S. Hapdey

Comparative assessment of methods for estimating tumor volume and standardized uptake value in (18)F-FDG PET.

In 18F-FDG PET, tumors are often characterized by their metabolically active volume and standardized uptake value (SUV). However, many approaches have been proposed to estimate tumor volume and SUV from 18F-FDG PET images, none of them being widely agreed upon. We assessed the accuracy and robustness of 5 methods for tumor volume estimates and of 10 methods for SUV estimates in a large variety of configurations. Methods: PET acquisitions of an anthropomorphic phantom containing 17 spheres (volumes between 0.43 and 97 mL, sphere-to-surrounding-activity concentration ratios between 2 and 68) were used. Forty-one nonspheric tumors (volumes between 0.6 and 92 mL, SUV of 2, 4, and 8) were also simulated and inserted in a real patient 18F-FDG PET scan. Four threshold-based methods (including one, Tbgd, accounting for background activity) and a model-based method (Fit) described in the literature were used for tumor volume measurements. The mean SUV in the resulting volumes were calculated, without and with partial-volume effect (PVE) correction, as well as the maximum SUV (SUVmax). The parameters involved in the tumor segmentation and SUV estimation methods were optimized using 3 approaches, corresponding to getting the best of each method or testing each method in more realistic situations in which the parameters cannot be perfectly optimized. Results: In the phantom and simulated data, the Tbgd and Fit methods yielded the most accurate volume estimates, with mean errors of 2% ± 11% and −8% ± 21% in the most realistic situations. Considering the simulated data, all SUV not corrected for PVE had a mean bias between −31% and −46%, much larger than the bias observed with SUVmax (−11% ± 23%) or with the PVE-corrected SUV based on Tbgd and Fit (−2% ± 10% and 3% ± 24%). Conclusion: The method used to estimate tumor volume and SUV greatly affects the reliability of the estimates. The Tbgd and Fit methods yielded low errors in volume estimates in a broad range of situations. The PVE-corrected SUV based on Tbgd and Fit were more accurate and reproducible than SUVmax.

Simultaneous positron emission tomography (PET) assessment of metabolism with 18F-fluoro-2-deoxy-d-glucose (FDG), proliferation with 18F-fluoro-thymidine (FLT), and hypoxia with 18fluoro-misonidazole (F-miso) before and during radiotherapy in patients with non-small-cell lung cancer (NSCLC): A pilot study

OBJECTIVES To investigate the changes in tumour proliferation (using FLT), metabolism (using FDG), and hypoxia (using F-miso) during curative (chemo-) radiotherapy (RT) in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Thirty PET scans were performed in five patients (4 males, 1 female) that had histological proof of NSCLC and were candidates for curative-intent RT. Three PET-CT (Biograph S16, Siemens) scans were performed before (t(0)) and during (around dose 46 Gy, t(46)) RT with minimal intervals of 48 h between each PET-CT scan. The tracers used were (18)fluoro-2deoxyglucose (FDG) for metabolism, (18)fluorothymidine (FLT) for proliferation, and (18)F-misonidasole (F-miso) for hypoxia. The 3 image sets obtained at each time point were co-registered (rigid: n=9, elastic: n=1, Leonardo, TrueD, Siemens) using FDG PET-CT as reference. VOIs were delineated (40% SUV(max) values were used as a threshold) for tumours and lymph nodes on FDG PET-CT, and they were automatically pasted on FLT and F-miso PET-CT images. ANOVA and correlation analyses were used for comparison of SUV(max) values. RESULTS Four tumours and twelve nodes were identified on initial FDG PET-CT images. FLT SUV(max) values were significantly lower (p<0.0006) at t(46) in both tumours and nodes. The decrease in FDG SUV(max) values had a trend towards significance (p=0.048). F-Miso SUV(max) values were significantly higher in tumours than in nodes (p=0.02) and did not change during radiotherapy (p=0.39). A significant correlation was observed between FLT and FDG uptake (r=0.56, p<10(-4)) when all data were pooled together, and they remained similar when the before and during RT data were analysed separately. FDG and F-miso uptakes were significantly correlated (r=0.59, p=0.0004) when all data were analysed together. The best fit was obtained after adjusting for lesion type (tumour vs. node). This correlation was observed for the SUV(max) measured during RT (r=0.70, p=0.008) but not for the pre-RT data (r=0.19, p=0.35). The weak correlation between FLT and F-miso uptakes only became significant (r=0.66, p=0.002) when the analysis was restricted to the data acquired during RT. CONCLUSION Three different PET acquisitions can be performed quasi-simultaneously (4-7 days) before and during radiotherapy in patients with NSCLC. Our results at 46 Gy suggest that a fast decrease in the proliferation of both tumours and nodes exists during radiotherapy with differences in metabolism (borderline significant decrease) and hypoxia (stable).

