18F-FSPG PET/CT Imaging of System xC- Transporter Activity in Patients with Primary and Metastatic Brain Tumors.

Background The PET tracer (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (18F-FSPG) targets the system xC- cotransporter, which is overexpressed in various tumors. Purpose To assess the role of 18F-FSPG PET/CT in intracranial malignancies. Materials and Methods Twenty-six patients (mean age, 54 years ± 12; 17 men; 48 total lesions) with primary brain tumors (n = 17) or brain metastases (n = 9) were enrolled in this prospective, single-center study (ClinicalTrials.gov identifier: NCT02370563) between November 2014 and March 2016. A 30-minute dynamic brain 18F-FSPG PET/CT scan and a static whole-body (WB) 18F-FSPG PET/CT scan at 60-75 minutes were acquired. Moreover, all participants underwent MRI, and four participants underwent fluorine 18 (18F) fluorodeoxyglucose (FDG) PET imaging. PET parameters and their relative changes were obtained for all lesions. Kinetic modeling was used to estimate the 18F-FSPG tumor rate constants using the dynamic and dynamic plus WB PET data. Imaging parameters were correlated to lesion outcomes, as determined with follow-up MRI and/or pathologic examination. The Mann-Whitney U test or Student t test was used for group mean comparisons. Receiver operating characteristic curve analysis was used for performance comparison of different decision measures. Results 18F-FSPG PET/CT helped identify all 48 brain lesions. The mean tumor-to-background ratio (TBR) on the whole-brain PET images at the WB time point was 26.6 ± 24.9 (range: 2.6-150.3). When 18F-FDG PET was performed, 18F-FSPG permitted visualization of non-18F-FDG-avid lesions or allowed better lesion differentiation from surrounding tissues. In participants with primary brain tumors, the predictive accuracy of the relative changes in influx rate constant Ki and maximum standardized uptake value to discriminate between poor and good lesion outcomes were 89% and 81%, respectively. There were significant differences in the 18F-FSPG uptake curves of lesions with good versus poor outcomes in the primary brain tumor group (P < .05) but not in the brain metastases group. Conclusion PET/CT imaging with (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (18F-FSPG) helped detect primary brain tumors and brain metastases with a high tumor-to-background ratio. Relative changes in 18F-FSPG uptake with multi-time-point PET appear to be helpful in predicting lesion outcomes. Clinical trial registration no. NCT02370563 © RSNA, 2022 Online supplemental material is available for this article.

The State of Peptide Receptor Radionuclide Therapy and Its Sequencing among Current Therapeutic Options for Gastroenteropancreatic Neuroendocrine Tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the most common form of neuroendocrine neoplasia, but there is no current consensus for the sequencing of approved therapies, particularly with respect to peptide receptor radionuclide therapy (PRRT). This comprehensive review evaluates the data supporting approved therapies for GEP-NETs and recommendations for therapeutic sequencing with a focus on how PRRT currently fits within sequencing algorithms. The current recommendations for PRRT sequencing restrict its use to metastatic, inoperable, progressive midgut NETs; however, this may change with emerging data to suggest that PRRT might be beneficial as neoadjuvant therapy for inoperable tumors, is more tolerable than other treatment modalities following first-line standard dose somatostatin analogs, and can be used as salvage therapy after disease relapse following prior successful cycles of PRRT. PRRT has also been shown to reduce tumor burden, improve quality of life, and prolong the time to disease progression in a broad spectrum of patients with GEP-NETs. As the various potential benefits of PRRT in GEP-NET therapy continues to expand, it is necessary to review and critically evaluate our treatment algorithms for GEP-NETs.

Neuroendocrine Tumor Therapy: 177Lu-DOTATATE.

