Annals of Nuclear Medicine (v.32, #2)

Evaluation of amyloid status in a cohort of elderly individuals with memory complaints: validation of the method of quantification and determination of positivity thresholds by Marie-Odile Habert; Hugo Bertin; Mickael Labit; Mamadou Diallo; Sullivan Marie; Kelly Martineau; Aurélie Kas; Valérie Causse-Lemercier; Hovagim Bakardjian; Stéphane Epelbaum; Gael Chételat; Marion Houot; Harald Hampel; Bruno Dubois; Jean-François Mangin; C. Audrain; H. Bakardjian; H. Benali; H. Bertin; L. Boukadida; F. Cacciamani; V. Causse-Lemercier; E. Cavedo; P. Chiesa; O. Colliot; A. Dos Santos; B. Dubois; S. Durrleman; S. Epelbaum; G. Gagliardi; R. Genthon; M.-O. Habert; H. Hampel; N. Jungalee; A. Kas; S. Lehericy; F. Lamari; C. Letondor; M. Levy; S. Lista; F. Mochel; F. Nyasse; C. Poisson; M. C. Potier; M. Revillon; K. Rojkova; P. Roy; K. Santos-Andrade; A. Santos; V. Simon; M. Sole; C. Tandetnik; M. Thiebaud De Schotten (75-86).
Our aim is to validate the process steps implemented by the French CATI platform to assess amyloid status, obtained from 18F-Florbetapir PET scans, in a cohort of 318 cognitively normal subjects participating in the INSIGHT-preAD study. Our objective was to develop a method with partial volume effect correction (PVEC) on untransformed PET images, using an automated pipeline (“RACHEL”) adapted to large series of patients and including quality checks of results.We compared RACHEL using different options (with and without PVEC, different sets of regions of interest), to two other methods validated in the literature, referred as the “AVID” and “CAEN” methods. A standard uptake value ratio (SUVR) was obtained with the different methods for participants to another French study, IMAP, including 26 normal elderly controls (NEC), 11 patients with mild cognitive impairment (MCI) and 16 patients with Alzheimer’s disease (AD). We determined two cutoffs for RACHEL method by linear correlation with the other methods and applied them to the INSIGHT-preAD subjects.RACHEL including PVEC and a combination of the whole cerebellum and the pons as a reference region allowed the best discrimination between NEC and AD participants. A strong linear correlation was found between RACHEL and the other two methods and yielded the two cutoffs of 0.79 and 0.88. According to the more conservative threshold, 19.8% of the INSIGHT-preAD subjects would be considered amyloid positive, and 27.7% according to the more liberal threshold.With our method, we clearly discriminated between NEC with negative amyloid status and patients with clinical AD. Using a linear correlation with other validated cutoffs, we could infer our own positivity thresholds and apply them to an independent population. This method might be useful to the community, especially when the optimal cutoff could not be obtained from a population of healthy young adults or from correlation with post-mortem results.
Keywords: Brain PET; 18F-Florbetapir; Amyloid burden quantification; Alzheimer’s disease

Use of quantitative SPECT/CT reconstruction in 99mTc-sestamibi imaging of patients with renal masses by Krystyna M. Jones; Lilja B. Solnes; Steven P. Rowe; Michael A. Gorin; Sara Sheikhbahaei; George Fung; Eric C. Frey; Mohamad E. Allaf; Yong Du; Mehrbod S. Javadi (87-93).
Technetium-99m (99mTc)-sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) has previously been shown to allow for the accurate differentiation of benign renal oncocytomas and hybrid oncocytic/chromophobe tumors (HOCTs) apart from other malignant renal tumor histologies, with oncocytomas/HOCTs showing high uptake and renal cell carcinoma (RCC) showing low uptake based on uptake ratios from non-quantitative single-photon emission computed tomography (SPECT) reconstructions. However, in this study, several tumors fell close to the uptake ratio cutoff, likely due to limitations in conventional SPECT/CT reconstruction methods. We hypothesized that application of quantitative SPECT/CT (QSPECT) reconstruction methods developed by our group would provide more robust separation of hot and cold lesions, serving as an imaging framework on which quantitative biomarkers can be validated for evaluation of renal masses with 99mTc-sestamibi.Single-photon emission computed tomography data were reconstructed using the clinical Flash 3D reconstruction and QSPECT methods. Two blinded readers then characterized each tumor as hot or cold. Semi-quantitative uptake ratios were calculated by dividing lesion activity by background renal activity for both Flash 3D and QSPECT reconstructions.The difference between median (mean) hot and cold tumor uptake ratios measured 0.655 (0.73) with the QSPECT method and 0.624 (0.67) with the conventional method, resulting in increased separation between hot and cold tumors. Sub-analysis of 7 lesions near the separation point showed a higher absolute difference (0.16) between QPSECT and Flash 3D mean uptake ratios compared to the remaining lesions.Our finding of improved separation between uptake ratios of hot and cold lesions using QSPECT reconstruction lays the foundation for additional quantitative SPECT techniques such as SPECT-UV in the setting of renal 99mTc-sestamibi and other SPECT/CT exams. With robust quantitative image reconstruction and biomarker analysis, there may be an expanded role for SPECT/CT imaging in renal masses and other pathologic conditions.
Keywords: Quantitative; SPECT; RCC; Sestamibi; Oncocytoma

