Alternative positron emission tomography with non-conventional positron emitters: effects of their physical properties on image quality and potential clinical applications

The increasing amount of clinically relevant information obtained by positron emission tomography (PET), primarily with fluorine-18 labelled 2-deoxy-2-fluoro-d-glucose, has generated a demand for new routes for the widespread and cost-efficient use of positron-emitting radiopharmaceuticals. New dual-head single-photon emission tomography (SPET) cameras are being developed which offer coincidence detection with camera heads lacking a collimator or SPET imaging with specially designed collimators and additional photon shielding. Thus, not only satellite PET imaging units but also nuclear medicine units investing in these new SPET/PET systems need to examine all available alternatives for rational radionuclide supplies from host cyclotrons. This article examines 25 ”alternative” positron-emitting radionuclides, discusses the impact of their decay properties on image quality and reviews methods for their production as well as for their application in imaging techniques.     

Delayed cerebral radionecrosis with a high uptake of 11C-methionine on positron emission tomography and 201Tl-chloride on single-photon emission computed tomography

A 47-year-old woman, who 2.5 years previously had undergone resection of a malignant astrocytoma of the left temporal lobe followed by radiotherapy, was found to have a mass in the left frontal lobe. This showed high uptake of thallium-201 (²⁰¹Tl) on single-photon emission computed tomography and ¹¹C-methionine on positron-emission tomography, suggesting recurrent tumour. Histological examination of the resected lesion, however, revealed it to be radionecrosis. This case thus illustrates a diagnostic pitfall in the use of these investigations for distinguishing radionecrosis from recurrent malignant glioma. Received: 19 September 1997 Accepted: 16 October 1997     

Fluorodeoxyglucose positron emission tomography in the initial staging of germ cell tumours

Testicular cancer is a rare tumour with the potential for cure at diagnosis. It is important, however, to identify those patients with metastases at presentation so as to ensure that the optimum treatment strategy is employed. Many criteria have been used to try to place patients into high- or low-risk groups, with variable success. Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has the potential to identify active disease and thereby influence further management. Here we report on a retrospective study of the use of FDG-PET in the detection of metastatic testicular carcinoma at diagnosis. Thirty-one patients [13 with seminoma and 18 with non-seminomatous germ cell tumours (13 teratomas, 5 mixed)] were staged by FDG-PET scanning. The imaging was performed using a Siemens ECAT 951 scanner. All results were assessed on the basis of histology or clinical follow-up. FDG-PET scan identified metastatic disease in ten and was negative in 16; there were no false-positives and five false-negatives. There were six patients in whom FDG-PET was negative and computed tomography was regarded as suspicious but follow-up was inconclusive. The positive predictive value was 100%. The negative predictive value was 76% or 91%, depending on whether the aforementioned six cases were regarded as true-negatives or false-negatives. It may be concluded that FDG-PET is capable of detecting metastatic disease at diagnosis that is not identified by other imaging techniques. These preliminary results are sufficient to suggest that a large prospective study should be performed to evaluate the role of FDG-PET in primary staging of disease. Received 27 November 1999 and in revised form 21 January 2000     

Imaging metastatic testicular germ cell tumours with18FDG positron emission tomography: prospects for detection and management

The aim of this study was to investigate the role of positron emission tomography (PET) with [¹⁸F]fluoro-2-deoxyglucose (¹⁸FDG) in metastatic testicular germ cell tumours. Twenty-one patients with stage II–IV testicular germ cell tumours were imaged by PET with a multiwire proportional chamber PET system and¹⁸FDG. Avid¹⁸FDG uptake was seen in metastatic disease from primary seminoma and malignant teratoma. Normal tissue uptake was seen in differentiated teratoma or necrotic, fibrotic tissue.¹⁸FDG standard uptake values and tumour to normal tissue ratios were 6.0±1.4 and 1.7±0.4 (mean ± 1SD), respectively, for malignant tissue. Reduction of¹⁸FDG tumour to normal tissue ratios from pre-treatment to on-treatment scans was predictive of response (n=3). No significant reduction in¹⁸FDG uptake was seen in patients not responding to therapy (n=2). These results suggest a role for¹⁸FDG PET in the detection and management of metastatic testicular germ cell tumours.     