OBJECTIVE: The purposes of this article are to increase understanding of the concepts of theranostics and peptide receptor radionuclide therapy (PRRT) as they apply to neuroendocrine tumors (NETs); review the key 1, 2, and 3 clinical trial data leading to the approval of 177Lu-tetraazacyclododecanetetraacetic acid-octreotide (177Lu-DOTATATE); and foster understanding of the practical aspects and future directions of PRRT for NETs. CONCLUSION: In January 2018, 177Lu-DOTATATE therapy was approved in the United States (previously approved in Europe in September 2017) for adult patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, including those of the foregut, midgut, and hindgut. The results of the phase 3 Neuroendocrine Tumors Therapy (NETTER-1) trial show favorable outcomes with respect to the primary endpoint of progression-free survival and a host of secondary objectives, including overall survival, objective response rate, and quality of life measures. Patient selection is based on a number of specific factors and should be sequenced carefully with respect to other available therapies, ideally in multidisciplinary cancer conferences. Establishing the therapy at a new institution can be somewhat involved, but once it is established, the therapy is fairly straightforward to administer and is well tolerated with limited side-effects and toxicity. A number of approaches and issues are still to be worked out, and this therapy will continue to be studied and optimized.

Characterization of Physiologic (18)F FSPG Uptake in Healthy Volunteers.

Purpose To evaluate the normal biodistribution and kinetics of (S)-4-(3-[18F]fluoropropyl)-l-glutamic acid ((18)F FSPG) in healthy volunteers and to compare (18)F FSPG mean and maximum standardized uptake values (SUVmean and SUVmax, respectively) with those of (18)F fluorodeoxyglucose (FDG) across a variety of organs. Materials and Methods This protocol was reviewed and approved by all appropriate regulatory authorities. An 8-mCi (±10%) dose of (18)F FSPG was given to five subjects (three women, two men), and seven whole-body positron emission tomography (PET) scans were performed 5, 10, 20, 30, 45, 150, and 240 minutes after injection. Regions of interest were analyzed on the resultant (18)F FSPG images to evaluate the kinetics of this radiotracer. The images obtained 45 minutes after injection were used to measure SUVmean and SUVmax in additional regions of the body. These values were compared with similar values obtained with (18)F FDG PET published previously. Descriptive statistics, including average and standard deviation across the five subjects, were used. (18)F FSPG SUVmean and SUVmax were compared. Results On the (18)F FSPG images obtained 45 minutes after injection, there was only low-grade background activity in the majority of analyzed regions. Prominent activity was seen throughout the pancreas. Clearance of the radiotracer through the kidneys and collection in the bladder also were seen. SUV quantification shows notable differences between (18)F FSPG and (18)F FDG in the pancreas ((18)F FSPG SUVmean, 8.2; (18)F FDG SUVmean, 1.3), stomach ((18)F FSPG SUVmax, 3.6; (18)F FDG SUVmax, 1.6), and brain ((18)F FSPG SUVmean, 0.08; (18)F FDG SUVmean, 7.8). The kinetic data showed rapid clearance of the radiotracer from the blood pool and most organs, except the pancreas. Conclusion (18)F FSPG is a PET radiopharmaceutical characterized by rapid clearance from most healthy tissues, except the pancreas and kidneys. A consistent biodistribution pattern was observed with low background uptake. The physiologic uptake of this new radiotracer throughout the body is described in more detail, which is important for improved interpretative accuracy and understanding potential clinical applications. (©) RSNA, 2016.

Fusion dual-tracer SPECT-based hepatic dosimetry predicts outcome after radioembolization for a wide range of tumour cell types.

PURPOSE: Fusion dual-tracer SPECT imaging enables physiological rather than morphological voxel-based partitioning and dosimetry for (90)Y hepatic radioembolization (RE). We evaluated its prognostic value in a large heterogeneous cohort of patients with extensive hepatic malignancy. METHODS: A total of 122 patients with primary or secondary liver malignancy (18 different cell types) underwent SPECT imaging after intraarterial injection of (99m)Tc macroaggregated albumin (TcMAA) as a simulation of subsequent (90)Y microsphere distribution, followed by administration of an excess of intravenous (99m)Tc-labelled sulphur colloid (TcSC) as a biomarker for functional liver, and a second SPECT scan. TcMAA distribution was used to estimate (90)Y radiation absorbed dose in tumour (D T) and in functional liver. Laboratory and clinical follow-up were recorded for 12 weeks after RE, and radiographic responses according to (m)RECIST were evaluated at 3 and 6 months. Dose-response relationships were determined for efficacy and toxicity. RESULTS: Patients were treated with a median of 1.73 GBq activity of resin microspheres (98 patients) or glass microspheres (24 patients), in a whole-liver approach (97 patients) or a lobar approach (25 patients). The objective response rate was 41% at 3 months and 48% at 6 months. Response was correlated with D T (P < 0.01). Median overall survival was 10.1 months (95% confidence interval 7.4 - 12.8 months). Responders lived for 36.0 months compared to 8.7 months for nonresponders (P < 0.01). Stratified for tumour cell type, D T was independently associated with survival (P < 0.01). Absorbed dose in functional liver was correlated with toxicity grade change (P < 0.05) and RE-induced liver disease (P < 0.05). CONCLUSION: Fusion dual-tracer SPECT imaging offers a physiology-based functional imaging tool to predict efficacy and toxicity of RE. This technique can be refined to define dosing thresholds for specific tumour types and treatments, but appears generally predictive even in a heterogeneous cohort.

