks") are the suspension components which slow, then stop, the up-and-down bouncing movement of your vehicle's springs through a process known as dampening. Without shocks to calm things down, springs will continue to extend and release energy they absorb from bumps in the road at an uncontrolled rate - bouncing for a long time until their kinetic energy finally dissipates. Needless to say, this would produce an extremely bouncy ride that would be hard to control over uneven road surfaces.
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- Performance Suspension PartsShocks Versus Struts: The Big Answers Revealed!Shock absorbers, also known simply as "shocks" (which is what we will call them for the rest of this article), are the suspension components which stop your car or truck from bouncing up and down after hitting a bump. They are a major contributor to your ride comfort and safety.
- Replacement Suspension PartsHow to Inspect Your Suspension SystemThe very first thing to know about timely suspension system diagnosis is that the stability and steering control of your vehicle and, what is more important, your safety on the road depends on how often you make it. Automotive suspension belongs to one of those car systems that are constantly exposed to high loads and thus are prone to wear and tear. Most specialists recommend inspecting suspension system after every 6,500-7,500 miles or when there are any signs of its breakage.
- Performance Suspension PartsHow Low Can You Go?Lowering is high on the list of many people who want to improve the appearance of their car. If you want to lower your car with the coil springs, then replacing them with lowering springs is the way to go. But what if you want to lower your car and also make it handle better? If that's your goal then consider coil-over shocks.
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Price reduced..last baby looking for his forever home. Has gotten 1st set of shot, and has been dewormed. Ready to give puppy kisses and steel your heart. Mom is long hair chihuahua, Dad is pure bred Yorkie.
Jul 20 -
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Adorable Toy Chorkie Puppies Ready by August 26th. 4 Girls $600 each, Mom is a Chihuahua, only 4 lbs and Dad is a purebred Yorkie only 3 lbs. Puppies should be 4 lbs full grown. Very sweet and playful, they have been raised in my living room, spoiled and socialized. Included are their first puppy shot, health records, vitamins and food. A $200 deposit will hold your choice until she is ready ...
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I have one female chorky that looks like her mother a chihuahua very cute healthy and playful should be around 5-6lbs if interested please text or call 619-306-7641 asking price $125
Jun 9 -
San Diego :
San Diego - Dogs & puppies
Very sweet and playful. Small size. First set of shots and deworm.
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Riverside - Dogs & puppies
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