Cost-effectiveness of Fluorine-18-Fluorodeoxyglucose positron emission tomography in tumours other than lung cancer: A systematic review

AIM: To systematically review published data on the cost-effectiveness of Fluorine-18-Fluorodeoxyglucose positron emission tomography (FDG-PET) or PET/computed tomography (PET/CT) in tumours other than lung cancer.METHODS: A comprehensive literature search of studies published in PubMed/MEDLINE, Scopus and Embase databases through the 10^th of October in 2013 was carried out. A search algorithm based on a combination of the terms: (1) “PET” or “ PET/computed tomography (PET/CT)” or “positron emission tomography”; and (2) “cost-effectiveness” or “cost-utility” or “cost-efficacy” or “technology assessment” or “health technology assessment” was used. Only cost-effectiveness or cost-utility analyses in English language were included. Exclusion criteria were: (1) articles not within the field of interest of this review; (2) review articles, editorials or letters, conference proceedings; and (3) outcome evaluation studies, cost studies or health technology assessment reports. For each included study, information was collected concerning basic study, type of tumours evaluated, perspective/type of study, results, unit and comparison alternatives.RESULTS: Sixteen studies were included. Head and neck tumours were evaluated in 4 articles, lymphoma in 4, colon-rectum tumours in 3 and breast tumours in 2. Only one article was retrieved for melanoma, oesophagus and ovary tumours. Cost-effectiveness results of FDG-PET or PET/CT ranged from dominated to dominant.CONCLUSION: Literature evidence about the cost-effectiveness of FDG-PET or PET/CT in tumours other than lung cancer is still limited. Nevertheless, FDG-PET or PET/CT seems to be cost-effective in selective indications in oncology (staging and restaging of head and neck tumours, staging and treatment evaluation in lymphoma).     

Value of image fusion using single photon emission computed tomography with integrated low dose computed tomography in comparison with a retrospective voxel-based method in neuroendocrine tumours

The objective was the evaluation of single photon emission computed tomography (SPECT) with integrated low dose computed tomography (CT) in comparison with a retrospective fusion of SPECT and high-resolution CT and a side-by-side analysis for lesion localisation in patients with neuroendocrine tumours. Twenty-seven patients were examined by multidetector CT. Additionally, as part of somatostatin receptor scintigraphy (SRS), an integrated SPECT–CT was performed. SPECT and CT data were fused using software with a registration algorithm based on normalised mutual information. The reliability of the topographic assignment of lesions in SPECT–CT, retrospective fusion and side-by-side analysis was evaluated by two blinded readers. Two patients were not enrolled in the final analysis because of misregistrations in the retrospective fusion. Eighty-seven foci were included in the analysis. For the anatomical assignment of foci, SPECT–CT and retrospective fusion revealed overall accuracies of 91 and 94% (side-by-side analysis 86%). The correct identification of foci as lymph node manifestations (n=25) was more accurate by retrospective fusion (88%) than from SPECT–CT images (76%) or by side-by-side analysis (60%). Both modalities of image fusion appear to be well suited for the localisation of SRS foci and are superior to side-by-side analysis of non-fused images especially concerning lymph node manifestations.     

Fluorinated tracers for imaging cancer with positron emission tomography

2-[¹⁸F]fluoro-2-deoxy-d-glucose (FDG) is currently the only fluorinated tracer used in routine clinical positron emission tomography (PET). Fluorine-18 is considered the ideal radioisotope for PET imaging owing to the low positron energy (0.64 MeV), which not only limits the dose rate to the patient but also results in a relatively short range of emission in tissue, thereby providing high-resolution images. Further, the 110-min physical half-life allows for high-yield radiosynthesis, transport from the production site to the imaging site and imaging protocols that may span hours, which permits dynamic studies and assessment of potentially fairly slow metabolic processes. The synthesis of fluorinated tracers as an alternative to FDG was initially tested using nucleophilic fluorination of the molecule, as performed when radiolabelling with iodine-124 or bromide-76. However, in addition to being long, with multiple steps, this procedure is not recommended for bioactive molecules containing reactive groups such as amine or thiol groups. Radiochemical yields are also often low. More recently, radiosynthesis from prosthetic group precursors, which allows easier radiolabelling of biomolecules, has led to the development of numerous fluorinated tracers. Given the wide availability of ¹⁸F, such tracers may well develop into important routine tracers. This article is a review of the literature concerning fluorinated radiotracers recently developed and under investigation for possible PET imaging in cancer patients. Two groups can be distinguished. The first includes generalist tracers, i.e. tracers amenable to use in a wide variety of tumours and indications, very similar in this respect to FDG. These are tracers for non-specific cell metabolism, such as protein synthesis, amino acid transport, nucleic acid synthesis or membrane component synthesis. The second group consists of specific tracers for receptor expression (i.e. oestrogens or somatostatin), cell hypoxia or bone metabolism.     