Case 207: Hodgkin lymphoma with paraneoplastic hypercalcemic pancreatitis.

A 15-year-old girl presented with a 2-month history of 30-lb (13.6 kg) weight loss, chest and abdominal pain, nausea, bilious emesis, cough, and shortness of breath. Initial blood count (performed at an outside hospital) showed elevated white blood cell and platelet counts but low hemoglobin and hematocrit levels. On examination, she had adenopathy in the left axillary and supraclavicular regions, fullness in the left chest, and abdominal guarding. Ultrasonography (US)-guided fine-needle aspiration biopsy of the left anterior chest wall mass was nondiagnostic, and lumbar puncture and bone marrow biopsies were negative. At that time, the patient underwent several imaging studies-including chest radiography; bone scanning; contrast material-enhanced computed tomography (CT) of the chest, abdomen, and pelvis; and fluorine 18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT-all performed within 1 week of each other. Pertinent serum laboratory values at the time of these tests were as follows: calcium level, 17 mg/dL (4.25 mmol/L) (normal range, 8.5-10.5 mg/dL [2.1-2.6 mmol/L]); ionized calcium level, 2.3 mmol/L (normal range, 1.1-1.3 mmol/L); lipase level, 2423 U/L (normal level, <300 U/L); amylase level, 1435 U/L (normal level, <140 U/L); lactate dehydrogenase level, 253 U/L (normal level, <240 U/L), albumin level, 2.6 g/dL (26 g/L) (normal level, 3.5-5.0 g/dL [35-50 g/L]), and creatinine level, 1.7 mg/dL (150.3 µmol/L) (normal level, <1.2 mg/dL [<106.1 µmol/L]). A follow-up PET/CT scan was performed approximately 2 months later after initial therapy.

Clinical [18F]FSPG Positron Emission Tomography Imaging Reveals Heterogeneity in Tumor-Associated System xc- Activity.

BACKGROUND: (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) positron emission tomography/computed tomography (PET/CT) provides a readout of system xc- transport activity and has been used for cancer detection in clinical studies of different cancer types. As system xc- provides the rate-limiting precursor for glutathione biosynthesis, an abundant antioxidant, [18F]FSPG imaging may additionally provide important prognostic information. Here, we performed an analysis of [18F]FSPG radiotracer distribution between primary tumors, metastases, and normal organs from cancer patients. We further assessed the heterogeneity of [18F]FSPG retention between cancer types, and between and within individuals. METHODS: This retrospective analysis of prospectively collected data compared [18F]FSPG PET/CT in subjects with head and neck squamous cell cancer (HNSCC, n = 5) and non-small-cell lung cancer (NSCLC, n = 10), scanned at different institutions. Using semi-automated regions of interest drawn around tumors and metastases, the maximum standardized uptake value (SUVmax), SUVmean, SUV standard deviation and SUVpeak were measured. [18F]FSPG time-activity curves (TACs) for normal organs, primary tumors and metastases were subsequently compared to 18F-2-fluoro-2-deoxy-D-glucose ([18F]FDG) PET/CT at 60 min post injection (p.i.). RESULTS: The mean administered activity of [18F]FSPG was 309.3 ± 9.1 MBq in subjects with NSCLC and 285.1 ± 11.3 MBq in those with HNSCC. The biodistribution of [18F]FSPG in both cohorts showed similar TACs in healthy organs from cancer patients. There was no statistically significant overall difference in the average SUVmax of tumor lesions at 60 min p.i. for NSCLC (8.1 ± 7.1) compared to HNSCC (6.0 ± 4.1; p = 0.29) for [18F]FSPG. However, there was heterogeneous retention between and within cancer types; the SUVmax at 60 min p.i. ranged from 1.4 to 23.7 in NSCLC and 3.1-12.1 in HNSCC. CONCLUSION: [18F]FSPG PET/CT imaging from both NSCLC and HNSCC cohorts showed the same normal-tissue biodistribution, but marked tumor heterogeneity across subjects and between lesions. Despite rapid elimination through the urinary tract and low normal-background tissue retention, the diagnostic potential of [18F]FSPG was limited by variability in tumor retention. As [18F]FSPG retention is mediated by the tumor's antioxidant capacity and response to oxidative stress, this heterogeneity may provide important insights into an individual tumor's response or resistance to therapy.

