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Diuretic scintigraphy includes single-photon emitting radiotracers for planar and single photon emission computed tomography (SPECT) imaging as well as agents for positron emission tomography (PET). These radiotracers provide split-renal functional parameters, including glomerular filtration rate, effective renal plasma flow, tubular function, and/or renal blood flow. Beyond measuring kidney function, the tracer principle also allows for the assessment of various pathophysiological processes in the renal parenchyma, for example ongoing inflammation, activation of angiotensin II type 1 receptor in patients with renovascular hypertension, deterioration of mitochondrial complex I following acute or chronic kidney injury, or characterization of indeterminate renal masses. Providing a whole-body read-out, PET also enables the assessment of kidney-organ interactions, for example cardiorenal crosstalk after primary cardiac injury. This manuscript provides an overview of established clinical applications for single-photon-emitting and PET radiotracers for renal radionuclide imaging. Future perspectives in the field will also be highlighted, such as introduction of PET-guided strategies for drug dose optimization and the recent introduction of radiotracers targeting fibroblast activation protein inhibition, which may allow differentiation between acute inflammatory vs chronic fibrosis in the kidneys., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: This study is aimed at investigating the impact of frame numbers in preclinical electrocardiogram- (ECG-) gated 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) on systolic and diastolic left ventricular (LV) parameters in rats., Methods: 18 F-FDG PET imaging using a dedicated small animal PET system with list mode data acquisition and continuous ECG recording was performed in diabetic and control rats. The list-mode data was sorted and reconstructed with different numbers of frames (4, 8, 12, and 16) per cardiac cycle into tomographic images. Using an automatic ventricular edge detection software, left ventricular (LV) functional parameters, including ejection fraction (EF), end-diastolic (EDV), and end-systolic volume (ESV), were calculated. Diastolic variables (time to peak filling (TPF), first third mean filling rate (1/3 FR), and peak filling rate (PFR)) were also assessed., Results: Significant differences in multiple parameters were observed among the reconstructions with different frames per cardiac cycle. EDV significantly increased by numbers of frames (353.8 ± 57.7  μ l ∗ , 380.8 ± 57.2  μ l ∗ , 398.0 ± 63.1  μ l ∗ , and 444.8 ± 75.3  μ l at 4, 8, 12, and 16 frames, respectively; ∗ P < 0.0001 vs. 16 frames), while systolic (EF) and diastolic (TPF, 1/3 FR and PFR) parameters were not significantly different between 12 and 16 frames. In addition, significant differences between diabetic and control animals in 1/3 FR and PFR in 16 frames per cardiac cycle were observed ( P < 0.005), but not for 4, 8, and 12 frames., Conclusions: Using ECG-gated PET in rats, measurements of cardiac function are significantly affected by the frames per cardiac cycle. Therefore, if you are going to compare those functional parameters, a consistent number of frames should be used., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Christoph Eissler et al.)

Purpose: In this study, we aimed to quantitatively investigate the biodistribution of [ 18 F]DCFPyL in patients with prostate cancer (PCa) and to determine whether uptake in normal organs correlates with an increase in tumor burden., Procedures: Fifty patients who had been imaged with [ 18 F]DCFPyL positron emission tomography/computed tomography (PET/CT) were retrospectively included in this study. Forty of 50 (80 %) demonstrated radiotracer uptake on [ 18 F]DCFPyL PET/CT compatible with sites of PCa. Volumes of interests (VOIs) were set on normal organs (lacrimal glands, parotid glands, submandibular glands, liver, spleen, and kidneys) and on tumor lesions. Mean standardized uptake values corrected to lean body mass (SUL mean ) and mean standardized uptake values corrected to body weight (SUV mean ) for normal organs were assessed. For the entire tumor burden, SUL mean/max , SUV mean , tumor volume (TV), and the total activity in the VOI were obtained using tumor segmentation. A Spearman's rank correlation coefficient was used to investigate correlations between normal organ uptake and tumor burden., Results: There was no significant correlation between TV with the vast majority of the investigated organs (lacrimal glands, parotid glands, submandibular glands, spleen, and liver). Only the kidney showed significant correlation: With an isocontour threshold at 50 %, left kidney uptake parameters correlated significantly with TV (SUV mean , ρ = - 0.214 and SUL mean , ρ = - 0.176, p < 0.05, respectively)., Conclusions: Only a minimal sink effect with high tumor burden in patients imaged with [ 18 F]DCFPyL was observed. Other factors, such as a high intra-patient variability of normal organ uptake, may be a much more important consideration for personalized dosimetry with PSMA-targeted therapeutic agents structurally related to [ 18 F]DCFPyL than the tumor burden.

Prostate-specific membrane antigen (PSMA)-targeted PET imaging for prostate cancer with 68 Ga-labeled compounds has rapidly become adopted as part of routine clinical care in many parts of the world. However, recent years have witnessed the start of a shift from 68 Ga- to 18 F-labeled PSMA-targeted compounds. The latter imaging agents have several key advantages, which may lay the groundwork for an even more widespread adoption into the clinic. First, facilitated delivery from distant suppliers expands the availability of PET radiopharmaceuticals in smaller hospitals operating a PET center but lacking the patient volume to justify an onsite 68 Ge/ 68 Ga generator. Thus, such an approach meets the increasing demand for PSMA-targeted PET imaging in areas with lower population density and may even lead to cost-savings compared to in-house production. Moreover, 18 F-labeled radiotracers have a higher positron yield and lower positron energy, which in turn decreases image noise, improves contrast resolution, and maximizes the likelihood of detecting subtle lesions. In addition, the longer half-life of 110 min allows for improved delayed imaging protocols and flexibility in study design, which may further increase diagnostic accuracy. Moreover, such compounds can be distributed to sites which are not allowed to produce radiotracers on-site due to regulatory issues or to centers without access to a cyclotron. In light of these advantageous characteristics, 18 F-labeled PSMA-targeted PET radiotracers may play an important role in both optimizing this transformative imaging modality and making it widely available. We have aimed to provide a concise overview of emerging 18 F-labeled PSMA-targeted radiotracers undergoing active clinical development. Given the wide array of available radiotracers, comparative studies are needed to firmly establish the role of the available 18 F-labeled compounds in the field of molecular PCa imaging, preferably in different clinical scenarios., Competing Interests: Competing Interests: Martin G. Pomper is a coinventor on a patent covering [18F]DCFPyL and is entitled to a portion of any licensing fees and royalties generated by this technology. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. He has also received research funding from Progenics Phamaceuticals, the licensee of [18F]DCFPyL. Michael A. Gorin has served as a consultant to, and has received research funding from, Progenics Phamaceuticals. Steven P. Rowe has received research funding from Progenics Phamaceuticals., (© The author(s).)

