Rapid Standardized CT-Based Method to Determine Lean Body Mass SUV for PET-A Significant Improvement Over Prediction Equations.

In 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) studies, maximum standardized uptake value (SUVmax) is the parameter commonly used to provide a measurement of the metabolic activity of a tumor. SUV normalized by body mass is affected by the proportions of body fat and lean tissue, which present high variability in patients with cancer. SUV corrected by lean body mass (LBM), denoted as SUL, is recommended to provide more accurate, consistent, and reproducible SUV results; however, LBM is frequently estimated rather than measured. Given the increasing importance of a quantitative PET parameter, especially when comparing PET studies over time to evaluate disease response clinically, and its use in oncological clinical trials, we set out to evaluate the commonly used equations originally derived by James (1976) and Janmahasatian et al. (2005) against computerized tomography (CT)-derived measures of LBM. Methods: Whole-body 18F-FDG PET images of 195 adult patients with cancer were analyzed retrospectively. Representative liver SUVmean was normalized by total body mass. SUL was calculated using a quantitative determination of LBM based on the CT component of the PET/CT study (LBMCT) and compared against the equation-estimated SUL. Bland and Altman plots were generated for SUV-SUL differences. Results: This consecutive sample of patients undergoing usual care (men, n = 96; women, n = 99) varied in body mass (38-127 kg) and in Body Mass Index (BMI) (14.7-47.2 kg/m2). LBMCT weakly correlated with body mass (men, r2 = 0.32; women, r2 = 0.22), and thus SUV and SULCT were also weakly correlated (men, r2 = 0.24; women, r2 = 0.11). Equations proved inadequate for the assessment of LBM. LBM estimated by James' equation showed a mean bias (overestimation of LBM compared with LBMCT) in men (+6.13 kg; 95% CI 4.61-7.65) and in women (+6.32 kg; 95% CI 5.26-7.39). Janmahasatian's equation provided similarly poor performance. Conclusions: CT-based LBM determinations incorporate the patient's current body composition at the time of a PET/CT study, and the information garnered can provide care teams with information with which to more accurately determine FDG uptake values, allowing comparability over multiple scans and treatment courses and will provide a robust basis for the use of PET Response Criteria in Solid Tumors (PERCIST) in clinical trials.

Is Radiation-Induced Cardiac Toxicity Reversible? Prospective Evaluation of Patients With Breast Cancer Enrolled in a Phase 3 Randomized Controlled Trial.

PURPOSE: Myocardial perfusion defects after breast radiation therapy (RT) correlate with volume of irradiated left ventricle (LV). We aimed to determine the relationship between myocardial perfusion, LV dosimetry, and grade ≥2 late cardiac events in patients with breast cancer undergoing adjuvant RT. METHODS AND MATERIALS: A randomized study evaluated the benefit of inverse-planned intensity modulated radiation therapy over forward-planned intensity modulated radiation therapy for radiation toxicity in breast cancer. A secondary endpoint was evaluating cardiac perfusion by single-photon emission computed tomography done at baseline, 6 months, 1 year, 2 years, and 5 years post-RT. We used receiver operating curve and regression analysis to identify association between perfusion, radiation dose-volumes, and the risk of late cardiac events. RESULTS: Of 181 patients who received adjuvant RT, 102 were patients with cancer in the left breast (called in this study the left-sided group) and 79 were patients with cancer in the right breast (called in this study the right-sided group). Median follow-up was 127 months (range, 19-160 months). A significant worsening of perfusion defects occurred after RT in the left-sided group, which improved by 1 year. Late cardiac events were found among 16 patients (17.2%) in the left-sided group and 4 patients (5.5%) in the right-sided group. Perfusion changes did not correlate with late cardiac events, but LV dose-volumes correlated with late cardiac events. Maintaining the LV volume receiving 5 Gy and 10 Gy to <42 cc and <38cc, respectively, can reduce the risk of radiation-related late cardiac events at 10 years to <5% over baseline. CONCLUSIONS: RT was associated with short-term perfusion defects that improved within 1 year and was not correlated with late cardiac events. The ventricular volumes receiving 5 Gy and 10 Gy were correlated with late cardiac events.