Establishing a robust radioligand therapy program: A practical approach for North American centers.

Radioligand therapy (RLT) is a targeted approach to treating cancer that has been shown to be safe and effective in a variety of disease states, including gastroenteropancreatic neuroendocrine tumors, lymphoma, and most recently, advanced prostate cancer. In the United States, patient access to this therapy is currently variable. Implementation of new RLT programs and expansion of existing programs are needed to broaden patient access to and standardize the delivery of RLT, especially as new therapies are introduced into clinical practice. Drawing from experience in establishing RLT programs in different settings, we have developed practical recommendations for building and implementing a robust RLT program. In this review, we present our recommendations for minimal requirements and optimal requirements, as well as system considerations, and special issues associated with implementing an RLT program in North American centers.

Consideration of quality of life in the treatment decision-making for patients with advanced gastroenteropancreatic neuroendocrine tumors.

INTRODUCTION: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a complex and heterogenous family of solid malignancies that originate from neuroendocrine tissue in the gastrointestinal tract or pancreas. Most patients diagnosed with GEP-NETs present with advanced or metastatic disease, and quality of life (QoL) is often an important priority when selecting treatments for these patients. Patients with advanced GEP-NETs often experience a substantial and persistent symptom burden that undermines their QoL. Addressing a patient's individual symptoms through judicious selection of treatment may improve QoL. AREAS COVERED: The objectives of this narrative review are to summarize the impact of advanced GEP-NETs on patient QoL, assess the potential value of current treatments for maintaining or improving patient QoL, and offer a clinical framework for how these QoL data can be translated to inform clinical decision-making for patients with advanced GEP-NETs. EXPERT OPINION: Patients with advanced GEP-NETs experience a significant and persistent symptom burden that impacts their daily lifestyle, activities, work life, and financial health, leading to erosion of their QoL. Ongoing and future studies incorporating longitudinal QoL assessments and head-to-head treatment evaluations will further inform the incorporation of QoL into clinical decision-making.

Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline.

PURPOSE: To develop recommendations for systemic therapy for well-differentiated grade 1 (G1) to grade 3 (G3) metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS: ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS: Eight randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS: Somatostatin analogs (SSAs) are recommended as first-line systemic therapy for most patients with G1-grade 2 (G2) metastatic well-differentiated GI-NETs. Observation is an option for patients with low-volume or slow-growing disease without symptoms. After progression on SSAs, peptide receptor radionuclide therapy (PRRT) is recommended as systematic therapy for patients with somatostatin receptor (SSTR)-positive tumors. Everolimus is an alternative second-line therapy, particularly in nonfunctioning NETs and patients with SSTR-negative tumors. SSAs are standard first-line therapy for SSTR-positive pancreatic (pan)NETs. Rarely, observation may be appropriate for asymptomatic patients until progression. Second-line systemic options for panNETs include PRRT (for SSTR-positive tumors), cytotoxic chemotherapy, everolimus, or sunitinib. For SSTR-negative tumors, first-line therapy options are chemotherapy, everolimus, or sunitinib. There are insufficient data to recommend particular sequencing of therapies. Patients with G1-G2 high-volume disease, relatively high Ki-67 index, and/or symptoms related to tumor growth may benefit from early cytotoxic chemotherapy. For G3 GEP-NETs, systemic options for G1-G2 may be considered, although cytotoxic chemotherapy is likely the most effective option for patients with tumor-related symptoms, and SSAs are relatively ineffective. Qualifying statements are provided to assist with treatment choice. Multidisciplinary team management is recommended, along with shared decision making with patients, incorporating their values and preferences, potential benefits and harms, and other characteristics and circumstances, such as comorbidities, performance status, geographic location, and access to care.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Prospective comparison of combined 18F-FDG and 18F-NaF PET/CT vs. 18F-FDG PET/CT imaging for detection of malignancy.