Reliable standards and criteria for somatostatin receptor (SSTR) PET are still lacking. We herein propose a structured reporting system on a 5-point scale for SSTR PET imaging, titled SSTR-RADS version 1.0, which might serve as a standardized assessment for both diagnosis and treatment planning in neuroendocrine tumors. SSTR-RADS could guide the imaging specialist in interpreting SSTR PET scans, facilitate communication with the referring clinician so that appropriate workup for equivocal findings is pursued, and serve as a reliable tool for patient selection for planned peptide receptor radionuclide therapy., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: P-selectin is activated early after stroke, followed by a rapid decline. This time course can be used to generate important information on stroke onset. The latter is crucial for therapeutic decision-making of wake-up strokes (i.e. thrombolysis or not). Here, we evaluated the specific p-selectin inhibitor fucoidan labeled with gallium-68 (68Ga-Fucoidan) as an imaging biomarker for assessing p-selectin activation in acute ischemic stroke using Positron Emission Tomography (PET)., Methods: 68Ga-Fucoidan was investigated in rats brain at 2-5 h (n=16), and additionally at 24-26 h (n=9) and 48 h (n=3) after induction of photothrombic stroke or in sham-operated animals (n=6). Correlation of cerebral 68Ga-Fucoidan uptake with p-selectin expression was determined by exposing freshly cut brain cryosections to autoradiography and immunostaining using specific antibodies against p-selectin., Results: PET scans showed an increased accumulation of 68Ga-Fucoidan in the histologically proven ischemic stroke, as compared to the corresponding contralateral hemisphere in all except one animal. The median ratio between the uptake in the ischemic lesion and the contralateral region was 1.95 (1.45-2.41) at 2-5 h, 1.38 (1.05-1.89) at 24-26 h, and 1.09 (0.81-1.38) at 48 h after stroke, compared to 1.22 (0.99-1.49) for sham-operated animals. In the ex vivo autoradiography, 68Ga-Fucoidan accumulation co-localized with p-selectin as assessed by immunostaining. Control animals and those scanned at 24-26 h and 48 h after stroke exhibited no elevated 68Ga-Fucoidan uptake in either hemisphere., Conclusion: PET imaging using 68Ga-Fucoidan represents a valuable tool for assessing p-selectin activation in vivo discriminating ischemic stroke early after stroke onset., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

11 C-methionine (MET) has recently emerged as an accurate marker of tumor burden and disease activity in patients with multiple myeloma (MM). This dual-center study aimed at further corroboration of the superiority of MET as positron emission tomography (PET) tracer for staging and re-staging MM, as compared to 18 F-2`-deoxy-2`-fluoro-D-glucose (FDG). 78 patients with a history of solitary plasmacytoma (n=4), smoldering MM (SMM, n=5), and symptomatic MM (n=69) underwent both MET- and FDG-PET/computed tomography (CT) at the University Centers of Würzburg, Germany and Navarra, Spain. Scans were compared on a patient and on a lesion basis. Inter-reader agreement was also evaluated. In 2 patients, tumor biopsies for verification of discordant imaging results were available. MET-PET detected focal lesions (FL) in 59/78 subjects (75.6%), whereas FDG-PET/CT showed lesions in only 47 patients (60.3%; p<0.01), accordingly disease activity would have been missed in 12 patients. Directed biopsies of discordant results confirmed MET-PET/CT results in both cases. MET depicted more FL in 44 patients (56.4%; p<0.01), whereas in two patients (2/78), FDG proved superior. In the remainder (41.0%, 32/78), both tracers yielded comparable results. Inter-reader agreement for MET was higher than for FDG (κ = 0.82 vs κ = 0.72). This study demonstrates higher sensitivity of MET in comparison to standard FDG to detect intra- and extramedullary MM including histologic evidence of FDG-negative, viable disease exclusively detectable by MET-PET/CT. MET holds the potential to replace FDG as functional imaging standard for staging and re-staging of MM., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Purpose: The aim of this study was to synthesize and preclinically evaluate an 18 F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined., Methods: Several conditions for the labeling of 18 F-PSMA-11 via 18 F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed., Results: Quantitative labeling yields could be achieved with >97 % radiochemical purity. The 18 F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p < 4.2e-5). Results were confirmed by ex vivo gamma counter analysis of tissues after the last imaging time point. The highest absorbed dose was reported for the kidneys. The maximum effective dose for an administered activity of 200 MBq was 1.72 mSv., Conclusion: 18 F-PSMA-11 using direct labeling of chelate-attached peptide with aluminum-fluoride detected PSMA-expressing tumors with high tumor-to-liver ratios. The kidneys were the dose-limiting organs. Even by applying the most stringent dosimetric calculations, injected activities of up to 0.56 GBq are feasible., Competing Interests: Johannes Czernin is founder of Sofie Biosciences, which manufactures the Genisys4 scanner used in this manuscript. No other potential conflicts of interest are reported.

As an orphan malignancy, only limited treatment options are available in adrenocortical carcinoma (ACC). Non-invasive risk assessment has not been described but may be of value to stratify patients for treatment. We aimed to evaluate the potential value of intra-individual tumor heterogeneity as assessed by (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) for outcome prediction in treatment-naïve ACC patients. Ten patients with primary diagnosis of ACC were included in this study. Prior to any treatment initiation, baseline (18)F-FDG PET scans were performed. Tumor staging was performed using the European Network for the Study of Adrenal Tumors (ENS@T). Intratumoral heterogeneity of the primary tumor was assessed by manual segmentation using conventional PET parameters (standardized uptake values and tumor-to-liver ratios) and textural features. The impact of tumoral heterogeneity based on pre-therapeutic (18)F-FDG PET to predict progression-free (PFS) and overall survival (OS) was evaluated by receiver operating characteristic analysis. On average, tumor recurrence or progression was detected after median of 561 days (range 71-1434 days) after the pre-therapeutic baseline PET scan. 50 % of the patients died of ACC within the follow-up period (mean 983 ± 404 days). Pre-therapeutic tumor volume was associated with PFS (r = -0.67, p = 0.05) and Ki67 index with OS (r = -0.66, p = 0.04). ENS@T tumor stage was the only parameter to correlate with both PFS and OS (r = -0.82, p = 0.001, and r = -0.72, p = 0.01, respectively). In the subgroup of patients without distant metastases (ENS@T stages II and III), age and pre-therapeutic tumor volume correlated significantly with PFS (r = 0.96, p = 0.01 and r = -0.93, p = 0.02, respectively) and OS (r = 0.95, p = 0.02 and r = -0.90, p = 0.04, respectively). None of the investigated classic or textural PET parameters predicted PFS or OS. In this pilot study in treatment-naïve ACC patients, conventional (18)F-FDG PET-derived parameters and textural tumor heterogeneity features were not suitable to identify high-risk patients.

Background: Traumatic brain injury (TBI) is a major cause of death and disability. Neuroinflammation contributes to acute damage after TBI and modulates long-term evolution of degenerative and regenerative responses to injury. The aim of the present study was to evaluate the relationship of microglia activation to trauma severity, brain energy metabolism, and cellular reactions to injury in a mouse closed head injury model using combined in vivo PET imaging, ex vivo autoradiography, and immunohistochemistry., Methods: A weight-drop closed head injury model was used to produce a mixed diffuse and focal TBI or a purely diffuse mild TBI (mTBI) in C57BL6 mice. Lesion severity was determined by evaluating histological damage and functional outcome using a standardized neuroscore (NSS), gliosis, and axonal injury by immunohistochemistry. Repeated intra-individual in vivo μPET imaging with the specific 18-kDa translocator protein (TSPO) radioligand [(18)F]DPA-714 was performed on day 1, 7, and 16 and [(18)F]FDG-μPET imaging for energy metabolism on days 2-5 after trauma using freshly synthesized radiotracers. Immediately after [(18)F]DPA-714-μPET imaging on days 7 and 16, cellular identity of the [(18)F]DPA-714 uptake was confirmed by exposing freshly cut cryosections to film autoradiography and successive immunostaining with antibodies against the microglia/macrophage marker IBA-1., Results: Functional outcome correlated with focal brain lesions, gliosis, and axonal injury. [(18)F]DPA-714-μPET showed increased radiotracer uptake in focal brain lesions on days 7 and 16 after TBI and correlated with reduced cerebral [(18)F]FDG uptake on days 2-5, with functional outcome and number of IBA-1 positive cells on day 7. In autoradiography, [(18)F]DPA-714 uptake co-localized with areas of IBA1-positive staining and correlated strongly with both NSS and the number of IBA1-positive cells, gliosis, and axonal injury. After mTBI, numbers of IBA-1 positive cells with microglial morphology increased in both brain hemispheres; however, uptake of [(18)F]DPA-714 was not increased in autoradiography or in μPET imaging., Conclusions: [(18)F]DPA-714 uptake in μPET/autoradiography correlates with trauma severity, brain metabolic deficits, and microglia activation after closed head TBI.

