Preclinical Assessment of [68Ga]Ga-Cell Death Indicator (CDI): A Novel hsp90 Ligand for Positron Emission Tomography of Cell Death.

BACKGROUND: 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) when conjugated with a bifunctional chelator 2,2'-(7-(1-carboxy-4-((2,5-dioxopyrrolidin-1-yl)oxy)-4- oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODAGA) (hereafter referred to as Cell Death Indicator [CDI]), enters dead and dying cells and binds to 90kDa heat shock proteins (hsp90). OBJECTIVE: This study assesses stability, biodistribution, imaging, and radiation dosimetry of [68Ga]- Ga-CDI for positron emission tomography (PET). METHODS: Preparation of [68Ga]Ga-CDI was performed as previously described. Product stability and stability in plasma were assessed using high-performance liquid chromatography. Biodistribution and imaging were conducted in ten healthy male Lewis rats at 1 and 2 h following intravenous [68Ga]Ga-CDI injection. Human radiation dosimetry was estimated by extrapolation for a standard reference man and calculated with OLINDA/EXM 1.1. RESULTS: Radiochemical purity of [68Ga]Ga-CDI averaged 93.8% in the product and 86.7% in plasma at 4 h post-synthesis. The highest concentration of [68Ga]Ga-CDI is observed in the kidneys; [68Ga]Ga-CDI is excreted in the urine, and mean retained activity was 32.4% and 21.4% at 1 and 2 h post-injection. Lower concentrations of [68Ga]Ga-CDI were present in the small bowel and liver. PET CT was concordant and additionally demonstrated focal growth plate uptake. The effective dose for [68Ga]Ga-CDI is 2.16E-02 mSv/MBq, and the urinary bladder wall received the highest dose (1.65E-02 mSv/Mbq). CONCLUSION: [68Ga] Ga-CDI is stable and has favourable biodistribution, imaging, and radiation dosimetry for imaging of dead and dying cells. Human studies are underway.

18F-FDG PET-CT performed before and during radiation therapy of head and neck squamous cell carcinoma: Are they independent or complementary to each other?

INTRODUCTION: The aims of this study are to evaluate the prognostic value of metabolic parameters derived from (18) F-FDG PET-CT performed before definitive radiation therapy (RT) (prePET) in patients with mucosal primary head and neck squamous cell carcinoma (MPHNSCC) and to assess the additive prognostic values of FDG PET-CT performed during RT (iPET). METHODS: One hundred patients with MPHNSCC treated with radical RT underwent staging prePET and iPET performed during the third week of treatment. The maximum standardized uptake value (SUVmax ), metabolic tumour volume (MTV) and total lesional glycolysis (TLG) of primary tumour were analysed for both prePET and iPET, and results were correlated with loco-regional recurrence-free survival (LRFS), disease-free survival (DFS), metastatic failure-free survival (MFFS) and overall survival (OS), using Kaplan-Meier analysis. Optimal cut-offs (OC) for prePET and iPET were derived from Receiver Operating Characteristic curves. Patients with metabolic parameters above/below the individual OC of prePET as well as iPET (i.e. combined prePET and iPET (comPET)) were evaluated against their outcomes. RESULTS: Median age was 61 years (range 39-81), median follow-up of 20 months (range 4-70, mean 27), and AJCC 7th Edition clinical stage II, III and IV were 8, 24 and 68 patients respectively. Metabolic values below individual OC in comPET were found to be associated with statistically significant improvements (P < 0.05) in DFS, LRFS and OS. In addition, patients with SUVmax above the OC in comPET were associated with worse MFFS (P = 0.011) and confirmed on both univariate (P = 0.019) and multivariate analyses (P = 0.04). CONCLUSION: Addition of iPET significantly improves the prognostic values of all three metabolic parameters and can potentially be used in future adaptive local and systemic therapy trials.

Prognostic role of metabolic parameters of (18)F-FDG PET-CT scan performed during radiation therapy in locally advanced head and neck squamous cell carcinoma.