PURPOSE: Typically, (18)F-FDG PET/CT and (18)F-NaF PET/CT scans are done as two separate studies on different days to allow sufficient time for the radiopharmaceutical from the first study to decay. This is inconvenient for the patients and exposes them to two doses of radiation from the CT component of the examinations. In the current study, we compared the clinical usefulness of a combined (18)F-FDG/(18)F-NaF PET/CT scan with that of a separate (18)F-FDG-only PET/CT scan. METHODS: There were 62 patients enrolled in this prospective trial. All had both an (18)F-FDG-alone PET/CT scan and a combined (18)F-FDG/(18)F-NaF PET/CT scan. Of the 62 patients, 53 (85%) received simultaneous tracer injections, while 9 (15%) received (18)F-NaF subsequent to the initial (18)F-FDG dose (average delay 2.2 h). Images were independently reviewed for PET findings by two Board-Certified nuclear medicine physicians, with discrepancies resolved by a third reader. Interpreters were instructed to only report findings that were concerning for malignancy. Reading the (18)F-FDG-only scan first for half of the patients controlled for order bias. RESULTS: In 15 of the 62 patients (24%) neither the (18)F-FDG-only PET/CT scan nor the combined (18)F-FDG/(18)F-NaF PET/CT scan identified malignancy. In the remaining 47 patients who had PET findings of malignancy, a greater number of lesions were detected in 16 of 47 patients (34%) using the combined (18)F-FDG/(18)F-NaF PET/CT scan compared to the (18)F-FDG-only PET/CT scan. In 2 of these 47 patients (4%), the (18)F-FDG-only scan demonstrated soft tissue lesions that were not prospectively identified on the combined study. In 29 of these 47 patients (62%), the combined scan detected an equal number of lesions compared to the (18)F-FDG-only scan. Overall, 60 of all the 62 patients (97%) showed an equal or greater number of lesions on the combined scan than on the (18)F-FDG-only scan. CONCLUSION: The current study demonstrated that (18)F-FDG and (18)F-NaF can be combined in a single PET/CT scan by administering the two radiopharmaceuticals simultaneously or in sequence on the same day. In addition to patient convenience and reduced radiation exposure from the CT component, the combined (18)F-FDG/(18)F-NaF PET/CT scan appeared to increase the sensitivity for detection of osseous lesions compared to the (18)F-FDG-only PET/CT scan in the studied population.

Pilot pharmacokinetic and dosimetric studies of (18)F-FPPRGD2: a PET radiopharmaceutical agent for imaging α(v)ß(3) integrin levels.