Chemokine receptor-4 (CXCR4) has been reported to be overexpressed in glioblastoma (GBM) and to be associated with poor survival. This study investigated the feasibility of non-invasive CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine receptor ligand (68)Ga-Pentixafor. 15 patients with clinical suspicion on primary or recurrent glioblastoma (13 primary, 2 recurrent tumors) underwent (68)Ga-Pentixafor-PET/CT for assessment of CXCR4 expression prior to surgery. O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET/CT images were available in 11/15 cases and were compared visually and semi-quantitatively (SUVmax, SUVmean). Tumor-to-background ratios (TBR) were calculated for both PET probes. (68)Ga-Pentixafor-PET/CT results were also compared to histological CXCR4 expression on neuronavigated surgical samples. (68)Ga-Pentixafor-PET/CT was visually positive in 13/15 cases with SUVmean and SUVmax of 3.0±1.5 and 3.9±2.0 respectively. Respective values for (18)F-FET were 4.4±2.0 (SUVmean) and 5.3±2.3 (SUVmax). TBR for SUVmean and SUVmax were higher for (68)Ga-Pentixafor than for (18)F-FET (SUVmean 154.0±90.7 vs. 4.1±1.3; SUVmax 70.3±44.0 and 3.8±1.2, p<0.01), respectively. Histological analysis confirmed CXCR4 expression in tumor areas with high (68)Ga-Pentixafor uptake; regions of the same tumor without apparent (68)Ga-Pentixafor uptake showed no or low receptor expression. In this pilot study, (68)Ga-Pentixafor retention has been observed in the vast majority of glioblastoma lesions and served as readout for non-invasive determination of CXCR4 expression. Given the paramount importance of the CXCR4/SDF-1 axis in tumor biology, (68)Ga-Pentixafor-PET/CT might prove a useful tool for sensitive, non-invasive in-vivo quantification of CXCR4 as well as selection of patients who might benefit from CXCR4-directed therapy.

Multiple myeloma (MM) remains an essentially incurable hematologic malignancy originating from clonal plasma cells. This study evaluated the usefulness of the radiotracers (11)C-methionine (MET) and (18)F-2`-deoxy-2`-fluorodeoxyglucose (FDG) for staging and re-staging in MM. 43 patients with MM underwent both MET- and FDG-PET/CT for staging or re-staging within 3±2 days. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with the degree of bone marrow (BM) involvement and standard clinical parameters of disease activity. Additionally, BM samples were stained for L-type amino acid transporter 1 (LAT1) expression in 15 patients. MET-PET detected focal lesions (FL) in 39/43 subjects (90.7%), whereas 10 patients were missed in FDG-PET/CT (detection rate, 33/43; 76.7%; p<0.05). MET depicted more FL in 28/43 patients (65.1%; p<0.001), whereas in the remainder (34.9%, n=15) both tracers yielded comparable results. LAT1 was highly expressed on the cell surface of myeloma cells. Both FDG and MET uptake correlated significantly with biopsy-proven BM involvement (p<0.001), with MET demonstrating a stronger correlation (SUVmean, r=0.9 vs r=0.6; SUVmax, r=0.88 vs r=0.58). Abnormal beta-2-microglobulin and free light chain levels correlated with the presence of focal intramedullary lesions detected in MET- or FDG-PET/CT (MET, p=0.006 and p=0.01, respectively; FDG, p=0.02 and p=0.01). MET appears to be superior to FDG for staging and re-staging of both intra- and extramedullary MM lesions. Tracer uptake correlates with BM involvement, β2m and FLC levels and appears to be a more accurate marker of tumor burden and disease activity.

CXCR4 is a G-protein-coupled receptor that mediates recruitment of blood cells toward its ligand SDF-1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination and poor prognosis. We evaluated the novel CXCR4 probe [(68)Ga]Pentixafor for in vivo mapping of CXCR4 expression density in mice xenografted with human CXCR4-positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [(68)Ga]Pentixafor PET provided images with excellent specificity and contrast. In 10 of 14 patients with advanced MM [(68)Ga]Pentixafor PET/CT scans revealed MM manifestations, whereas only nine of 14 standard [(18)F]fluorodeoxyglucose PET/CT scans were rated visually positive. Assessment of blood counts and standard CD34(+) flow cytometry did not reveal significant blood count changes associated with tracer application. Based on these highly encouraging data on clinical PET imaging of CXCR4 expression in a cohort of MM patients, we conclude that [(68)Ga]Pentixafor PET opens a broad field for clinical investigations on CXCR4 expression and for CXCR4-directed therapeutic approaches in MM and other diseases., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)

Introduction: Peptide receptor radionuclide therapy (PRRT) is a treatment option for both iodine-refractory differentiated and advanced medullary thyroid cancer (TC). It requires over-expression of somatostatin receptor subtype II (SSTR) that can be non-invasively assessed by positron emission tomography (PET). Assessment of tumor heterogeneity is increasingly used as a tool for prognostication prediction. We investigated the potential of SSTR-PET to assess intraindividual tumor heterogeneity and thereby treatment response prior to PRRT., Methods: 12 patients with progressive radioiodine-refractory differentiated (1 papillary, 1 oxyphilic, 2 oncocytic, 4 follicular) or medullary (n=4) TC were enrolled. SSTR-PET was performed at baseline. Conventional PET parameters and heterogeneity parameters were analyzed regarding their potential to predict progression-free (PFS, mean, 221 days) and overall survival (OS, mean, 450 days). Parameters of a subgroup of lesions (n=23) were also correlated with morphological response according to modified RECIST criteria., Results: In patient-based analysis, all conventional parameters failed to predict PFS. Several textural parameters showed a significant capability to assess PFS. Thereby, "Grey level non uniformity" had the highest area under the curve (AUC, 0.93) in Receiver operating characteristics analysis followed by "Contrast" (AUC, 0.89). In lesion-based analysis, only "Entropy" revealed potential to evaluate disease progression. OS could not be assessed by any parameter investigated., Conclusions: Tumor heterogeneity seems to be a predictor of response to PRRT in patients with iodine-refractory differentiated/advanced medullary thyroid cancer and outperforms conventional PET parameters like standardized uptake value. In a "theranostic" approach, assessment of textural parameters may help in selecting patients who might benefit from PRRT., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: The aim of this retrospective two-centre study was to investigate the clinical impact of (11)C-choline PET/CT on treatment management decisions in patients with recurrent prostate cancer (rPCa) after radical therapy., Methods: Enrolled in this retrospective study were 150 patients (95 from Bologna, 55 from Würzburg) with rPCa and biochemical relapse (PSA mean ± SD 4.3 ± 5.5 ng/mL, range 0.2-39.4 ng/mL) after radical therapy. The intended treatment before PET/CT was salvage radiotherapy of the prostatic bed in 95 patients and palliative androgen deprivation therapy (ADT) in 55 patients. The effective clinical impact of (11)C-choline PET/CT was rated as major (change in therapeutic approach), minor (same treatment, but modified therapeutic strategy) or none. Multivariate binary logistic regression analysis included PSA level, PSA kinetics, ongoing ADT, Gleason score, TNM, age and time to relapse., Results: Changes in therapy after (11)C-choline PET/CT were implemented in 70 of the 150 patients (46.7%). A major clinical impact was observed in 27 patients (18%) and a minor clinical impact in 43 (28.7%). (11)C-choline PET/CT was positive in 109 patients (72.7%) detecting local relapse (prostate bed and/or iliac lymph nodes and/or pararectal lymph nodes) in 64 patients (42.7%). Distant relapse (paraaortic and/or retroperitoneal lymph nodes and/or bone lesions) was seen in 31 patients (20.7%), and both local and distant relapse in 14 (9.3%). A significant difference was observed in PSA level and PSA kinetics between PET-positive and PET-negative patients (p < 0.05). In multivariate analysis, PSA level, PSA doubling time and ongoing ADT were significant predictors of a positive scan (p < 0.05). In statistical analysis no significant differences were observed between the Bologna and Würzburg patients (p > 0.05). In both centres the same criteria to validate PET-positive findings were used: in 17.3% of patients by histology and in 82.7% of patients by correlative imaging and/or clinical follow-up (follow-up mean 20.5 months, median 18.3 months, range 6.2-60 months)., Conclusion: (11)C-Choline PET/CT had a significant impact on therapeutic management in rPCa patients. It led to an overall change in 46.7% of patients, with a major clinical change implemented in 18% of patients. Further prospective studies are needed to evaluate the effect of such treatment changes on patient survival.