Assessment of a commercially available automatic deformable registration system.

In recent years, a number of approaches have been applied to the problem of deformable registration validation. However, the challenge of assessing a commercial deformable registration system - in particular, an automatic registration system in which the deformable transformation is not readily accessible - has not been addressed. Using a collection of novel and established methods, we have developed a comprehensive, four-component protocol for the validation of automatic deformable image registration systems over a range of IGRT applications. The protocol, which was applied to the Reveal-MVS system, initially consists of a phantom study for determination of the system's general tendencies, while relative comparison of different registration settings is achieved through postregistration similarity measure evaluation. Synthetic transformations and contour-based metrics are used for absolute verification of the system's intra-modality and inter-modality capabilities, respectively. Results suggest that the commercial system is more apt to account for global deformations than local variations when performing deform-able image registration. Although the protocol was used to assess the capabilities of the Reveal-MVS system, it can readily be applied to other commercial systems. The protocol is by no means static or definitive, and can be further expanded to investigate other potential deformable registration applications.

A comparative PET imaging study of 44gSc- and 68Ga-labeled bombesin antagonist BBN2 derivatives in breast and prostate cancer models.

INTRODUCTION: Radiolabeled peptides play a central role in nuclear medicine as radiotheranostics for targeted imaging and therapy of cancer. We have recently proposed the use of metabolically stabilized GRPR antagonist BBN2 for radiolabeling with 18F and 68Ga and subsequent PET imaging of GRPRs in prostate cancer. The present work studied the impact of 44gSc- and 68Ga-labeled DOTA complexes attached to GRPR antagonist BBN2 on the in vitro GRPR binding affinity, and their biodistribution and tumor uptake profiles in MCF7 breast and PC3 prostate cancer models. METHODS: DOTA-Ava-BBN2 was radiolabeled with radiometals 68Ga and 44gSc. Gastrin-releasing peptide receptor (GRPR) affinities of peptides were assessed in PC3 prostate cancer cells. GRPR expression profiles were studied in human breast cancer tissue samples and MCF7 breast cancer cells. PET imaging of 68Ga- and 44gSc-labeled peptides was performed in MCF7 and PC3 xenografts as breast and prostate cancer models. RESULTS: Radiopeptides [68Ga]Ga-DOTA-Ava-BBN2 and [44gSc]Sc-DOTA-Ava BBN2 were prepared in radiochemical yields of 70-80% (decay-corrected), respectively. High binding affinities were found for both peptides (IC50 = 15 nM (natGa) and 5 nM (natSc)). Gene expression microarray analysis revealed high GRPR mRNA expression levels in estrogen receptor (ER)-positive breast cancer, which was further confirmed with Western blot and immunohistochemistry. However, PET imaging showed only low tumor uptake of both radiotracers in MCF7 xenografts ([68Ga]Ga-DOTA-BBN2 (SUV60min 0.27 ± 0.06); [44gSc]Sc-DOTA-BBN2 (SUV60min 0.20 ± 0.03)). In contrast, high tumor uptake and retention were found for both radiopeptides in PC3 tumors ([68Ga]Ga-DOTA-BBN2 (SUV60min 0.46 ± 0.07); [44gSc]Sc-DOTA-BBN2 (SUV60min 0.51 ± 0.11)). CONCLUSIONS: Comparison of 68Ga- and 44gSc-labeled DOTA-Ava-BBN2 peptides revealed slight but noticeable differences of the radiometal with an impact on the in vitro GRPR receptor binding properties in PC3 cells. No differences were found in their in vivo biodistribution profiles in MCF7 and PC3 xenografts. Radiopeptides [68Ga]Ga-DOTA-Ava-BBN2 and [44gSc]Sc-DOTA-Ava-BBN2 displayed comparable tumor uptake and retention profiles with rapid blood and renal clearance profiles in both tumor models. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: The favorable PET imaging performance of [44gSc]Sc-DOTA-Ava-BBN2 in prostate cancer should warrant the development of an [43Sc]Sc-DOTA-Ava-BBN2 analog for clinical translation which comes with a main γ-line of much lower energy and intensity compared to 44gSc.