PURPOSE: To assess the safety, biodistribution, and dosimetric properties of the positron emission tomography (PET) radiopharmaceutical agent fluorine 18 ((18)F) FPPRGD2 (2-fluoropropionyl labeled PEGylated dimeric RGD peptide [PEG3-E{c(RGDyk)}2]), which is based on the dimeric arginine-glycine-aspartic acid (RGD) peptide sequence and targets α(v)ß(3) integrin, in the first volunteers imaged with this tracer. MATERIALS AND METHODS: The protocol was approved by the institutional review board, and written informed consent was obtained from all participants. Five healthy volunteers underwent whole-body combined PET-computed tomography 0.5, 1.0, 2.0, and 3.0 hours after tracer injection (mean dose, 9.5 mCi ± 3.4 [standard deviation] [351.5 MBq ± 125.8]; mean specific radioactivity, 1200 mCi/mmol ± 714 [44.4 GBq/mmol ± 26.4]). During this time, standard vital signs, electrocardiographic (ECG) readings, and blood sample values (for chemistry, hematologic, and liver function tests) were checked at regular intervals and 1 and 7 days after the injection. These data were used to evaluate tracer biodistribution and dosimetric properties, time-activity curves, and the stability of laboratory values. Significant changes in vital signs and laboratory values were evaluated by using a combination of population-averaged generalized estimating equation regression and exact paired Wilcoxon tests. RESULTS: The administration of (18)F-FPPRGD2 was well tolerated, with no marked effects on vital signs, ECG readings, or laboratory values. The tracer showed the same pattern of biodistribution in all volunteers: primary clearance through the kidneys (0.360 rem/mCi ± 0.185 [0.098 mSv/MBq ± 0.050]) and bladder (0.862 rem/mCi ± 0.436 [0.233 mSv/MBq ± 0.118], voiding model) and uptake in the spleen (0.250 rem/mCi ± 0.168 [0.068 mSv/MBq ± 0.046]) and large intestine (0.529 rem/mCi ± 0.236 [0.143 mSv/MBq ± 0.064]). The mean effective dose of (18)F-FPPRGD2 was 0.1462 rem/mCi ± 0.0669 (0.0396 mSv/MBq ± 0.0181). With an injected dose of 10 mCi (370 MBq) and a 1-hour voiding interval, a patient would be exposed to an effective radiation dose of 1.5 rem (15 mSv). Above the diaphragm, there was minimal uptake in the brain ventricles, salivary glands, and thyroid gland. Time-activity curves showed rapid clearance from the vasculature, with a mean 26% ± 17 of the tracer remaining in the circulation at 30 minutes and most of the activity occurring in the plasma relative to cells (mean whole blood-plasma ratio, 0.799 ± 0.096). CONCLUSION: (18)F-FPPRGD2 has desirable pharmacokinetic and biodistribution properties. The primary application is likely to be PET evaluation of oncologic patients-especially those with brain, breast, or lung cancer. Specific indications may include tumor staging, identifying patients who would benefit from antiangiogenesis therapy, and separating treatment responders from nonresponders early.

Initial evaluation of (4S)-4-(3-[18F]fluoropropyl)-L-glutamate (FSPG) PET/CT imaging in patients with head and neck cancer, colorectal cancer, or non-Hodgkin lymphoma.

PURPOSE: (4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid ([18F]FSPG) measures system xC- transporter activity and shows promise for oncologic imaging. We present data on tumor uptake of this radiopharmaceutical in human subjects with head and neck cancer (HNC), colorectal cancer (CRC), and non-Hodgkin lymphoma (NHL). METHODS: A total of 15 subjects with HNC (n = 5), CRC (n = 5), or NHL (n = 5) were recruited (mean age 66.2 years, range 44-87 years). 301.4 ± 28.1 MBq (8.1 ± 0.8 mCi) of [18F]FSPG was given intravenously to each subject, and 3 PET/CT scans were obtained 0-2 h post-injection. All subjects also had a positive [18F]FDG PET/CT scan within 1 month prior to the [18F]FSPG PET scan. Semi-quantitative and visual comparisons of the [18F]FSPG and [18F]FDG scans were performed. RESULTS: [18F]FSPG showed strong uptake in all but one HNC subject. The lack of surrounding brain uptake facilitated tumor delineation in the HNC patients. [18F]FSPG also showed tumor uptake in all CRC subjects, but variable uptake in the NHL subjects. While the absolute [18F]FDG SUV values were comparable or higher than [18F]FSPG, the tumor-to-background SUV ratios were greater with [18F]FSPG than [18F]FDG. CONCLUSIONS: [18F]FSPG PET/CT showed promising results across 15 subjects with 3 different cancer types. Concordant visualization was mostly observed between [18F]FSPG and [18F]FDG PET/CT images, with some inter- and intra-individual uptake variability potentially reflecting differences in tumor biology. The tumor-to-background ratios were greater with [18F]FSPG than [18F]FDG in the cancer types evaluated. Future studies based on larger numbers of subjects and those with a wider array of primary and recurrent or metastatic tumors are planned to further evaluate the utility of this novel tracer.

Clinical Evaluation of (4S)-4-(3-[18F]Fluoropropyl)-L-glutamate (18F-FSPG) for PET/CT Imaging in Patients with Newly Diagnosed and Recurrent Prostate Cancer.