The aim of this study was to investigate the prognostic value of 18F-fluoro-deoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) in 37 patients with a history of multiple myeloma (MM) and suspected or confirmed recurrence after stem cell transplantation (SCT). All patients had been heavily pre-treated. Time to progression (TTP) and overall survival (OS) were correlated to a number of different PET-derived as well as clinical parameters. Impact on patient management was assessed. Absence of FDG-avid MM foci was a positive prognostic factor for both TTP and OS (p<0.01). Presence of >10 focal lesions correlated with both TTP (p<0.01) and OS (p<0.05). Interestingly, presence of >10 lesions in the appendicular skeleton proved to have the strongest association with disease progression. Intensity of glucose uptake and presence of extramedullary disease were associated with shorter TTP (p=0.037 and p=0.049, respectively). Manifestations in soft tissue structures turned out to be a strong negative predictor for both, TTP and OS (p<0.01, respectively). PET resulted in a change of management in 30% of patients. Our data underline the prognostic value of 18F-FDG-PET/CT in MM patients also in the setting of post-SCT relapse. PET/CT has a significant impact on patient management.

For noninvasive in vivo imaging of proliferation, 18F-FLT PET/CT remains a promising tool, owing to its correlation with proliferation indexes in many tumor entities. Future clinical applications will focus on monitoring response to cancer therapy, whereas tumor detection will be limited to organs with high physiologic 18F-FDG uptake. Use and interpretation of 18F-FLT requires knowledge of the physiologic tracer distribution and how it will be affected by anticancer treatment. Further studies are needed to determine the optimal timing of 18F-FLT PET/CT imaging in the course of cancer therapies or at the conclusion of therapy.

Despite improved survival in the Rituximab (R) era, a considerable number of patients with diffuse large B-cell lymphoma (DLBCL) ultimately die from the disease. Functional imaging using [18F]fluorodeoxyglucose-PET is suggested for assessment of residual viable tumor very early during treatment but is compromised by non-specific tracer retention in inflammatory lesions. The PET tracer [18F]fluorodeoxythymidine (FLT) as surrogate marker of tumor proliferation may overcome this limitation. We present results of a prospective clinical study testing FLT-PET as superior and early predictor of response to chemotherapy and outcome in DLBCL. 54 patients underwent FLT-PET prior to and one week after the start of R-CHOP chemotherapy. Repetitive FLT-PET imaging was readily implemented into the diagnostic work-up. Our data demonstrate that the reduction of FLT standard uptake valuemean (SUVmean) and SUVmax one week after chemotherapy was significantly higher in patients achieving complete response (CR, n=48; non-CR, n=6; p<0.006). Martingale-residual and Cox proportional hazard analyses showed a significant monotonous decrease of mortality risk with increasing change in SUV. Consistent with these results, early FLT-PET response showed relevant discriminative ability in predicting CR. In conclusion, very early FLT-PET in the course of R-CHOP chemotherapy is feasible and enables identification of patients at risk for treatment failure.

Background: Examinations using 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) are becoming increasingly more important in clinical practice for the diagnosis and therapy of cancer patients., Question: What role does FDG-PET/CT examination play in the diagnosis and therapy of rectal cancer?, Results: The FDG-PET/CT method is especially valuable during postoperative care when a recurrence is suspected. Especially when tumor marker levels rise with no other symptoms, FDG-PET/CT can be used to evaluate unclear lesions in the liver and unclear tissue formations at the surgery site and distinguish between scar tissue and recurring tumors. Currently, there is increasing evidence that a survival prognosis may be possible based on the tracer uptake of FDG-PET/CT. There is also a great interest in the possibility of evaluating the success of neoadjuvant therapy with FDG-PET/CT., Discussion: Despite some limitations FDG-PET/CT plays a significant role in the diagnosis and treatment of patients with rectal cancer.

Musculoskeletal tumors comprise a multitude of tumor entities with different grades of malignancy, biological behavior, and therapeutic options. Positron emission tomography (PET) using the glucose analog [18F]fluorodeoxyglucose (FDG) is an established imaging modality for detection and staging of cancer, despite some shortcomings. Numerous studies have evaluated the role of PET imaging musculoskeletal tumors beyond FDG. The use of more specific novel PET radiopharmaceuticals such as the proliferation marker [18F]fluorodeoxythymidine (FLT), the bone-imaging agent [18F]sodium fluoride, amino acid tracers ([11C]methionine, [18F]fluoroethyltyrosine), or biomarkers of neoangiogenesis ([18F]galacto-RGD) can potentially provide insights into the biology of musculoskeletal tumors with focus on tumor grading, treatment monitoring, posttherapy assessment, and estimation of individual prognosis. In this article, we review the potential role of these alternative PET tracers in musculoskeletal disorders with emphasis on oncologic applications., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Amino acid transport imaging with 18F-FDOPA PET is increasingly used for detection of glioblastoma recurrence. However, a standardized image interpretation for 18F-FDOPA brain PET studies has not yet been established. This study compares visual and semiquantitative analysis parameters for detection of tumor recurrence and correlates them with progression-free survival (PFS)., Methods: One-hundred ten patients (72 male:38 female) with suspected tumor recurrence who underwent 18F-FDOPA PET imaging were studied. PET scans were analyzed visually (5-point scale) and semiquantitatively (lesion-to-striatum- and lesion- to-normal-brain-tissue ratios using both SUV(mean) and SUV(max)). Accuracies for recurrence detection were calculated using histopathology and clinical follow-up for validation. Receiving operator characteristic and Kaplan-Meier survival analysis were performed to derive imaging-based prediction of PFS and overall survival (OS)., Results: Accuracies for detection of glioblastoma recurrence were similar for visual (82%) and semiquantitative (range, 77%-82%) analysis. Both visual and semiquantitative indices were significant predictors of PFS, with mean lesion-to normal brain tissue ratios providing the best discriminator (mean survival, 39.4 vs 9.3 months; P < .001). None of the investigated parameters was predictive for OS., Conclusions: Both visual and semiquantitative indices detected glioblastoma recurrence with high accuracy and were predictive for PFS. Lesion-to-normal-tissue ratios were the best discriminators of PFS; however, none of the investigated parameters predicted OS. These retrospectively established analysis parameters need to be confirmed prospectively.

Unlabelled: The assessment of myocardial radiotracer kinetics, including cardiac extraction fraction and washout, requires the study of isolated perfused hearts to avoid analytic error due to tracer recirculation and systemic metabolites. Analysis of the isolated perfused rat heart by a high-resolution small-animal PET system may offer both reliable evaluation of cardiac tracer kinetics and tomographic images., Methods: An isolated perfused heart system was modified to accommodate the small PET gantry bore size. Isolated rat hearts were perfused via the Langendorff method under a constant flow of Krebs-Henseleit buffer containing (18)F-FDG with a rate of 5 mL/min and placed in the field of view of the commercially available small-animal PET system. Dynamic PET imaging was then performed, with (18)F-FDG uptake in the isolated perfused heart verified by γ counter measurements. Additionally, a rat heart of myocardial infarction was also studied in this system with static PET imaging., Results: Dynamic PET acquisition of the isolated heart under constant (18)F-FDG infusion demonstrated continuous increase of activity in the heart. Correlation between cardiac activity (MBq) measured with the PET system and measurements made with the γ counter were excellent (R(2) = 0.98, P < 0.001, n = 10). Tracer input rate (MBq/min) was also well correlated with cardiac tracer uptake rate (MBq/min) (R(2) = 0.87, P < 0.001, n = 12). PET imaging of the heart with myocardial infarction showed a clear tracer uptake defect corresponding to the location of scar tissue identified by autoradiography and histology., Conclusion: Combining the Langendorff method of isolated rat heart perfusion with high-resolution small-animal PET allows for the reliable quantification of myocardial tracer kinetics. This novel assay is readily adapted to available small-animal PET systems and may be useful for understanding myocardial PET tracer kinetics.