Oncological applications of positron emission tomography with fluorine-18 fluorodeoxyglucose

Positron emission tomography (PET) is now primarily used in oncological indication owing to the successful application of fluorine-18 fluorodeoxyglucose (FDG) in an increasing number of clinical indications at different stages of diagnosis, and for staging and follow-up. This review first considers the biological characteristics of FDG and then discusses methodological considerations regarding its use. Clinical indications are considered, and the results achieved in respect of various organs and tumour types are reviewed in depth. The review concludes with a brief consideration of the ways in which clinical PET might be improved.     

Feasibility of imaging photodynamic injury to tumours by high-resolution positron emission tomography

One early effect of the treatment of tumours by the new modality photodynamic therapy (PDT) is a reduction in tumour glucose levels. We have employed the widely used positron-emitting glucose analogue flurorine-18 fluoro-2-deoxy-d-glucose ([¹⁸F]-FDG), to determine whether, in principle, PDT-induced injury might be delineated non-invasively and quantitatively by positron emission tomography (PET). The scanner was of the high-density avalanche-chamber (HIDAC) type with a resolution of 2.6 mm. Subcutaneous T50/80 mouse mammary tumours, sensitised by haematoporphyrin ester, were illuminated by graded doses of interstitial 630 nm light. Thirty hours later, any remaining viable tumour was detected (a) by region-of-interest analysis of the PET images and (b) by gamma counting the excised tumour. PET measurements of % uptake of [¹⁸F]-FDG into tumour correlated closely with ex vivo gamma counting (slope=0.976, r²⁼0.995), validating the in situ method. Uptake into untreated, control tumours was 3.8%±1.1% of the injected activity. Uptake of [¹⁸F]-FDG into treated tumours decreased by 0.7% for every 100 mm³ reduction in remaining viable histological volume. Outcome was further compared with that measured by (a) T2-weighted proton imaging on a 4.7-T magnetic resonance imaging (MRI) system and (b) histological analysis of subsequently sectioned tumours. PET using [¹⁸F]-FDG described the absolute volume of surviving tumour histological mass to the same degree as high-resolution MRI. The conclusion of these initial studies is that PET with [¹⁸F]-FDG, although non-specific, quantitatively described at early times the extent of tumour destruction by PDT. Received 1 April and in revised form 9 May 1998     

Resting state rCBF mapping with single-photon emission tomography and positron emission tomography: magnitude and origin of differences

Single-photon emission tomography (SPET), using technetium-99m hexamethylpropylene amine oxime, and positron emission tomography (PET), using oxygen-15 butanol were compared in six healthy male volunteers with regard to the mapping of resting state regional cerebral blood flow (rCBF). A computerized brain atlas was utilized for 3D regional analyses and comparison of 64 selected and normalized volumes of interest (VOIs). The normalized mean rCBF values in SPET, as compared to PET, were higher in most of the Brodmann areas in the frontal and parietal lobes (4.8% and 8.7% respectively). The average differences were small in the temporal (2.3%) and occipital (1.1%) lobes. PET values were clearly higher in small VOIs like the thalamus (12.3%), hippocampus (12.3%) and basal ganglia (9.9%). A resolution phantom study showed that the in-plane SPET/PET system resolution was 11.0/7.5 mm. In conclusion, SPET and PET data demonstrated a fairly good agreement despite the superior spatial resolution of PET. The differences between SPET and PET rCBF are mainly due to physiological and physical factors, the data processing, normalization and co-registration methods. In order to further improve mapping of rCBF with SPET it is imperative not only to improve the spatial resolution but also to apply accurate correction techniques for scatter, attenuation and non-linear extraction. Received 3 August and in revised form 1 October 1997     

Measurement of absolute bone blood flow by positron emission tomography

A method of measuring bone blood flow has been developed using ¹⁸F sodium fluoride and positron emission tomography. The blood flow levels are in line with those obtained experimentally from microsphere embolisation. This investigative method could be applied to elucidate a number of clinical questions involving bone perfusion.     