Development of a generic thresholding algorithm for the delineation of 18FDG-PET-positive tissue: application to the comparison of three thresholding models

An iterative generic algorithm has been developed to compare three thresholding models used to delineate gross tumour volume on (18)F-FDG PET images. 3D volume was extracted and characteristic parameters were measured. Three fitting models using different parameters were studied: model 1 (volume, contrast), model 2 (contrast) and model 3 (SUV). The calibration was performed using a cylindrical phantom filled with hot spheres. To validate the models, two other phantoms were used. The calibration procedure showed a better fitting model for model 1 (R(2) from 0.94 to 1.00) than for model 3 (0.95) and model 2 (0.69). The validation study shows that model 3 yielded large volume measurement errors. Models 1 and 2 gave close results with no significant differences. Model 2 was preferred because it presents less error dispersion and needs fewer characteristic parameters, making it easier to implement. Our results show the importance of developing a generic algorithm to compare the performances of fitting models objectively and to validate results on other phantoms than the ones used during the calibration process to avoid methodological biases.

Does Recombinant Human Thyrotropin-Stimulated Positron Emission Tomography with [18F]Fluoro-2-Deoxy-d-Glucose Improve Detection of Recurrence of Well-Differentiated Thyroid Carcinoma in Patients with Low Serum Thyroglobulin?

BACKGROUND Thyrotropin (TSH) stimulates thyrocyte metabolism, glucose transport, and glycolysis. The interest in using recombinant human TSH (rhTSH) stimulation of fluoro-2-deoxy-D-glucose (FDG) with positron emission tomography (PET) has been shown, but mainly for patients with high serum thyroglobulin (Tg) concentration. We evaluated the use of rhTSH-stimulated PET-FDG in patients with low serum Tg concentration. METHODS Sixty-one PET/computed tomography (CT)-FDG (Biograph Sensation 16; Siemens Medical Solutions, Knoxville, TN) were performed in 44 patients (28 women and 16 men; 51 +/- 16 years) with positive Tg levels, negative or no contributive iodine-131 whole-body scintigraphy results, and no contributive morphological imaging results (ultrasound, magnetic resonance imaging, and CT). Thirty-eight patients had papillary carcinoma and six had follicular thyroid carcinoma. All patients had previously undergone total thyroidectomy and postoperative iodine ablation of thyroid bed remnant tissue. The rhTSH-stimulated PET/CT-FDG (5 MBq/kg) was performed after two 0.9 mg intramuscular doses of rhTSH (Thyrogen; Genzyme) which were administered 48 and 24 hours before imaging, while patients continued levothyroxine (LT(4)). Blood sampling was performed immediately before FDG injection for measurement of serum TSH and Tg concentrations (TSH(1) and Tg(1)) and after 48 hours (TSH(2) and Tg(2)). PET/CT-FDG findings were compared with the Tg: (i) at the initial iodine treatment during T(4) withdrawal (Tg(ini)), (ii) under T(4) (Tg(T4)) within 3 months before the PET/CT-FDG, (iii) with Tg(1), and (iv) with Tg(2). PET/CT-FDG findings were correlated with the findings of histology, iodine-131 whole-body scintigraphy, morphological imaging, or clinical follow-up. RESULTS The mean Tg(ini) was 785 +/- 2707 microg/L for a TSH of 73 +/- 64 mU/L. The mean Tg(T4) was 7 +/- 15 microg/L (T(4) = 195 +/- 59 microg/day; mean TSH of 0.24 +/- 0.57 mU/L). Among the 44 patients, PET/CT-FDG findings were positive in 20 and negative in 24. Among the 61 PET/CT-FDG, 25 PET/CT-FDG were positive (41%). Among the 25 positive PET, the Tg(T4) values were less than 10 microg/L for 19, including 9 true-positive patients (20% of the 44 patients). There was no difference of PET/CT-FDG results (positive vs. negative) as related to the serum Tg concentrations (p = 0.99 for Tg(ini), p = 0.95 for Tg(T4), p = 0.07 for Tg(1), and p = 0.42 for Tg(2)). No relation was observed with PET/CT-FDG results and initial tumor size (p = 0.52) or node metastasis (p = 0.14). CONCLUSION In the diagnosis of recurrent disease in patients with differentiated thyroid carcinoma and low Tg level, the sensitivity of rhTSH-stimulated PET/CT-FDG seems to be low and no correlation was observed between PET/CT-FDG findings and Tg level. However, positive PET-FDG results have been found in 9/44 (20%) patients with serum Tg levels lower than 10 microg/L. Therefore, this series shows that a cutoff value of 10 microg/L for the Tg under T(4) is probably not the best criteria to select patient candidates for PET/CT-FDG examination to detect the recurrence of differentiated thyroid carcinoma.