PURPOSE: To evaluate the prognostic value of (18)F-FDG PET-CT performed in the third week (iPET) of definitive radiation therapy (RT) in patients with newly diagnosed locally advanced mucosal primary head and neck squamous-cell-carcinoma (MPHNSCC). METHODOLOGY: Seventy-two patients with MPHNSCC treated with radical RT underwent staging PET-CT and iPET. The maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV) and total lesional glycolysis (TLG) of primary tumour (PT) and index node (IN) [defined as lymph node(s) with highest TLG] were analysed, and results were correlated with loco-regional recurrence-free survival (LRFS), disease-free survival (DFS), metastatic failure-free survival(MFFS) and overall survival (OS), using Kaplan-Meier analysis. RESULTS: Optimal cutoffs (OC) were derived from receiver operating characteristic curves: SUVmax-PT = 4.25 g/mL, MTVPT = 3.3 cm(3), TLGPT = 9.4 g, for PT, and SUVmax-IN = 4.05 g/mL, MTVIN = 1.85 cm(3) and TLGIN = 7.95 g for IN. Low metabolic values in iPET for PT below OC were associated with statistically significant better LRFS and DFS. TLG was the best predictor of outcome with 2-year LRFS of 92.7 % vs. 71.1% [p = 0.005, compared with SUVmax (p = 0.03) and MTV (p = 0.022)], DFS of 85.9% vs. 60.8% [p = 0.005, compared with SUVmax (p = 0.025) and MTV (p = 0.018)], MFFS of 85.9% vs. 83.7% [p = 0.488, compared with SUVmax (p = 0.52) and MTV (p = 0.436)], and OS of 81.1% vs. 75.0% [p = 0.279, compared with SUVmax (p = 0.345) and MTV (p = 0.512)]. There were no significant associations between the percentage reduction of primary tumour metabolic parameters and outcomes. In patients with nodal disease, metabolic parameters below OC (for both PT and IN) were significantly associated with all oncological outcomes, while TLG was again the best predictor: LRFS of 84.0% vs. 55.3% (p = 0.017), DFS of 79.4% vs. 38.6% (p = 0.001), MFFS 86.4% vs. 68.2% (p = 0.034) and OS 80.4% vs. 55.7% (p = 0.045). CONCLUSION: The metabolic parameters of iPET can be useful predictors of patient outcome and potentially have a role in adaptive therapy for MPHNSCC. Among the three parameters, TLG was found to be the best prognostic indicator of oncological outcomes.

Workflow and radiation safety implications of (18)F-FDG PET/CT scans for radiotherapy planning.

UNLABELLED: The use of (18)F-FDG PET/CT for radiotherapy planning may lead to better tumor volume definition. Reproduction of the patient's position when setting up an (18)F-FDG PET/CT scan for radiotherapy planning is more accurate if a radiation therapist is involved. The aim of this study was to compare setup time and staff radiation dose between radiation therapists and nuclear medicine technologists. METHODS: Forty patients with newly diagnosed head and neck or non-small cell lung cancer were prospectively recruited into this study. Twenty patients (10 with head and neck cancer and 10 with non-small cell lung cancer) underwent (18)F-FDG PET/CT for radiotherapy planning, and 20 patients (10 with head and neck cancer and 10 with non-small cell lung cancer) underwent (18)F-FDG PET/CT for staging. Setup time was measured, and a radiation monitor recorded the highest dose (µSv/h) to staff during setup. RESULTS: For radiation therapists, the mean setup time for a lung scan (in min:s) was 5:22 ± 2:11 (range, 2:22-9:23), with a highest dose of 4.94 ± 3.78 µSv (range, 2.02-15.23 µSv), and the mean setup time for a head and neck scan was 4:49 ± 1:45 (range, 2:03-8:21), with a highest dose of 3.93 ± 1.45 µSv (range, 1.19-6.83 µSv). For nuclear medicine technologists, the mean setup time for a lung scan was 1:58 ± 0:24 (range, 1:17-2:38), with a highest dose of 3.30 ± 1.28 µSv (range, 1.92-5.47 µSv), and the mean setup time for a head and neck scan was 2:12 ± 0:38 (range, 1:03-3:16), with a highest dose of 3.10 ± 1.78 µSv (range, 1.56-7.49 µSv). CONCLUSION: This study showed that setup time and operator radiation dose were greater for radiation therapists setting up planning (18)F-FDG PET/CT scans than for nuclear medicine technologists setting up routine (18)F-FDG PET/CT scans. These results have implications for scheduling of radiotherapy planning PET/CT; however, the additional radiation dose was not considered to be significant.