Initial results of hypoxia imaging using 1-alpha-D: -(5-deoxy-5-[18F]-fluoroarabinofuranosyl)-2-nitroimidazole ( 18F-FAZA).

PURPOSE: Tumour hypoxia is thought to play a significant role in the outcome of solid tumour therapy. Positron emission tomography (PET) is the best-validated noninvasive technique able to demonstrate the presence of hypoxia in vivo. The locally developed PET tracer for imaging hypoxia, 1-alpha-D: -(5-deoxy-5-[(18)F]-fluoroarabinofuranosyl)-2-nitroimidazole ((18)F-FAZA), has been shown to accumulate in experimental models of tumour hypoxia and to clear rapidly from the circulation and nonhypoxic tissues. The safety and general biodistribution patterns of this radiopharmaceutical in patients with squamous cell carcinoma of the head and neck (HNSCC), small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC), malignant lymphoma, and high-grade gliomas, were demonstrated in this study. METHODS: Patients with known primary or suspected metastatic HNSCC, SCLC or NSCLC, malignant lymphoma or high-grade gliomas were dosed with 5.2 MBq/kg of (18)F-FAZA, then scanned 2-3 h after injection using a PET or PET/CT scanner. Images were interpreted by three experienced nuclear medicine physicians. The location and relative uptake scores (graded 0 to 4) of normal and abnormal (18)F-FAZA biodistribution patterns, the calculated tumour-to-background (T/B) ratio, and the maximum standardized uptake value were recorded. RESULTS: Included in the study were 50 patients (32 men, 18 women). All seven patients with high-grade gliomas showed very high uptake of (18)F-FAZA in the primary tumour. In six out of nine patients with HNSCC, clear uptake of (18)F-FAZA was observed in the primary tumour and/or the lymph nodes in the neck. Of the 21 lymphoma patients (15 with non-Hodgkin's lymphoma and 6 with Hodgkin's disease), 3 demonstrated moderate lymphoma-related uptake. Of the 13 lung cancer patients (12 NSCLC, 1 SCLC), 7 had increased (18)F-FAZA uptake in the primary lung tumour. No side effects of the administration of (18)F-FAZA were observed. CONCLUSION: This study suggests that (18)F-FAZA may be a very useful radiopharmaceutical to image hypoxia in the tumour types selected. Especially the high uptake by gliomas was encouraging. Given the good imaging properties, including acceptable T/B ratios in the tumour categories studied, (18)F-FAZA could be considered as a very promising agent for assessing the hypoxic fraction of these tumour types.

Prostate positioning errors associated with two automatic registration based image guidance strategies.

Daily image guidance for helical tomotherapy prostate patients is based on the registration of pre-treatment megavoltage CT (MVCT) images and the original planning CT. The goal of registration, whether manual or automatic, is the overlap of the prostate; otherwise prostate misplacement may compromise the efficacy of treatment or lead to increased toxicity. A previous study demonstrated that without the aid of implanted fiducials, manual registration results in inaccurate prostate positioning. The objective of this work is to quantify prostate misplacement that results from automatic bone matching (BM) and image matching (IM) registration algorithms. 204 MVCT images from 8 high risk tomotherapy prostate patients were incorporated into this retrospective study. BM and IM registration algorithms--based on maximization of mutual information of bony anatomy only and the entire image, respectively--were used to independently register MVCT images to their respective planning images. A correlation coefficient based algorithm that uses known planning CT contour information was used for automatic prostate localization in each MVCT image. Daily prostate misplacement was determined by repositioning as calculated from the BM and the IM algorithms. Mean (+/- SD) and maximum 3D prostate positioning errors were 3.7 +/- 2.1 mm and 11.8 mm for bone matching and 4.6 +/- 2.3 mm and 11.5 mm for image matching. In terms of translational directions, IM would lead to prostate positioning error > or = 3 mm in any of the LR, AP or SI directions in 62% of treatment fractions. The corresponding value for BM is 51%. The values for positioning errors > or = 5 mm were 29% and 17% for IM and BM, respectively. This data suggests automatic daily image guidance for tomotherapy prostate patients should be based on bone matching instead of image matching.