Biases affecting the measurements of tumor-to-background activity ratio in PET

The influence of various factors on the biases affecting tumor-to-background activity ratio (TBR) estimates in positron emission tomography (PET) was studied using analytical simulations of an anthropomorphic phantom. The impact of attenuation correction (AC) on TBR as a function of tumor location and tumor-to-background density ratio was studied. The TBR changes that would be observed when a tumor with uniform uptake turns to a tumor with nonuniform uptake due a necrotic process were characterized. Major parameters affecting the bias in TBR estimates were the tumor diameter, the TBR, whether AC had been performed and the spatial resolution of the PET scanner. Our results suggest that a necrotic process gets detectable if the necrotic volume is at least 50% of the total tumor volume for a necrosis-to-tumor activity ratio of 0.5. We discuss how our results regarding TBR biases translate into standardized uptake values biases.

Quantification in simultaneous 99mTc/123I brain SPECT using generalized spectral factor analysis: a Monte Carlo study

In SPECT, simultaneous 99mTc/123I acquisitions allow comparison of the distribution of two radiotracers in the same physiological state, without any image misregistration, but images can be severely distorted due to cross-talk between the two isotopes. We propose a generalized spectral factor analysis (GSFA) method for solving the cross-talk issue in simultaneous 99mTc/123I SPECT. In GSFA, the energy spectrum of the photons in any pixel is expressed as a linear combination of five common spectra: 99mTc and 123I photopeaks and three scatter spectra. These basis spectra are estimated from a factor analysis of all spectra using physical priors (e.g. Klein–Nishina distributions). GSFA was evaluated on 99mTc/123I Monte Carlo simulated data and compared to images obtained using recommended spectral windows (WIN) and to the gold standard (GS) images (scatter-free, cross-talk-free and noise-free). Using GSFA, activity concentration differed by less than 9% compared to GS values against differences from −23% to 110% with WIN in the 123I and 99mTc images respectively. Using GSFA, simultaneous 99mTc/123I imaging can yield images of similar quantitative accuracy as when using sequential and scatter-free 99mTc/123I imaging in brain SPECT.

Realistic and Efficient Modeling of Radiotracer Heterogeneity in Monte Carlo Simulations of PET Images With Tumors

Monte Carlo simulations are extensively used in PET to evaluate the accuracy with which PET images can yield reliable estimates of parameters of interest. For such applications, the simulated images should be as realistic as possible so that conclusions can be extrapolated to clinical PET images. In this work, we describe a method for introducing realistic modeling of radiotracer heterogeneity into Monte Carlo simulations of patient PET scans. The modeling of the complex physiological activity distribution in healthy regions is directly based on real patient PET/CT images, and realistic tumor shapes can be included into these regions. This method represents a competitive alternative to the use of complex anthropomorphic phantoms such as the XCAT, that require a fixed activity per structure. The method is extended to the simulation of serial PET scans with tumor changes, as acquired in the context of therapy monitoring, and this extension is validated using a patient study. Using the proposed method, very realistic patient PET images can be produced for evaluation purposes.In addition, a strategy to efficiently simulate many sets of pathological cases, based on a unique background physiological activity distribution, is described and carefully assessed using a numerical phantom. The background activity is simulated only once, while tumors are simulated separately. The data are then recombined in a specific way so that the final image has the same properties as images produced by simulating pathological and tumor activities at the same time.

Does enhanced CT influence the biological GTV measurement on FDG-PET images?