PURPOSE: (4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid (18F-FSPG) is a radiopharmaceutical for PET imaging of system xC - activity, which can be upregulated in prostate cancer. We present data on the first evaluation of patients with newly diagnosed or recurrent prostate cancer with this radiopharmaceutical. EXPERIMENTAL DESIGN: Ten patients with primary and 10 patients with recurrent prostate cancer were enrolled in this prospective multicenter study. After injection of 300 MBq of 18F-FSPG, three whole-body PET/CT scans were obtained. Visual analysis was compared with step-section histopathology when available as well as other imaging studies and clinical outcomes. Metabolic parameters were measured semiquantitatively. Expression levels of xCT and CD44 were evaluated by IHC for patients with available tissue samples. RESULTS: 18F-FSPG PET showed high tumor-to-background ratios with a relatively high tumor detection rate on a per-patient (89%) and per-lobe (87%) basis. The sensitivity was slightly higher with imaging at 105 minutes in comparison with 60 minutes. The maximum standardized uptake values (SUVmax) for cancer was significantly higher than both normal (P < 0.005) and benign pathology (P = 0.011), while there was no significant difference between normal and benign pathology (P = 0.120). In the setting of recurrence, agreement with standard imaging was demonstrated in 7 of 9 patients (78%) and 13 of 18 lesions (72%), and revealed true local recurrence in a discordant case. 18F-FSPG accumulation showed moderate correlation with CD44 expression. CONCLUSIONS: 18F-FSPG is a promising tumor imaging agent for PET that seems to have favorable biodistribution and high cancer detection rate in patients with prostate cancer. Further studies are warranted to determine the diagnostic value for both initial staging and recurrence, and how it compares with other investigational radiotracers and conventional imaging modalities.

Uncommon causes of thyrotoxicosis.

Apart from the common causes of thyrotoxicosis, such as Graves' disease and functioning nodular goiters, there are more than 20 less common causes of elevated free thyroid hormones that produce the symptoms and signs of thyrotoxicosis. This review describes these rarer conditions and includes 14 illustrative patients. Thyrotropin and free thyroxine should be measured and, when the latter is normal, the free triiodothyronine level should be obtained. Measurement of the uptake of (123)I is recommended for most patients.

18F-FDG PET/CT evaluation of patients with ovarian carcinoma.

PURPOSE: The role of F-FDG PET has been studied in ovarian carcinoma, but its sensitivity and specificity calculations are based on dedicated PET acquisition, not PET/CT in the majority of the published studies. Therefore, we were prompted to review our experience with PET/CT in the management of patients with ovarian carcinoma. MATERIALS AND METHODS: This is a retrospective study of 43 women with ovarian carcinoma, 27-80 years old (average: 53.9+/-7.8), who had whole-body PET/CT at our institution from 1 January 2003 to 31 August 2006. We reviewed the patients' outcomes from medical records and compared them to the interpretation of the PET/CT scans. Sensitivity and specificity were calculated using a 2 x 2 table with pathology results (79.1% of the patients) or clinical follow-up (20.9% of the cases) as the 'gold standard'. Confidence interval (CI) estimations were performed using the Wilson score method. RESULTS: All patients had advanced stage ovarian cancer and the study was requested for re-staging. A total of 60 scans were performed: 30 patients had one scan, nine patients had two scans and four patients had three scans. The administered doses of F-FDG ranged from 381.1 to 769.6 MBq (average: 569.8+/-73.3). PET/CT had a sensitivity of 88.4% (95% CI: 75.1-95.4) and a specificity of 88.2% (95% CI: 64.4-97.9) for detection of ovarian cancer. The SUV max of the detected lesions ranged from 3 to 27 (average: 9.4+/-5.9). The CA-125 tumor marker ranged from 3 to 935 kU/ml (average: 265.2) in patients with positive scans and 4-139 kU/ml (average: 17.1) in patients with negative scans. This difference was statistically significant (P value: 0.0242). CONCLUSION: This study confirms the good results of F-FDG PET/CT for identification of residual/recurrent ovarian cancer, as well as for distant metastases localization. PET/CT should be an integral part in evaluation of patients with high-risk ovarian cancer or rising values of tumor markers (CA-125), prior to selection of the most appropriate therapy.

Standard OSEM vs. regularized PET image reconstruction: qualitative and quantitative comparison using phantom data and various clinical radiopharmaceuticals.