Comparison of scandium-44 g with other PET radionuclides in pre-clinical PET phantom imaging.

PURPOSE: The decay characteristics of radionuclides in PET studies can impact image reconstruction. 44gSc has been the topic of recent research due to potential theranostic applications and is a promising radiometal for PET imaging. In this study, the reconstructed images from phantom measurements with scandium in a small-animal PET scanner are compared with 18F and two prominent radiometals: 64Cu and 68Ga METHODS: Three phantoms filled with 18F, 64C, 68Ga, and 44gSc were imaged in the Siemens Inveon PET scanner. The NEMA image quality phantom was used to determine the recovery coefficients (RCs), spill-over ratios (SORs), and noise (%SD) under typical pre-clinical imaging conditions. Image contrast was determined using a Derenzo phantom, while the coincidence characteristics were investigated using an NEC phantom. Three reconstruction algorithms were used, namely filtered back projection (FBP), ordered subset expectation maximization (OSEM), and maximum a-posteriori (MAP). RESULTS: Image quality parameters were measured for 18F, 64Cu, 68Ga, and 44gSc respectively; using FBP, the %SD are 5.65, 5.88, 7.28, and 7.70; the RCs for the 5-mm rod are 0.849, 1.01, 0.615, and 0.825; the SORs in water are 0.0473, 0.0595, 0.141, 0.0923; and the SORs in air are 0.0589, 0.0484, 0.0525, and 0.0509. The contrast measured in the 2.5-mm rods are 0.674, 0.637, 0.196, and 0.347. The NEC rate with 44gSc increased at a slower rate than 18F and 68Ga as a function of activity in the field of view. CONCLUSION: 44gSc demonstrates intermediate behavior relative to 18F and 68Ga with regard to RC and contrast measurements. It is a promising radionuclide for preclinical imaging.

Prognostic utility of pre- and post-treatment FDG-PET parameters in anal squamous cell carcinoma.

BACKGROUND AND PURPOSE: We prospectively assessed the contributions of PET to initial staging, early detection of treatment failures, and prognostication in patients with anal squamous cell carcinoma (ASCC). MATERIALS AND METHODS: Consecutive patients with ASCC referred for radical chemoradiotherapy (CRT) consented to undergo FDG-PET imaging pre-treatment and at 3 and 6 months post-treatment. Clinicopathologic data were collected and CT and PET imaging reviewed for contribution to staging and recurrence detection. Maximum standardized uptake value (SUVmax), peak standardized uptake value (SUVpeak), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were assessed for association with progression-free survival (PFS), cause-specific survival (CSS), and overall survival (OS) using the Kaplan-Meier and Cox regression models. RESULTS: Between 2009 and 2016, 73 patients with clinical stages I-IIIB ASCC completed curative-intent CRT. Median follow-up was 48 months. 14 patients died and 18 patients experienced disease progression. 4-year PFS, CSS, and OS were 73%, 87%, and 84%, respectively. A pre-treatment MTV >35 cm3 predicted for worse PFS (p = 0.011) and CSS (p = 0.024) on univariate and multivariate analyses, employing an MTV definition of voxels ≥25% of SUVmax. Higher 6-month post-treatment SUVmax and SUVpeak predicted for worse PFS and OS (p ≤ 0.011). Pre-treatment SUVmax, SUVpeak, and TLG, and 3-month post-treatment SUVmax and SUVpeak did not significantly correlate with survival outcomes. CONCLUSIONS: Our findings support that pre-treatment MTV provides meaningful prognostic information, with suggestion that an MTV delineation threshold of voxels ≥25% of SUVmax is appropriate in the anal region. Post treatment, the combination of clinical examination and PET effectively detected all treatment failures. Higher 6-month post-treatment SUVmax and SUVpeak predicted worse PFS and OS; however, the optimal timing of post-treatment PET imaging remains unclear.

Use of a simulated annealing algorithm to fit compartmental models with an application to fractal pharmacokinetics.