Automatic lung segmentation in functional SPECT images using active shape models trained on reference lung shapes from CT by Grigorios-Aris Cheimariotis; Mariam Al-Mashat; Kostas Haris; Anthony H. Aletras; Jonas Jögi; Marika Bajc; Nicolaos Maglaveras; Einar Heiberg (94-104).
Image segmentation is an essential step in quantifying the extent of reduced or absent lung function. The aim of this study is to develop and validate a new tool for automatic segmentation of lungs in ventilation and perfusion SPECT images and compare automatic and manual SPECT lung segmentations with reference computed tomography (CT) volumes.A total of 77 subjects (69 patients with obstructive lung disease, and 8 subjects without apparent perfusion of ventilation loss) performed low-dose CT followed by ventilation/perfusion (V/P) SPECT examination in a hybrid gamma camera system. In the training phase, lung shapes from the 57 anatomical low-dose CT images were used to construct two active shape models (right lung and left lung) which were then used for image segmentation. The algorithm was validated in 20 patients, comparing its results to reference delineation of corresponding CT images, and by comparing automatic segmentation to manual delineations in SPECT images.The Dice coefficient between automatic SPECT delineations and manual SPECT delineations were 0.83 ± 0.04% for the right and 0.82 ± 0.05% for the left lung. There was statistically significant difference between reference volumes from CT and automatic delineations for the right (R = 0.53, p = 0.02) and left lung (R = 0.69, p < 0.001) in SPECT. There were similar observations when comparing reference volumes from CT and manual delineations in SPECT images, left lung (bias was − 10 ± 491, R = 0.60, p = 0.005) right lung (bias 36 ± 524 ml, R = 0.62, p = 0.004).Automated segmentation on SPECT images are on par with manual segmentation on SPECT images. Relative large volumetric differences between manual delineations of functional SPECT images and anatomical CT images confirms that lung segmentation of functional SPECT images is a challenging task. The current algorithm is a first step towards automatic quantification of wide range of measurements.
Keywords: Image segmentation; V/P SPECT; CT; Active shape model

Evaluation of bone metastatic burden by bone SPECT/CT in metastatic prostate cancer patients: defining threshold value for total bone uptake and assessment in radium-223 treated patients by Takuro Umeda; Mitsuru Koizumi; Shohei Fukai; Noriaki Miyaji; Kazuki Motegi; Shuto Nakazawa; Tomohiro Takiguchi (105-113).
To establish a new three-dimensional quantitative evaluation method for bone metastasis, we applied bone single photon emission tomography with computed tomography (SPECT/CT). The total bone uptake (TBU), which measures active bone metastatic burden, was calculated as the sum of [mean uptake obtained as standardized uptake value (SUV) above a cut-off level] × (the volume of the lesion) in the trunk using bone SPECT/CT. We studied the threshold value and utility of TBU in prostate cancer patients treated with radium-223 (Ra-223) therapy.To establish the threshold value of TBU, we compared bone metastatic and non-metastatic regions in 61 prostate cancer patients with bone metastasis and 69 without. Five fixed sites in each patient were selected as evaluation points and divided into bone metastatic and non-metastatic sites. Sensitivity and specificity analysis was applied to establish the threshold level. Using the obtained threshold value, we then calculated the TBU in nine prostate cancer patients who received Ra-223 therapy, and compared the results with the bone scan index (BSI) by BONENAVI® and visual evaluation of bone scintigraphy.Uptake was significantly lower in non-metastatic sites in patients with bone metastasis than in patients without metastasis. Sensitivity and specificity analysis revealed SUV = 7.0 as the threshold level. There was a discrepancy between TBU and BSI change in two of the nine patients, in whom TBU change correlated with visual judgement, but BSI change did not. In two patients, BSI was nearly 0 throughout the course, but the TBU was positive and changed, although the change was not large. These results suggest that TBU may be more accurate and sensitive than BSI for quantitative evaluation of active bone metastatic burden.We established a threshold value (SUV > 7.0) for three-dimensional TBU for evaluating active bone metastatic burden in prostate cancer patients using bone SPECT/CT. Despite the small number of patients, we expect the change in TBU could be more accurate and sensitive than the change in BSI among patients who received Ra-223.
Keywords: Bone SPECT/CT; TBU; Prostate cancer; Ra-therapy