We investigated the block sequential regularized expectation maximization (BSREM) algorithm. ACR phantom measurements with different count statistics and 60 PET/CT research scans from the GE Discovery 600 and 690 scanners were reconstructed using BSREM and the standard-of-care OSEM algorithm. Hot concentration recovery and cold contrast recovery were measured from the phantom data. Two experienced nuclear medicine physicians reviewed the clinical images blindly. Liver SNR liver and SUVmax of the smallest lesion detected in each patient were also measured. The relationship between the maximum and mean hot concentration recovery remained monotonic below 1.5 maximum concentration recovery. The mean cold contrast recovery remained stable even for decreasing statistics with a highest absolute difference of 4% in air and 2% in bone for each reconstruction method. The D600 images resulted in an average 30% higher SNR than the D690 data for BSREM; there was no difference in SNR results between the two scanners with OSEM. The small lesion SUVmax values on the BSREM images with ß of 250, 350 and 450, respectively were on average 80%, 60% and 43% (D690) and 42%, 29%, and 21% (D600) higher than in the case of OSEM. In conclusion, BSREM can outperform OSEM in terms of contrast recovery and organ uniformity over a range of PET tracers, but a task dependent regularization strength parameter (beta) selection may be necessary. To avoid image noise and artifacts, our results suggest that using higher beta values (at least 350) may be appropriate, especially if the data has low count statistics.

Comparison Between Different PET and CT-Based Imaging Interpretation Criteria at Interim Imaging in Patients With Diffuse Large B-Cell Lymphoma.

OBJECTIVE: To evaluate the predictive value of interim PET (iPET) in diffuse large B-cell lymphoma (DLBCL) using 5 different imaging interpretation criteria: Deauville 5-point scale criteria, International Harmonization Project (IHP) criteria, Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, European Organization for Research and Treatment of Cancer, and PET Response Criteria in Solid Tumors (PERCIST) 1.0. METHODS: We retrospectively reviewed records from 38 patients with DLBCL who underwent baseline and iPET at our institution. Imaging was interpreted according to the previously mentioned criteria. Results were correlated with end-of-treatment response, based on reports at the end of treatment radiological examinations, overall survival (OS), and progression-free survival (PFS) to assess and compare the predictive value of iPET according to each criterion. We also evaluated the concordance between different criteria. RESULTS: The Deauville and PERCIST criteria were the most reliable for predicting end-of-treatment response, reporting an accuracy of 81.6%. They also correlated with OS and PFS (P = 0.0004 and P = 0.0001, and P = 0.0007 and P = 0.0002, for Deauville and PERCIST, respectively). Interim PET according to European Organization for Research and Treatment of Cancer also predicted the end-of-treatment response with an accuracy of 73.7% and had a significant correlation with OS (P = 0.007) and PFS (P = 0.007). In contrast, the IHP criteria and RECIST did not predict outcomes: the accuracy for end-of-treatment response was 34.2% and 36.8%, respectively, with no significant correlation with OS or PFS (P = 0.182 and P = 0.357, and P = 0.341 and P = 0.215, for OS and PFS, respectively). CONCLUSIONS: The predictive value of iPET in DLBCL patients is most reliable using the Deauville and PERCIST criteria. Criteria that rely on anatomical characteristics, namely, RECIST and IHP criteria, are less accurate in predicting patient outcomes in DLBCL.

Recurrent silent thyroiditis: a report of four patients and review of the literature.

Silent thyroiditis, excluding postpartum thyroiditis and destructive amiodarone thyroiditis, is a relatively uncommon cause of thyrotoxicosis and recurrent cases are even rarer. We present four patients with recurrent silent thyroiditis. The number of episodes ranged from two to nine. All four patients had episodes that were similar in duration (4-6 weeks) as well as in their clinical (no viral prodrome or neck pain), biochemical (high total triiodothyronine [T(3)], free thyroxine [T(4)], and low thyrotropin [TSH] presence of antibodies to thyroid antigens), and scintigraphic (low radioiodine uptake) findings. Individual symptoms and symptom-free duration (from 1 to 4 years) were more variable. No associations were found with regard to medications, pregnancies, or other disease states previously implicated in thyroiditis. One patient was unsuccessfully prescribed thyroid hormone to prevent recurrence. Three were treated with radioablative iodine therapy during the recovery phase of an episode; they became hypothyroid and take replacement l-thyroxine. They have remained symptom free.