OBJECTIVES To test the influence of media injection in PET/CT on the functional or gross tumour volume measurement. PATIENTS AND METHODS Thirty-three patients (56 ± 19 years) with non-Hodgkins lymphoma (n=22) or Hodgkins disease (n=11) were prospectively studied at staging. PET/CTs were performed 60 min after injection of FDG. Iopamiron 300 (Iopamidol, 1.5cc/kg) was injected immediately after, followed 50s later by a second craniocaudal CT (CT+). PET images were successively reconstructed using the unenhanced CT (PET-) and the CT+ (PET+) for attenuation correction using iterative reconstruction (4 iterations, 8 subsets, 5mm post-filtering). The SUVmax, SUVmean, SUVpeak and functional tumoural volume were measured in tumoural lymphadenopathies or malignant tissues (n=56 VOIs) using 5 3D-thresholding methods on PET- and PET+ images: absolute SUV value of 2.5; 40% of SUVmax, and 3 adaptative thresholding methods (Vauclin, Black and Schaefer methods). RESULTS The SUVmean and the volume measurement were significantly different (p<0.001) for the five segmentation methods for PET- (p<0.001) and PET+ (p<0.001). The SUVmax, SUVmean and SUVpeak increased significantly in PET+ compared to PET- (2-5%). The SUVpeak was not significantly different for the five segmentation methods. The functional volume measurements were significantly different between PET- and PET+ only for the 2.5 segmentation method (+3%; p=0.001), but not for the 40%, Vauclin, Black and Schaefer methods. CONCLUSION The functional volume could be measured in PET/CT when CT was performed with enhanced media. Caution should be taken when using the volume delineation method. Volume delineation methods using absolute threshold may artefactually increase the functional volume when enhanced CT is used for attenuation correction. The delineation volume using the relative or adaptative method should be preferred when contrast media are used for PET/CT.

New Fetal Dose Estimates from 18F-FDG Administered During Pregnancy: Standardization of Dose Calculations and Estimations with Voxel-Based Anthropomorphic Phantoms.

Data from the literature show that the fetal absorbed dose from 18F-FDG administration to the pregnant mother ranges from 0.5E−2 to 4E–2 mGy/MBq. These figures were, however, obtained using different quantification techniques and with basic geometric anthropomorphic phantoms. The aim of this study was to refine the fetal dose estimates of published as well as new cases using realistic voxel-based phantoms. Methods: The 18F-FDG doses to the fetus (n = 19; 5–34 wk of pregnancy) were calculated with new voxel-based anthropomorphic phantoms of the pregnant woman. The image-derived fetal time-integrated activity values were combined with those of the mothers’ organs from the International Commission on Radiological Protection publication 106 and the dynamic bladder model with a 1-h bladder-voiding interval. The dose to the uterus was used as a proxy for early pregnancy (up to 10 wk). The time-integrated activities were entered into OLINDA/EXM 1.1 to derive the dose with the classic anthropomorphic phantoms of pregnant women, then into OLINDA/EXM 2.0 to assess the dose using new voxel-based phantoms. Results: The average fetal doses (mGy/MBq) with OLINDA/EXM 2.0 were 2.5E–02 in early pregnancy, 1.3E–02 in the late part of the first trimester, 8.5E–03 in the second trimester, and 5.1E–03 in the third trimester. The differences compared with the doses calculated with OLINDA/EXM 1.1 were +7%, +70%, +35%, and −8%, respectively. Conclusion: Except in late pregnancy, the doses estimated with realistic voxelwise anthropomorphic phantoms are higher than the doses derived from old geometric phantoms. The doses remain, however, well below the threshold for any deterministic effects. Thus, pregnancy is not an absolute contraindication of a clinically justified 18F-FDG PET scan.

Monte Carlo simulations of respiratory gated 18 F-FDG PET for the assessment of volume measurement methods

In PET/CT thoracic imaging, respiratory motion has been reported as a limiting factor reducing image quality and biasing lesion volume measurement. One solution consists in performing respiratory gated PET acquisitions. The aim of this study was to evaluate the impact of respiratory gating on Monte-Carlo realistic PET data, simulated using the 4D-NCAT numerical phantom on the GATE platform. To obtain reconstructed images as close as possible to those obtained in clinical conditions, a particular attention was paid to apply the same type of reconstruction and correction processes on the simulated data as on real clinical ones. The whole set of simulations required a CPU time of 140 000 h generating 1.5 To of data, including simulations of 147 respiratory gated and 49 ungated thoracic exams. Comparison of the displacement volume (DV) measurements using conventional PET acquisitions versus respiratory gated acquisitions was performed, using an automatic iterative segmentation method and a fixed 40% threshold. The segmentation of gated and ungated frames using the 40% fixed threshold needed time consuming initial manual exclusion of noisy structures and so not considered as an automatic method. This step was not necessary when the automatic iterative method was used. Accuracy on DV measurement using the automatic approach was largely improved on gated compared to ungated images. This improved accuracy might have a significant impact when patient treatment is performed using ungated external radiotherapy.