Objectives: The aim of this study is to evaluate the quality of I-124 PET images with and without prompt gamma compensation (PGC) by comparing the recovery coefficients (RC), the signal to noise ratios (SNR) and the contrast to F-18 and Ga-68. Furthermore, the influence of the PGC on the quantification and image quality is evaluated., Methods: For measuring the image quality the NEMA NU2-2001 PET/SPECT-Phantom was used containing 6 spheres with a diameter between 10 mm and 37 mm placed in water with different levels of background activity. Each sphere was filled with the same activity concentration measured by an independently cross-calibrated dose calibrator. The "hot" sources were acquired with a full 3D PET/CT (Biograph mCT®, Siemens Medical USA). Acquisition times were 2 min for F-18 and Ga-68, and 10 min for I-124. For reconstruction an OSEM algorithm was applied. For I-124 the images were reconstructed with and without PGC. For the calculation of the RCs the activity concentrations in each sphere were determined; in addition, the influence of the background correction was studied., Results: The RCs of Ga-68 are the smallest (79%). I-124 reaches similar RCs (87% with PGC, 84% without PGC) as F-18 (84%). showing that the quantification of I-124 images is similar to F-18 and slightly better than Ga-68. With background activity the contrast of the I-124 PGC images is similar to Ga-68 and F-18 scans. There was lower background activity in the I-124 images without PGC, which probably originates from an overcorrection of the scatter contribution. Consequently, the contrast without PGC was much higher than with PGC. As a consequence PGC should be used for I-124., Conclusions: For I-124 there is only a slight influence on the quantification depending on the use of the PGC. However, there are considerable differences with respect to I-124 image quality.

Context: Adrenal tumors are highly prevalent and represent a wide range of different pathological entities. Conventional imaging often provides only limited information on the origin of these lesions. Novel specific imaging methods are, therefore, of great clinical interest., Objective: We evaluated [(123)I]iodometomidate ([(123)I]IMTO) imaging for noninvasive characterization of adrenal masses., Design/setting: This was a prospective monocentric diagnostic study in a tertiary care center., Patients and Intervention: A total of 51 patients with an adrenal lesion underwent [(123)I]IMTO imaging after injection of 185 MBq of [(123)I]IMTO. Sequential planar whole-body scans until 24 hours postinjection and single photon emission computed tomography (SPECT)/computed tomography imaging 4 to 6 hours postinjection were performed., Main Outcome Measure: Sensitivity and specificity of [(123)I]IMTO imaging for the noninvasive characterization of adrenal lesions were measured., Results: Adrenocortical tissue showed high and specific tracer uptake with a short investigation time and low radiation exposure. Qualitative analysis of SPECT/computed tomography data resulted in a sensitivity of 89% and a specificity of 85% for differentiating adrenocortical tumors from lesions of nonadrenocortical origin. Receiver-operating characteristic analysis of semiquantitative data revealed a sensitivity of 83% and a specificity of 86% for identification of adrenocortical lesions at a cutoff value of tumor to liver ratio of 1.3., Conclusions: [(123)I]IMTO is a highly specific radiotracer for imaging of adrenocortical tissue with a short investigation time and low radiation exposure. Because of the general availability of SPECT technology, [(123)I]IMTO scintigraphy has the potential to become a widely used tool to noninvasively characterize the biology of adrenal lesions.

Background: The clinical utility of modern hybrid imaging modalities for detecting recurrent bone or soft tissue sarcoma remains to be determined. In this report, the authors present a clinical study on the diagnostic accuracy and incremental value of integrated (18) F-fluorodeoxyglucose positron emission tomography/computed tomography ((18) F-FDG PET/CT) in patients with a history of sarcoma who have clinically suspected disease recurrence., Methods: Forty-three patients who had a history of bone or soft tissue sarcoma and had documented complete remission underwent (18) F-FDG PET/CT. Image analysis was performed independently for (18) F-FDG PET (n = 43) and for contrast-enhanced spiral CT (CE-CT) (n = 30) by 2 separate readers, whereas combined (18) F-FDG PET/CT (n = 43) images were analyzed in consensus by both readers. Imaging findings were rated on a 5-point scale and finally were reported as malignant, benign, or equivocal. Imaging findings were validated either by histopathology (n = 24) or by clinical follow-up (n = 19)., Results: (18) F-FDG PET/CT had greater sensitivity and specificity compared with CE-CT alone (94% and 92% vs 78% and 67%, respectively), resulting in significantly greater accuracy (93% vs 73%; P = .03). (18) F-FDG PET/CT was particularly superior regarding detection of local recurrence or soft tissue lesions (sensitivity and specificity: 83% and 100% vs 50% and 100%, respectively) or bone metastases (100% and 100% vs 85% and 88%, respectively)., Conclusions: (18) F-FDG PET/CT had greater diagnostic accuracy in the detection of recurrent bone or soft tissue sarcoma compared with CE-CT alone. The detection of local recurrence was the most evident advantage of (18) F-FDG PET/CT over CE-CT. Cancer 2013. © 2012 American Cancer Society., (Copyright © 2012 American Cancer Society.)

Purpose: To investigate whether the tumour uptake of radionuclide in peptide receptor radionuclide therapy (PRRT) of meningioma can be predicted by a PET scan with (68)Ga-labelled somatostatin analogue., Methods: In this pilot trial, 11 meningioma patients with a PET scan indicating somatostatin receptor expression received PRRT with 7.4 GBq (177)Lu-DOTATOC or (177)Lu-DOTATATE, followed by external beam radiotherapy. A second PET scan was scheduled for 3 months after therapy. During PRRT, multiple whole-body scans and a SPECT/CT scan of the head and neck region were acquired and used to determine the kinetics and dose in the voxel with the highest radionuclide uptake within the tumour. Maximum voxel dose and retention of activity 1 h after administration in PRRT were compared to the maximum standardized uptake values (SUV(max)) in the meningiomas from the PET scans before and after therapy., Results: The median SUV(max) in the meningiomas was 13.7 (range 4.3 to 68.7), and the maximum fractional radionuclide uptake in voxels of size 0.11 cm³ was a median of 23.4 × 10(-6) (range 0.4 × 10(-6) to 68.3 × 10(-6)). A strong correlation was observed between SUV(max) and the PRRT radionuclide tumour retention in the voxels with the highest uptake (Spearman's rank test, P < 0.01). Excluding one patient who showed large differences in biokinetics between PET and PRRT and another patient with incomplete data, linear regression analysis indicated significant correlations between SUV(max) and the therapeutic uptake (r = 0.95) and between SUV(max) and the maximum voxel dose from PRRT (r = 0.76). Observed absolute deviations from the values expected from regression were a median of 5.6 × 10(-6) (maximum 9.3 × 10(-6)) for the voxel fractional radionuclide uptake and 0.40 Gy per GBq (maximum 0.85 Gy per GBq) (177)Lu for the voxel dose from PRRT., Conclusion: PET with (68)Ga-labelled somatostatin analogues allows the pretherapeutic assessment of tumour radionuclide uptake in PRRT of meningioma and an estimate of the achievable dose.