The prevalence and clinical significance of (18) F-2-fluoro-2-deoxy-D-glucose (FDG) uptake in the thyroid gland on PET or PET-CT in patients with lymphoma.

F(18) -2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) has become a well established tool in staging and assessing therapy response in lymphoma. Incidental thyroid uptake on PET is not uncommon and can pose a diagnostic and management challenge. We retrospectively evaluate the prevalence and clinical significance of incidental FDG uptake in the thyroid gland in patients with lymphoma. 1868 lymphoma patients underwent PET and PET-CT between August 2002 and August 2008. 52 patients (2.8%) demonstrated FDG thyroid uptake (M = 17, F = 35; mean age 63 yr). Thyroid uptake was determined as focal or diffuse, maximum standardized uptake values (SUVmax) recorded as well as SUV max ratio compared to background mediastinum activity (SUVR). Corresponding CT findings on PET-CT were evaluated independently. Results were correlated with clinical, histopathological and imaging follow-up. 30 (1.6%) patients had focal thyroid uptake. 16 (53%) had histological confirmation either by surgery (n = 7) or FNA under USS (n = 9). The final diagnosis was benign in 12/30 patients and malignant in 9/30. The malignancy risk for focal thyroid uptake was 30%. Five patients had intercurrent thyroid cancer (four papillary, one microinvasive follicular) and four had lymphomatous involvement. There was no significant difference between the mean sizes of benign (23.7 mm, range 12-34) and malignant nodules (23.6 mm, range 8-48). The mean SUVmax of malignant and benign nodules was 4.4 (range 1.8-10.1) and 3.2 (range 1.8-6.9) respectively with no statistically significant difference. 22 (1.2%) patients had diffuse FDG uptake in thyroid and benign aetiology was found in all with adequate follow-up (15/22). Focal FDG thyroid uptake on PET or PET-CT in lymphoma patients warrants further investigations. The malignancy risk is 30% either due to intercurrent thyroid cancer or lymphomatous involvement. SUVmax, SUVR and CT attenuation characteristics are not helpful in distinguishing between benign and malignant aetiologies. Diffuse thyroid uptake has a benign aetiology.

Positron emission tomography and colorectal cancer.

Colorectal cancer (CRC) is a major cause of cancer-related morbidity and mortality. Molecular imaging using positron emission tomography (PET) is now an integral part of multidisciplinary cancer care. In this review, we discuss the role of PET in CRC including well established indications in the assessment of recurrent disease and emerging applications such as initial staging, monitoring therapy efficacy and using PET for radiotherapy planning. With rapid advancement in imaging technology, we also discuss the future potential of combining PET and magnetic resonance imaging and the use of novel radiotracers.

Treatment response in liver metastases following 90Y SIR-spheres: an evaluation with PET.

Selective internal radiation therapy (SIRT) with radiolabeled Yttrium-90 (90Y) microspheres is a relatively new therapeutic option for patients with primary or secondary hepatic malignancy. However, the evaluation of the therapeutic efficacy on anatomic imaging alone is suboptimal. Functional imaging with F18-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) is increasingly utilised in therapy monitoring in malignancy and provides an accurate assessment of metabolic response. We report a case of a 75-year-old gentleman with colorectal hepatic metastases who demonstrated a dramatic metabolic response on PET scan following SIRT. This case illustrates the utility of FDG PET in the assessment of the therapeutic efficacy of 90Y microspheres in colorectal hepatic metastases.

F-18 FDG positron emission tomography and benign fractures.

PURPOSE: F-18 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) has been used extensively in the imaging of cancer, including metastatic skeletal disease. Although uptake into benign osseous disease has been reported, there is very limited information regarding uptake into benign fractures. This report provides additional information regarding the appearance of benign fractures on FDG-PET images. MATERIALS AND METHODS: Four case reports of FDG-PET scanning are presented in patients with proved benign fractures. RESULTS: In three of these cases, FDG uptake was noted in fractures when images were obtained 17 days to 8 weeks after injury, with the most avid uptake observed when FDG-PET imaging was performed 17 days after fracture. In the patient in whom imaging was performed 8 weeks after fracture, no uptake of FDG was seen in a benign fracture. CONCLUSIONS: Fractures may accumulate FDG to varying degrees, and false-positive findings may occur when FDG-PET imaging is performed to assess for metastases, although the different pattern of uptake and clinical correlation usually allows accurate differentiation of fracture from skeletal metastases.