Increasingly, fractals are being incorporated into pharmacokinetic models to describe transport and chemical kinetic processes occurring in confined and heterogeneous spaces. However, fractal compartmental models lead to differential equations with power-law time-dependent kinetic rate coefficients that currently are not accommodated by common commercial software programs. This paper describes a parameter optimization method for fitting individual pharmacokinetic curves based on a simulated annealing (SA) algorithm, which always converged towards the global minimum and was independent of the initial parameter values and parameter bounds. In a comparison using a classical compartmental model, similar fits by the Gauss-Newton and Nelder-Mead simplex algorithms required stringent initial estimates and ranges for the model parameters. The SA algorithm is ideal for fitting a wide variety of pharmacokinetic models to clinical data, especially those for which there is weak prior knowledge of the parameter values, such as the fractal models.

Modeling fractal-like drug elimination kinetics using an interacting random-walk model.

We introduce an interacting random-walk model to describe the residence time of drug molecules undergoing a series of sojourn times in the body before being permanently eliminated under either homogeneous or heterogeneous conditions. We show that short-term correlations between drug molecules lead to Michaelis-Menten kinetics while long-term correlations lead to transient fractal-like kinetics. By combining both types of correlation, fractal-like Michaelis-Menten kinetics are achieved, and the simulations confirm previous analytical results.

131I-MIBG Therapy in a Metastatic Small Bowel Neuroendocrine Tumor Patient Undergoing Hemodialysis.

Systemic radioisotope therapy with I-metaiodobenzylguanidine (I-MIBG) is an effective form of targeted therapy for neuroendocrine tumors. One of the absolute contraindications to administering I-MIBG therapy listed in the 2008 European Association of Nuclear Medicine guidelines is renal insufficiency requiring dialysis, although this contraindication is not evidence based. We describe a 68-year-old woman with a metastatic small bowel neuroendocrine tumor who developed renal insufficiency requiring hemodialysis. Imaging and dosimetry with I-MIBG were performed and showed that the radiation doses to the whole body and lungs were within safe limits. She was treated with 1820 MBq of I-MIBG with no short-term adverse reactions.

Chest X-ray Artifact Caused by Bilateral 99mTc-Antimony Trisulfite Injection for Sentinel Node Imaging in a Patient With Breast Cancer.

A 52-year-old woman diagnosed with invasive ductal carcinoma of both breasts had a chest x-ray for preoperative assessment. A striking artifact was noted by the x-ray technologist, who, as a result, became very concerned about radiation exposure from the patient. The patient had undergone bilateral sentinel lymph node injections in the nuclear medicine department with Tc-antimony trisulfite colloid just 2 hours before the chest x-ray. Radiation exposure to the x-ray technologist was determined to be similar to 8 hours of naturally occurring background radiation (∼2.96 µSv).

Ectopic Corticotropin-Producing Neuroendocrine Tumor of the Pancreas Treated With 177Lu DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy.

A 57-year-old woman diagnosed with ectopic Cushing syndrome was found to have a 111In-octreotide-avid corticotropin-producing pancreatic neuroendocrine tumor with liver metastases. She was treated with 4 induction and 4 maintenance cycles of 177Lu-DOTATATE, which normalized her serum corticotropin levels and dramatically reduced the size of the pancreatic primary and liver metastases.

Thresholding in PET images of static and moving targets.

Continued therapeutic gain in the treatment of non-small-cell lung cancer (NSCLC) will depend upon our ability to escalate the dose to the primary tumour while minimizing normal tissue toxicity. Both these objectives are facilitated by the accurate definition of a target volume that is as small as possible. To this end, both tumour immobilizations via deep inspiratory breath-hold, along with positron emission tomography (PET), have emerged as two promising approaches. Though PET is an excellent means of defining the general location of a tumour focus, its ability to define exactly the geometric extent of such a focus strongly depends upon selection of an appropriate image threshold. However, in clinical practice, the image threshold is typically not chosen according to consistent, well-established criteria. This study explores the relationship between image threshold and the resultant PET-defined volume using a series of F-18 radiotracer-filled hollow spheres of known internal volumes, both static and under oscillatory motion. The effects of both image threshold and tumour motion on the resultant PET image are examined. Imaging data are further collected from a series of simulated gated PET acquisitions in order to test the feasibility of a patient-controlled gating mechanism during deep inspiratory breath-hold. This study illustrates quantitatively considerable variability in resultant PET-defined tumour volumes depending upon numerous factors, including image threshold, size of the lesion, the presence of tumour motion and the scanning protocol. In this regard, when using PET in treatment planning for NSCLC, the radiation oncologist must select the image threshold very carefully to avoid either under-dosing the tumour or overdosing normal tissues.