Rational evaluation of the therapeutic effect and dosimetry of auger electrons for radionuclide therapy in a cell culture model by Ayaka Shinohara; Hirofumi Hanaoka; Tetsuya Sakashita; Tatsuhiko Sato; Aiko Yamaguchi; Noriko S. Ishioka; Yoshito Tsushima (114-122).
Radionuclide therapy with low-energy auger electron emitters may provide high antitumor efficacy while keeping the toxicity to normal organs low. Here we evaluated the usefulness of an auger electron emitter and compared it with that of a beta emitter for tumor treatment in in vitro models and conducted a dosimetry simulation using radioiodine-labeled metaiodobenzylguanidine (MIBG) as a model compound.We evaluated the cellular uptake of 125I-MIBG and the therapeutic effects of 125I- and 131I-MIBG in 2D and 3D PC-12 cell culture models. We used a Monte Carlo simulation code (PHITS) to calculate the absorbed radiation dose of 125I or 131I in computer simulation models for 2D and 3D cell cultures. In the dosimetry calculation for the 3D model, several distribution patterns of radionuclide were applied.A higher cumulative dose was observed in the 3D model due to the prolonged retention of MIBG compared to the 2D model. However, 125I-MIBG showed a greater therapeutic effect in the 2D model compared to the 3D model (respective EC50 values in the 2D and 3D models: 86.9 and 303.9 MBq/cell), whereas 131I-MIBG showed the opposite result (respective EC50 values in the 2D and 3D models: 49.4 and 30.2 MBq/cell). The therapeutic effect of 125I-MIBG was lower than that of 131I-MIBG in both models, but the radionuclide-derived difference was smaller in the 2D model. The dosimetry simulation with PHITS revealed the influence of the radiation quality, the crossfire effect, radionuclide distribution, and tumor shape on the absorbed dose. Application of the heterogeneous distribution series dramatically changed the radiation dose distribution of 125I-MIBG, and mitigated the difference between the estimated and measured therapeutic effects of 125I-MIBG.The therapeutic effect of 125I-MIBG was comparable to that of 131I-MIBG in the 2D model, but the efficacy was inferior to that of 131I-MIBG in the 3D model, since the crossfire effect is negligible and the homogeneous distribution of radionuclides was insufficient. Thus, auger electrons would be suitable for treating small-sized tumors. The design of radiopharmaceuticals with auger electron emitters requires particularly careful consideration of achieving a homogeneous distribution of the compound in the tumor.
Keywords: Radionuclide therapy; Auger electron emitter; 125/131I-Metaiodobenzylguanidine (125/131I-MIBG); 3D cell culture model; Computer simulation

Do clinical and laboratory variables have any impact on the diagnostic performance of 18F-FDG PET/CT in patients with fever of unknown origin? by Ana María García-Vicente; María Jesús Tello-Galán; Mariano Amo-Salas; Juan Ros-Izquierdo; German Andrés Jiménez-Londoño; Beatriz La Rosa Salas; Guadalupe Prado-Serrano Pradas; Francisco José Pena-Pardo; Ángel Soriano-Castrejón (123-131).
To assess the influence of clinical features and laboratory test results on the determination of fever of unknown origin (FUO) by means of 18F-FDG PET/CT.Retrospective and longitudinal analysis, including all the PET/CT studies requested for FUO. Reference standard was established by serology, cultures or biopsy with other laboratory tests or clinical follow-up when necessary. Clinical variables, inflammation markers, protein analysis, serology and culture results close to the PET scan were obtained. The final diagnosis was classified into three groups attending to the etiology; group 1: infection or neoplasm, group 2: vasculitis, autoimmune disease or non-infectious inflammatory disease and group 3: auto-limited fever or persistent fever without diagnosis. PET/CT scans were classified as positive or negative and helpful or not in the diagnosis of the fever origin. The effect of clinical features and laboratory variables on the PET/CT results was analyzed.Sixty-seven patients were evaluated. The final diagnosis was: Group 1 (25), Group 2 (20) and Group 3 (22). 89.6% of patients had a positive inflammation marker, 28.4% proteinogram alterations and 20.9% positive cultures. PET/CT was positive in 52/67 patients. PET/CT helped in the establishment of the fever origin in 35 cases and was especially helpful in groups 1 and 2. Sensitivity, specificity and accuracy of PET/CT were: 84, 31 and 61%. PET results shown significant relations with the final diagnosis (p = 0.035) and culture results (p = 0.037). No significant relations were observed with the rest of clinical or laboratory variables.18F-FDG PET/CT had a high sensitivity but a low specificity in the diagnosis of the fever origin, probably due to the high rate of diffuse and auto-limited aetiologies. Patients who are most likely to benefit from the PET/CT study would be those with several positive inflammation markers, reflecting a higher pre-test probability of active disease.
Keywords: Fever of unknown origin (FUO); 18F-FDG PET/CT; Inflammation markers; Diagnosis