Purpose: Despite recent advances in clinical imaging modalities, differentiation of pancreatic masses remains difficult. Here, we tested the diagnostic accuracy of molecular-based imaging including 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) positron emission tomography (PET) and [(18)F]fluorodeoxyglucose (FDG) PET/CT in patients with suspected pancreatic masses scheduled to undergo surgery., Methods: A total of 46 patients with pancreatic tumours suspicious for malignancy and scheduled for resective surgery were recruited prospectively. In 41 patients, FLT PET and FDG PET/CT scans were performed. A diagnostic CT performed on a routine basis was available in 31 patients. FLT PET and FDG PET/CT emission images were acquired according to standard protocols. Tracer uptake in the tumour [FDG and FLT standardized uptake value (SUV)] was quantified by the region of interest (ROI) technique. For FDG PET/CT analysis, correct ROI placement was ensured via side-by-side reading of corresponding CT images., Results: Of 41 patients, 33 had malignancy, whereas 8 patients had benign disease. Visual analysis of FDG and FLT PET resulted in sensitivity values of 91% (30/33) and 70% (23/33), respectively. Corresponding specificities were 50% (4/8) for FDG PET and 75% (6/8) for FLT PET. In the subgroup of patients with contrast-enhanced CT (n = 31), sensitivities were 96% (PET/CT), 88% (CT alone), 92% (FDG PET) and 72% (FLT PET), respectively. Mean FLT uptake in all malignant tumours was 3.0 (range SUV(max) 1.1-6.5; mean FDG SUV(max) 7.9, range 3.3-17.8; p < 0.001)., Conclusion: For differentiation of pancreatic tumours, FDG PET and FDG PET/CT showed a higher sensitivity but lower specificity than FLT PET. Interestingly, visual analysis of FLT PET led to two false-positive findings by misinterpreting physiological bowel uptake as pathological FLT uptake in the pancreas. Due to the limited number of patients, the clinical value of adding FLT PET to the diagnostic workup of pancreatic tumours remains to be determined.

In the past, enormous public and private investments have been made to reduce cancer incidence and mortality. Despite some improvements over the last 10 years, the overall outcome of the "war on cancer" has been disappointing. Among the reasons for this limited success is our inability to determine, whether the therapeutic target is present, and whether the target is reached by the drug. A further important issue is our limited ability to correctly assess response to treatment early after start of therapy which would allow for more individualized treatment approaches. PET and PET/CT with the glucose analogue 2'-[(18)F]-fluoro-2'-deoxy-D-glucose (FDG) are increasingly used to assess response to therapy in patients, and a converging large body of evidence is emerging that suggests that changes in glucose utilization during therapy can be used to predict clinical outcome. In this article we provide an overview of the utility of (18)F-FDG PET/CT imaging for early monitoring of cancer therapy and address current and future challenges for its more widespread adoption. First, we discuss general requirements that any imaging modality must meet to provide valid and valuable treatment response assessment. We will then review the strengths and limitations of CT (RECIST) and PET based response criteria. Finally, we will examine the role of FDG-PET/(CT) imaging for response assessments in solid tumors.

Unlabelled: Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma. Proliferation activity is considered an important prognostic marker. Immunohistochemical analysis from core biopsy or lymph node may not represent the proliferation rate. We investigated the in vivo proliferation marker 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) to characterize MCL., Methods: Eight untreated MCL patients were recruited prospectively. (18)F-FLT PET/CT was performed 45 min after injection of (18)F-FLT. (18)F-FDG PET/CT served as reference. Mean (18)F-FLT standardized uptake values were assessed per lesion and compared with respective (18)F-FDG uptake. Correlation of mean (18)F-FLT and (18)F-FDG uptake in the hottest lesion to Ki67 immunostaining was performed. Five patients underwent repetitive early (18)F-FLT PET., Results: All lymphoma lesions identified by (18)F-FDG PET/CT showed increased (18)F-FLT uptake. Semiquantitative analysis revealed a high mean (18)F-FLT standardized uptake value of 9.9 (range, 5.5-15.9). Mean (18)F-FLT uptake and Ki67 expressions showed a strong positive correlation., Conclusion: PET using (18)F-FLT as a biomarker for proliferative activity showed a high sensitivity for MCL. (18)F-FLT uptake shows a correlation with proliferation. Our results warrant further analysis of (18)F-FLT PET in MCL.

Background: Metabolic imaging of gastric cancer is limited due to the 30% of primary tumors that are not (18)F-fluorodeoxyglucose (FDG) avid. In contrast, the proliferation marker (18)F-fluorothymidine (FLT) has been shown to visualize also non-FDG-avid gastric tumors. In this study we tested whether FLT-positron emission tomography (PET) can improve the predictive potential of molecular imaging for assessing response to neoadjuvant therapy in gastric cancer compared with FDG-PET., Methods: 45 patients with gastric cancer underwent FDG- and FLT-PET before and 2 weeks after initiation of chemotherapy. FDG/FLT-PET findings and Ki67 immunohistochemistry were correlated with clinical and histopathological response and survival., Results: 14 patients had non-FDG-avid tumors, whereas all tumors could be visualized by FLT-PET. No significant association of clinical or histopathological response with any of the analyzed metabolic parameters [initial standardized uptake value (SUV), SUV after 2 weeks, change of SUV for FDG/FLT] was found. Univariate Cox regression analysis for Ki67 and metabolic parameters revealed significant prognostic impact for survival only for FLT SUV(mean) day 14 (p=0.048) and Ki67 (p=0.006). Multivariate Cox regression analysis (including clinical response, Lauren type, ypN category, and FLT SUV(mean) day 14) revealed Lauren type and FLT SUV(mean) day 14 as the only significant prognostic factors (p=0.006, p=0.002)., Conclusions: FLT uptake 2 weeks after initiation of therapy was shown to be the only imaging parameter with significant prognostic impact. Neither FLT-PET nor FDG-PET were correlated with histopathological or clinical response. However, these data must be interpreted with caution due to the single-center trial study design, relatively short follow-up, poor response rates, and unfavorable prognosis.

Background and Purpose: The present study evaluates the incidence of (11)C-choline PET/CT positive findings in patients with recurrent prostate cancer referred for salvage radiotherapy (SRT) and the influence on the definition of the planning target volume (PTV)., Material and Methods: Thirty-seven patients treated with radical prostatectomy and referred to SRT to the prostatic fossa because of biochemical relapse, were analysed retrospectively. All patients underwent (11)C-choline PET/CT before radiotherapy. The influence of PET/CT on the extent of the PTV was analysed. The median total follow up after SRT was 51.2 months., Results: 11/37 (30%) patients had a positive finding in the (11)C-choline PET/CT, 5 (13%) outside of the prostatic fossa (iliac lymph nodes), implicating an extension of the PTV. Patients with positive (11)C-choline PET/CT had a significant higher PSA value than patients with no pathologic uptake (p=0.03). Overall, at the end of follow up 56% of the patients had a PSA ≤ 0.2ng/ml and 44% had a biochemical relapse of prostate cancer., Conclusions: (11)C-choline PET/CT detects abnormalities outside of the prostatic fossa in 13% of patients referred for SRT because of biochemical relapse after radical prostatectomy, affecting the extent of the PTV. Prospective studies need to be implemented to evaluate the benefit of SRT with a PTV based on (11)C-choline PET/CT., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: FDG-PET/CT is increasingly used in staging of lung cancer as single "one stop shop" method. AIM, PATIENTS, METHODS: We prospectively included 104 neurological asymptomatic patients (65 years, 26% women) with primary diagnosis of lung cancer. In all patients PET/CT including cerebral imaging and cerebral MRI were performed., Results: Diagnosis of brain metastases (BM) was made by PET/CT in 8 patients only (7.7%), by MRI in 22 (21.2%). In 80 patients both PET/CT and MRI showed no BM. In 6 patients (5.8%) BM were detectable on PET/CT as well as on MRI. Exclusive diagnosis of BM by MRI with negative finding on PET/CT was present in 16 patients (15.4%). 2 patients (1.9%) had findings typical for BM on PET/CT but were negative on MRI. With MRI overall 100 BM were detected, with PET/CT only 17 BM (p < 0.01). For the diagnosis of BM PET/CT showed a sensitivity of 27.3%, specificity of 97.6%, positive predictive value of 75% and negative predictive value of 83.3%. BM diameter on PET/CT and MRI were consistent in 43%, in 57% BM were measured larger on MRI., Discussion: Compared to the gold standard of MRI for cerebral staging a considerable number of patients are falsely diagnosed as free from BM by PET/CT. MRI is more accurate than PET/CT for detecting multiple and smaller BM., Conclusion: In patients with a curative option MRI should be performed additionally to PET/CT for definitive exclusion of brain metastases.