11C-5-hydroxytryptophan positron emission tomography after radiofrequency ablation of neuroendocrine tumor liver metastases

AimThe aim was to assess the feasibility of ¹¹C-5-hydroxy-tryptophan positron emission tomography (¹¹C-5-HTP-PET) in the follow-up after radiofrequency ablation (RFA) of liver metastases from neuroendocrine tumors (NETs).BackgroundContrast-enhanced computed tomography (CECT) and contrast-enhanced ultrasound (CEUS) are commonly used to evaluate the liver after RFA of NETs. In general, ¹¹C-5-HTP-PET is more sensitive in the visualization of NETs, but no studies have investigated its role after RFA.MethodsSix consecutive patients with liver metastases from NETs were subjected to RFA treatment. All patients underwent baseline imaging before RFA and on two occasions (1–2 and 6–11 months) after RFA. The imaging consisted of ¹¹C-5-HTP-PET, CEUS and CECT on all three occasions.ResultsThirty RFA areas were evaluated, and residual tumors (RTs) were depicted in eight areas (22%). ¹¹C-5-HTP-PET depicted RTs after RFA with maximum sensitivity (100%) and specificity (100%), using radiological follow-up as the gold standard. ¹¹C-5-HTP-PET detected five out of eight RTs earlier than CECT or CEUS. In general, the sensitivity of ¹¹C-5-HTP-PET exceeded that of CECT and CEUS for early visualization of NET liver metastases.Conclusion¹¹C-5-HTP-PET can be used in the follow-up after RFA for the purpose of detecting RT, and it provides additional information to CEUS and CECT by detecting new lesions.     

MRI and 18F-fluorodeoxyglucose positron emission tomography in hemimegalencephaly

We report hemimegalencephaly in a 44-year-old woman with mental retardation, epilepsy and a mild hemiparesis. In addition to typical findings on MRI, 2-deoxy-2[¹⁸F]fluorodeoxyglucose positron-emission tomography (PET) demonstrated glucose hypometabolism of the affected hemisphere. The results of PET have been coregistered with morphological information from the MRI studies by image fusion. Received: 14 December 1999/Accepted: 15 February 2000     

Wavelet based multiresolution expectation maximization image reconstruction algorithm for positron emission tomography

Maximum Likelihood (ML) estimation based Expectation Maximization (EM) [IEEE Trans Med Imag, MI-1 (2) (1982) 113] reconstruction algorithm has shown to provide good quality reconstruction for positron emission tomography (PET). Our previous work [IEEE Trans Med Imag, 7(4) (1988) 273; Proc IEEE EMBS Conf, 20(2/6) (1998) 759] introduced the multigrid (MG) and multiresolution (MR) concept for PET image reconstruction using EM. This work transforms the MGEM and MREM algorithm to a Wavelet based Multiresolution EM (WMREM) algorithm by extending the concept of switching resolutions in both image and data spaces. The MR data space is generated by performing a 2D-wavelet transform on the acquired tube data that is used to reconstruct images at different spatial resolutions. Wavelet transform is used for MR reconstruction as well as adapted in the criterion for switching resolution levels. The advantage of the wavelet transform is that it provides very good frequency and spatial (time) localization and allows the use of these coarse resolution data spaces in the EM estimation process. The MR algorithm recovers low-frequency components of the reconstructed image at coarser resolutions in fewer iterations, reducing the number of iterations required at finer resolution to recover high-frequency components. This paper also presents the design of customized biorthogonal wavelet filters using the lifting method that are used for data decomposition and image reconstruction and compares them to other commonly known wavelets.     

The value of positron emission tomography in patients with non-small cell lung cancer

Background

Pre-operative assessment of non-small cell lung cancer (NSCLC) is a major application of positron emission tomography (FDG-PET). Despite substantial evidence of diagnostic accuracy, relatively little attention has been paid to its effects on patient outcomes. This paper addresses this by extending an existing decision model to include patient-elicited utilities.

Patients and methods

A decision-tree model of the effect of FDG-PET on pre-operative staging was converted to a Markov model. Utilities for futile and appropriate thoracotomy were elicited from 75 patients undergoing staging investigation for NSCLC. The decision model was then used to estimate the expected value of perfect information (EVPI) associated with three sources of uncertainty—the accuracy of PET, the accuracy of CT and the patient related utility of a futile thoracotomy.

Results

The model confirmed the apparent cost-effectiveness of FDG-PET and indicated that the EVPI associated with the utility of futile thoracotomy considerably exceeds that associated with measures of accuracy.

Conclusion

The study highlights the importance of patient related utilities in assessing the cost-effectiveness of diagnostic technologies. In the specific case of PET for pre-operative staging of NSCLC, future research effort should focus on such elicitation, rather than further refinement of accuracy estimates.     