Threshold modification for tumour imaging in non-small-cell lung cancer using positron emission tomography.

AIM: Positron emission tomography (PET) has been used increasingly in the staging and radiotherapy treatment planning of non-small-cell lung cancer (NSCLC). This study investigates the factors that affect the resultant size of a given image on PET. METHODS: PET was used to assess the geometric characteristics of a series of radioisotope-filled, stationary spheres of known volume, surrounded by positron-emitting radioactive tracer of variable activity. The resultant PET-derived spherical volumes were then referenced to the known spherical volumes in order to illustrate quantitatively the potential influence of image threshold, tumour size and background concentration. This influence was further illustrated by clinical examples. RESULTS: Considering the diameter of the spheres used in this study (10-48 mm), higher image thresholds were required for accurate rendering of the smallest spherical volumes. This inverse relationship was most consistently illustrated at the lowest background intensity ratios. CONCLUSION: PET-derived volumes of NSCLC must be interpreted with caution. The data presented in this study may be used to guide the selection of appropriate image thresholds for potential clinical application.

Resolution of Hyperreninemia, Secondary Hyperaldosteronism, and Hypokalemia With 177Lu-DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy in a Patient With Pancreatic Neuroendocrine Tumor.

A 54-year-old woman presented with a history of nausea, vomiting, diarrhea, and recurrent episodes of severe hypokalemia requiring hospitalization. Imaging revealed a pancreatic mass with liver metastases, histologically confirmed to be a neuroendocrine tumor. Elevated active renin and aldosterone levels were identified, and the patient was treated with 4 induction cycles of Lu-DOTATATE, which resolved the diarrhea, nausea, and hypokalemia, and normalized the renin and aldosterone levels. After 3 additional maintenance Lu-DOTATATE treatments, the pancreatic tumor had decreased in size, was deemed operable, and was resected. She remains on maintenance Lu-DOTATATE therapy with progression-free survival of 45 months thus far.

Glucagonoma Pancreatic Neuroendocrine Tumor Treated With 177Lu DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy.

A 56-year-old man presented with a history of 2 prior resections of a recurrent pancreatic glucagonoma in the past 4 years. Workup revealed new liver and abdominal nodal metastases with a rising serum glucagon level. He was started on peptide receptor radionuclide therapy with Lu DOTATATE, and his disease stabilized, while his glucagon levels decreased and also stabilized. After 4 induction and 2 maintenance cycles, he remains progression free for 23 months.

Metallic copper as a fiducial marker for both CT and PET.

There is great interest in augmenting computed tomography (CT) with information gained from other imaging modalities. Positron emission tomography (PET) provides valuable data related to patient physiology to aid in the delineation of tumor volumes. Combining the information provided by these imaging modalities requires accurate spatial registration of the two data sets. Fiducial based mapping provides straightforward registration based on corresponding landmark points or fiducials in the two image sets. When external fiducials are employed, consistent intermodality marker placement and centroid identification are essential to achieving an accurate and reliable registration. Similarity of marker design between modalities greatly aides in achieving this goal. Solid copper may serve as a fiducial marker in both CT and PET. Small spheres or wires of copper are readily visible in CT while neutron activation of these same markers produces positron emitting Copper-64 for detection by PET. The use of identical shaped markers in both imaging modalities greatly simplifies the task of intermodality centroid matching. Copper has excellent machining properties and, prior to activation, is easy and safe to handle. The feasibility of Cu as a marker for both CT and PET is demonstrated using imaging phantoms.