Diagnostic accuracy of 11C-methionine PET in detecting neuropathologically confirmed recurrent brain tumor after radiation therapy by Annika Kits; Heather Martin; Alejandro Sanchez-Crespo; Anna F. Delgado (132-141).
This study aims to determine the diagnostic test accuracy (DTA) of 11C-methionine (MET) PET in the discrimination between recurrent tumor and radiation-induced injury in neuropathologically confirmed cases.A retrospective cohort of 30 patients with previously irradiated intracranial tumors (23 gliomas, 6 metastases, and 1 meningioma) was included. All patients underwent a preoperative MET PET and postoperative neuropathological analysis. Maximum and mean standardized uptake values (SUV) were obtained in the lesion, in the contralateral mirror region, and in the contralateral frontal cortex. Lesion-to-background SUV ratios (SUR mirror and SUR cortex) were then calculated. The Mann–Whitney U test was used to evaluate differences in SUV ratios between confirmed recurrent tumor and radiation injury. DTA was determined through receiver operating characteristic (ROC) analysis.Twenty-one patients had recurrent tumor and nine had radiation injury. The area under the ROC curve (AUC) was 0.89 for SURmaxmirror and 0.88 for SURmaxcortex. The mean (SD) of SURmaxmirror was 2.37 (0.58) in tumor recurrence and 1.57 (0.40) in radiation necrosis (P ≤ 0.001). The corresponding values for SURmaxcortex were 2.13 (0.50) and 1.45 (0.37) (P = 0.001). Clinically relevant cutoffs were SURmaxmirror ≥ 1.99 giving a specificity of 100% for tumor recurrence with a sensitivity of 76% and SURmaxcortex ≥ 1.58 giving a sensitivity and specificity of 90 and 78%, respectively.Based on neuropathologically confirmed cases, the DTA of SURmaxmirror and SURmaxcortex from 11C-methionine PET was high when discriminating recurrent tumor from radiation injury.
Keywords: Radiation injury; 11C-methionine PET; Radiosurgery; Brain tumor recurrence; Gamma-knife surgery

A 3-variable prognostic score (3-PS) for overall survival prediction in metastatic castration-resistant prostate cancer treated with 223Radium-dichloride by Viviana Frantellizzi; Alessio Farcomeni; Giulia Anna Follacchio; Massimiliano Pacilio; Rosanna Pellegrini; Roberto Pani; Giuseppe De Vincentis (142-148).
In mCRPC patients treated with 223Ra, a major issue is the validation of reliable prognostic and predictive biomarkers to maximize clinical benefit and minimize toxicities and costs. Bearing in mind how changes in tALP did not meet statistical requirements as surrogate marker for survival, aim of this single-center retrospective study was to characterize the prognostic and predictive role of baseline clinical variables associated with overall survival in patients receiving 223Ra treatment.92 consecutive CRPC patients with symptomatic bone metastases receiving 223Ra treatment were included. Available baseline clinical data relevant to the survival analysis were retrospectively collected. The primary end-point of the study was overall survival, which was established from the first 223Ra administration until date of death from any cause.Median follow-up time from the first 223Ra administration was 6 months (range 1–31 months). The univariate analysis evaluating the prognostic value of all baseline clinical variables showed that patients’ weight, BMI, ECOG PS, Hb and tALP values were independently associated with OS. On multivariable analysis only baseline Hb value and ECOG PS remained significantly correlated with OS. To determine reliable baseline predictive factors for survival in patients receiving 223Ra treatment, we produced a predictive score. We tried all possible variable combinations, and found that the best score was obtained by combining baseline ECOG PS with Hb < 12 g/dl and PSA ≥ 20 ng/ml. This resulted in a score ranging from 0 to 4, with AUC 78.4% (p < 0.001).We propose a multidimensional clinical evaluation to select those mCRPC subjects suitable to receive the maximum benefit from 223Ra treatment.
Keywords: 223Ra-dichloride; mCRPC; Predictive score; PSA; Overall survival