Imaging of the dopaminergic neurotransmission system using single-photon emission tomography and positron emission tomography in patients with parkinsonism

Parkinsonism is a feature of a number of neurodegenerative diseases, including Parkinson’s disease, multiple system atrophy and progressive supranuclear palsy. The results of post-mortem studies point to dysfunction of the dopaminergic neurotransmitter system in patients with parkinsonism. Nowadays, by using single-photon emission tomography (SPET) and positron emission tomography (PET) it is possible to visualise both the nigrostriatal dopaminergic neurons and the striatal dopamine D₂ receptors in vivo. Consequently, SPET and PET imaging of elements of the dopaminergic system can play an important role in the diagnosis of several parkinsonian syndromes. This review concentrates on findings of SPET and PET studies of the dopaminergic neurotransmitter system in various parkinsonian syndromes.     

Effect of tissue heterogeneity on quantification in positron emission tomography

As a result of the limited spatial resolution of positron emission tomographic scanners, the measurements of physiological parameters are compromised by tissue heterogeneity. The effect of tissue heterogeneity on a number of parameters was studied by simulation and an analytical method. Five common tracer models were assessed. The input and tissue response functions were assumed to be free from noise and systematic errors. The kinetic model was assumed to be perfect. Two components with different kinetics were mixed in different proportions and contrast with respect to the model parameters. Different experimental protocols were investigated. Of three methods investigated for the measurement of cerebral blood flow (CBF) (steady state, dynamic, integral), the second one was least sensitive to errors caused by tissue heterogeneity and the main effect was an underestimation of the distribution volume. With the steady state method, errors in oxygen extraction fraction caused by tissue heterogeneity were always found to be less than the corresponding errors in CBF. For myocardial blood flow the steady state method was found to perform better than the bolus method. The net accumulation of substrate (i.e. rCMRgjc in the case of glucose analogs) was found to be comparatively insensitive to tissue heterogeneity. Individual rate constants such ask ₂ andk ₃ for efflux and metabolism of the substrate in the pool of unmetabolized substrate in the tissue, respectively, were found to be more sensitive. In studies of radioligand binding, using only tracer doses, the effect of tissue heterogeneity on the parameterk _on ·B _max could be considerable. In studies of radioligand binding using a protocol with two experiments, one with high and one with low specific activity,B _max was found to be insensitive whileK _d was very sensitive to tissue heterogeneity.     

A hybrid method of attenuation correction for positron emission tomography brain studies

A hybrid method for attenuation correction (HAC) in positron emission tomography (PET) brain studies is proposed. The technique requires the acquisition of two short (1 min) transmission scans immediately before or after the emission study, with the patient and the head fixation system in place and after removing the patient from the scanner with the head fixation system alone. The method combines a uniform map of attenuation coefficients for the patient's head with measured attenuation coefficients for the head fixation system to generate a hybrid attenuation map. The HAC method was calibrated on 30 PET cerebral studies for comparison with the conventional measured attenuation correction method by ROI analysis. Average differences of less than 3% were found for cortical and subcortical regions. The HAC technique is particularly suitable in a PET clinical environment, allowing a reduction of the total study time, greater comfort for patients and an increase in patient throughput.     

Positron emission tomography/computed tomography for staging and restaging of head and neck cancer: comparison with positron emission tomography read together with contrast-enhanced computed tomography

This retrospective study aimed to describe the differences between image readings done with combined positron emission tomography/computed tomography (PET/CT) and PET read together with contrast-enhanced CT (ceCT) in patients with squamous cell carcinoma of the head and neck. In 46 patients, no differences were found between the two readings for assessing infiltration of adjacent structures (P=.63), transgression of the midline (P=.67), lymph node involvement (P=.32), and T- and N stage. PET/CT and PET read together with ceCT have comparable diagnostic yield.     

Dynamic study of methionine uptake in glioma using positron emission tomography

In order to evaluate the methionine uptake of a glioma with positron emission tomography (PET), the kinetics of carbon-11 methionine was investigated in 11 patients by measuring the free ¹¹C-methionine in plasma as an input function following intravenous administration. When the mean clearance curve of free ¹¹C-methionine in plasma instead of individual ¹¹C-methionine clearance curves was used, mean differences in uptake rate and distribution volume were 4.0% and 4.6% respectively. By applying the mean clearance curve of free ¹¹C-methionine in 18 glioma patients, significant differences in ¹¹C-methionine uptake rate and distribution volume were found according to pathological grading. For the accurate evaluation of the metabolism of ¹¹C-methionine, it is therefore preferable that the actual level of free ¹¹C-methionine in the plasma be measured, especially for the follow-up of individual cases. The study also demonstrated that the mean clearance curve of ¹¹C-methionine in plasma might be employed as an input curve for calculating the uptake rate and distribution volume with small errors. Offprint requests to: K. Sato