Morphology-based imaging modalities have replaced classical conventional nuclear medicine modalities for detection of liver or pancreatic lesions. With positron emission tomography and the glucose analog F-18 fluorodeoxyglucose (FDG), a sensitive and specific modality for the detection of hepatic metastases and extrahepatic tumor deposits from hepatocellular or pancreatic cancer is available. F-18 FDG PET can increase the accuracy of staging primary tumors of the liver or the pancreas, and can be used for response monitoring. Radiopharmaceuticals such as Ga-68 DOTATOC and F-18 DOPA allow the specific detection of neuroendocrine pancreatic tumors and their metastatic deposits. Hybrid scanners such as PET-CT integrate morphologic and metabolic information, and allow to increase the sensitivity and specificity of noninvasive imaging in many tumor entities. The development of specific radiopharmaceuticals and technical innovations such as SPECT-CT has increased the reliability of conventional scintigraphic imaging. This chapter focuses on the use of PET-CT in hepatobiliary and pancreatic cancers.

Unlabelled: Although the diagnostic effectiveness of integrated PET/CT for staging of non-small cell lung cancer (NSCLC) has already been proven, it remains to be determined if tumor staging with combined metabolic and anatomic imaging is also cost-effective. The objective of this study was to evaluate from a payers' perspective the cost-effectiveness of staging NSCLC with CT alone (representing the mainstay diagnostic test) and with integrated PET/CT., Methods: The study is based on 172 NSCLC patients from a prospective clinical study who underwent diagnostic, contrast-enhanced helical CT and integrated PET/CT. Imaging was performed at the University Hospital Ulm between May 2002 and December 2004. To calculate treatment costs, we differentiated among cost for diagnosis, cost for nonsurgical treatment according to the clinical diagnosis, and cost for surgical procedures according to the clinical tumor stage., Results: The diagnostic effectiveness in terms of correct TNM staging was 40% (31/77) for CT alone and 60% (46/77) for PET/CT. For the assessment of resectability (tumor stages Ia-IIIa vs. IIIb-IV), 65 of 77 patients (84%) were staged correctly by PET/CT (CT alone, 70% [54/77]). The incremental cost-effectiveness ratios per correctly staged patient were $3,508 for PET/CT versus CT alone. The incremental cost-effectiveness ratios per quality-adjusted life year gained were $79,878 for PET/CT vs. CT alone, decreasing to $69,563 assuming a reduced loss of utility (0.10 quality-adjusted life years) due to surgical morbidity., Conclusion: Cost-effectiveness analyses showed that costs for PET/CT are within the commonly accepted range for diagnostic tests or therapies. Therefore, reimbursement of PET/CT for NSCLC staging can be also recommended from an economic point of view.

PET and PET/CT have changed the diagnostic algorithm in oncology. Health care systems worldwide have recently approved reimbursement for PET and PET/CT for staging of non-small cell lung cancer and differential diagnosis of solitary pulmonary nodules because PET and PET/CT have been found to be cost-effective for those uses. Additional indications that are covered by health care systems in the United States and several European countries include staging of gastrointestinal tract cancers, breast cancer, malignant lymphoma, melanoma, and head and neck cancers. Regarding these indications, diagnostic effectiveness and superiority over conventional imaging modalities have been shown, whereas cost-effectiveness has been demonstrated only in part. This article reports on the current knowledge of economic evaluations of PET and PET/CT in oncologic applications. Because more economic evaluations are needed for several clinical indications, we also report on the methodologies for conducting economic evaluations of diagnostic tests and suggest an approach toward the implementation of these tests in future clinical studies.

Purpose: In detecting pheochromocytoma (PHEO), positron emission tomography (PET) with the radiolabelled amine precursor (18)F-fluorodihydroxyphenylalanine ((18)F-DOPA) offers excellent specificity, while computed tomography (CT) provides high sensitivity and ability to localize lesions; therefore, the combination of these modalities could be advantageous in this setting. The aim of this study was to investigate whether combined (18)F-DOPA PET/CT more accurately detects and localizes PHEO lesions than does each modality alone., Methods: (18)F-DOPA PET, CT and (18)F-DOPA PET/CT images of 25 consecutive patients undergoing diagnostic scanning of suspected sporadic or multiple endocrine neoplasia type 2 syndrome-associated PHEO were reviewed retrospectively in randomized sequence. Two blinded observers scored the images regarding the likelihood of PHEO being present and localizable. Results were correlated with subsequent clinical history and, when available, histology., Results: Of the 19 lesions detected by all three modalities, PET identified each as positive for PHEO, but was unable to definitively localize 15 of 19 (79%). CT could definitively localize all 19 lesions, but could not definitively diagnose or exclude PHEO in 18 of 19 (95%) lesions. Furthermore, CT falsely identified as negative for PHEO one lesion which was judged to be positive for this tumor by both PET and PET/CT. Only in PET/CT scans were all 19 lesions accurately characterized and localized. On a per-patient basis, the sensitivity of (18)F-DOPA PET/CT for PHEO was 100% and the specificity 88%, with a 100% positive predictive value and an 88% negative predictive value., Conclusion: (18)F-DOPA PET/CT more accurately diagnoses and localizes adrenal and extra-adrenal masses suspicious for PHEO than do (18)F-DOPA PET or CT alone.

Morphological and functional imaging methods are used for staging of gastrointestinal stromal tumors (GIST) and to follow-up GIST patients undergoing therapy. Computed tomography is the most frequently used morphological imaging procedure and has been recommended as the imaging method of choice according to current GIST guidelines. However, positron emission tomography using [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG-PET) as the radiotracer has shown to be advantageous over morphological imaging procedures when assessing therapy response at an early time point. While tumor size reduction in morphological imaging typically requires time to develop, a decrease in FDG uptake can be detected as early as 24 h following therapy initiation. To overcome the limitations of size-based therapy response assessment on morphological imaging procedures, new density-based therapy response criteria have been developed and implemented for GIST. This review addresses both indications and accuracy of morphological and functional imaging modalities for GIST.

Objective: To evaluate [(11)C]choline positron emission tomography/computed tomography ([(11)C]choline PET/CT) for the detection of a biochemical recurrence of prostate cancer after radical prostatectomy., Methods: Retrospective analysis of [(11)C]choline PET/CT performed in 41 consecutive prostate cancer patients with a rising PSA. The mean time to biochemical relapse was 24 months. PSA levels were determined at time of examination, and patients received either a targeted biopsy or surgery. Histopathology reports served as reference for the evaluation of the [(11)C]choline PET/CT findings., Results: Mean PSA in [(11)C]choline PET/CT positive patients was 3.1 ng/ml (median 2.2 ng/ml, range 0.5-11.6 ng/ml) and 0.86 ng/ml in [(11)C]choline PET/CT negative patients (median 0.83 ng/ml, range 0.41-1.40 ng/ml). Six of 12 patients with PSA < 1.5 ng/ml [(11)C]choline PET/CT revealed a pathological uptake. Histopathology was positive in 6/12 patients in this group. At PSA levels ranging from 1.5 to 2.5 ng/ml all [(11)C]choline PET/CT were positive (n = 16), a positive histology was found in 12/16 patients (75%) and at PSA 2.5-5 ng/ml [(11)C]choline PET/CT was positive in 8/8 patients, confirmed by histology in 7/8 patients. Finally, at PSA higher than 5 ng/ml [(11)C]choline PET/CT identified 5/5 patients positive all confirmed by histology. The sensitivity of [(11)C]choline PET/CT for the detection of recurrence at PSA < 2.5 ng/ml was 89% with a positive predictive value of 72%., Conclusion: [(11)C]choline PET/CT is useful for re-staging of prostate cancer in patients with rising PSA even at levels below 1.5 ng/ml. Our study confirms results from other published studies on [(11)C]choline PET/CT in prostate cancer relapse.

Unlabelled: We determined the ability of PET with the thymidine analog 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) to detect hepatocellular carcinoma (HCC)., Methods: In this pilot study, (18)F-FLT PET was performed in 18 untreated patients with clinically suspected HCC. Routine diagnostic procedures included ultrasound, MRI, or contrast-enhanced spiral CT of the upper gastrointestinal tract in all patients. At 45-60 min after the intravenous injection of approximately 270-340 MBq of (18)F-FLT, emission and transmission scanning was performed with a high-resolution PET scanner. Tracer uptake in the tumor and surrounding liver tissue was evaluated semiquantitatively by calculation of mean and maximum standardized uptake values (SUVs). Results were correlated with those of the conventional imaging methods., Results: A total of 13 of 18 tumors (sensitivity, 72%; 95% confidence interval [CI], 47%-90%) showed focal (18)F-FLT uptake higher than surrounding liver activity and were detectable as hot lesions. Five tumors were characterized as photopenic lesions or contained a mixture of hot and cold lesions exhibiting a comparable or lower (18)F-FLT uptake than the surrounding liver tissue. When all lesions were considered, the mean (18)F-FLT SUV was 7.8 (range, 2.5-11.1), and the maximum (18)F-FLT SUV was 9.3 (range, 2.9-14.3). Histology and clinical follow-up revealed HCC in 16 patients and cholangiocarcinoma in 2 patients. In the subgroup of HCC, the sensitivity for tumor detection was 69% (11/16; 95% CI, 41%-89%). Correlation analysis demonstrated a significant positive relationship between the proliferation marker MIB-1 and the mean SUV (r = 0.66, P = 0.02). Survival analysis (Cox proportional hazards regression) for initial (18)F-FLT uptake (mean and maximum SUVs) revealed increased hazard ratios (mean SUV, 1.20; maximum SUV, 1.12), but because of the small number of events, these results were not statistically significant., Conclusion: In this pilot study, HCC tumors showed a mixed uptake pattern for the in vivo proliferation marker (18)F-FLT. A total of 69% of the HCC lesions showed (18)F-FLT uptake higher than that of the surrounding liver tissue, whereas the remaining lesions were photopenic or contained a mixture of hot and cold lesions. High initial (18)F-FLT uptake seems to be associated with reduced overall survival and could be an important prognostic factor if this tendency can be confirmed in a larger prospective trial.

Purpose: The aim of this study was to assess the clinical value of [(11)C]methionine-PET (MET-PET) for detection and localization of parathyroid adenomas in patients without prior thyroidectomy., Methods: A retrospective analysis of patients with suspected parathyroid adenomas undergoing imaging with MET-PET was performed. Prior thyroidectomy was an exclusion criterion. Forty-one patients with a total of 49 MET-PET scans were included. MET-PET consisted of whole-body images obtained 15-20 min after injection of 430 +/- 81 MBq of MET using a dedicated PET scanner. Imaging findings were validated by histology or other imaging studies and clinical follow-up on a lesion, side, and location basis. Comparison of PET results to other imaging modalities including ultrasound, MIBI scintigraphy, and morphological imaging [computed tomography (CT) and/or magnetic resonance imaging] and subgroup analysis of primary vs. secondary hyperparathyroidism was performed., Results: Twenty-three of 49 PET scans revealed pathologic findings, whereas 26 of 49 scans were negative. Validation of PET findings for detection and localization of parathyroid adenomas resulted in an overall sensitivity of MET-PET of 54%, 49%, and 35% on a lesion, side, and location basis, respectively. Sensitivity of MET-PET was inferior compared to ultrasonography (50% vs. 93%), MIBI scintigraphy (53% vs. 74%) and morphological imaging (52% vs. 74%). Subgroup analysis revealed higher sensitivity for MET-PET in secondary HPT (sHPT) than primary HPT (pHPT; 62% vs. 43%; side basis)., Conclusions: In patients with initial diagnosis of hyperparathyroidism and no prior thyroidectomy, the sensitivity of MET-PET for detection and localization of parathyroid adenomas is markedly lower compared to previous reports. While performance was better in sHPT, we believe that MET-PET cannot be recommended for pHPT localization in this clinically relevant subcollective. The clinical value of MET/PET in patients with hyperparathyroidism should be further investigated in a prospective study utilizing anatometabolic imaging with a PET/CT device.

Deregulated cell cycle progression is a hallmark of cancer. Accordingly, a major part of therapeutic drugs has been designed to inhibit cell proliferation and tumor growth. Metabolic imaging with positron emission tomography (PET) and the glucose analog 2'-[(18)F]fluoro-2'-deoxyglucose (FDG) has been demonstrated to sensitively detect malignant tumors and to identify responding tumors early in the course of anticancer treatment. However, tumoral uptake of FDG reflects proliferation only in part and is associated with false positive findings due to unspecific tracer retention in inflammatory processes. Most recent advances in cancer treatment have come from the development of disease specific, molecular agents, many of which induce cell cycle arrest (cytostatic effect) instead of tumor cell death (cytotoxic effect). Thus, evaluating alterations in DNA metabolism may reflect response to treatment better than alterations in glucose utilization. PET with the thymidine analog 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) enables non-invasive imaging and quantification of the proliferation fraction of tumors. Furthermore, FLT has been suggested as surrogate marker for assessment of response to treatment, especially when targeted drugs are utilized. This article reports on metabolic pathways of radionucleosides in proliferating cells. Methods for in vivo assessment of the proliferative activity in preclinical and clinical studies are described with a focus on early monitoring response to therapy.

The monoclonal antibody anti-CD66 labeled with (99m)Tc is widely used as Scintimun granulocyte for bone marrow immunoscintigraphy. Further, recently performed clinical radioimmunotherapy studies with [(90)Y]Y-anti-CD66 proved to be suitable for the treatment of hematologic malignancies. Before radioimmunotherapy with [(90)Y]Y-anti-CD66, dosimetric estimations are required to minimize radiotoxicity and determine individual applicable activities. Planar imaging, using gamma-emitting radionuclides, is conventionally carried out to estimate the absorbed organ doses. In contrast, immuno-PET (positron emission tomography) enables the quantification of anti-CD66 accumulation and provides better spatial and temporal resolution. Therefore, in this study, a semiautomated radiosynthesis of [(18)F]F-anti-CD66 was developed, using the (18)F-acylation agent, N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB). As a proof of concept, an intraindividual comparison between PET and conventional scintigraphy, using (18)F- and (99m)Tc-labeled anti-CD66 in 1 patient with high-risk leukemia, is presented. Both labeled antibodies displayed a similar distribution pattern with high preferential uptake in bone marrow. Urinary excretion of [(18)F]F-anti-CD66 was increased and bone marrow uptake reduced, in comparison to [(99m)Tc]Tc-anti-CD66. Nevertheless, PET-based dosimetry with [(18)F]F-anti-CD66 could provide additional information to support conventional scintigraphy. Moreover, [(18)F]F-anti-CD66 is ideally suited for bone marrow imaging using PET.