8. A Spherical Coordinate System for Tumor Identification in Positron Emission Tomography (PET) Imaging

Purpose: PET can be useful in determining the progression of malignant disease over time as well as the response to therapy. To achieve this, the physician must be able to unambiguously identify and characterize individual tumors among several different scans.Methods: We have developed a spherical coordinate system for identifying individual tumor sites on PET scans, using the carina on the transmission scan as a point of origin. Using this system, each tumor is given a set of spherical coordinates that identifies its position: a rho (rho, displacement from carina), a theta (θ, angle between the A-P axis and the tumor), and a phi (φ, angle between the cranial-caudal axis and the tumor).Results: We tested this method on a patient with metastatic thyroid cancer, who underwent 18FDG and 124I-Iodide PET scans in the same week. The patient had a total of 90 tumors, 82 of them identified in the 18FDG scan and 35 in the 124I-Iodide scan, with 27 tumors identified in both. For rho, θ, and φ among the 27 matching pairs of tumors, the mean differences were 6.80 + 5 mm, 6.22 + 4.54 degrees, and 5.51 + 5.81 degrees, respectively. After thorough analysis, we have determined that corresponding tumors with rho < 15 mm, θ and φ < 15 degrees difference usually indicate a match. The disparity in coordinate values between corresponding tumors can be explained by the distinctive uptake patterns of the radiopharmaceuticals.Conclusion: Within a mean difference of 6.8 mm and 6 degrees, this spherical coordinate system facilitates the identification and characterization of individual tumors among multiple scans, thus aiding in both the assessment of diagnostic capabilities of different tracers, and the tracking of tumors following therapy.     

Tumor Burden Assessment with Positron Emission Tomography with

Objective: In patients with advanced cancer, total tumor burden affects the likelihood of tumor response and has important implications for prognosis. The aim of this study was to select the optimum 2-[F-18]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG PET) tumor uptake parameter to accurately measure tumor burden in advanced metastatic renal cell cancer, in comparison with volumes measured with computed tomography (CT), as a reference test.Materials and Methods: Six patients with metastatic renal cell carcinoma measurable on CT were studied. CT and FDG PET scans were carried out on all patients within 4 weeks prior to their entry into a phase I-II radioimmunotherapy trial. CT-based evaluation of disease extent (tumor volume) and 4 PET-based measurements (standardized uptake value[SUVmax], SUVav, volume, and total lesion glycolysis [TLG]) were performed independently by a radiologist (VN) and a nuclear medicine physician (TA). The degree of correlation between conventional (CT) extent of disease and parameters describing tumor concentration of FDG was then determined.Results: Fifty-seven CT-measurable metastatic lesions in lung, abdomen, and scalp were evaluated in 6 patients. There was a high correlation between CT and FDG PET volume estimates for lesions greater than 5 cm(3) in size. However, a PET-derived parameter that embodies both FDG uptake and lesion size, the TLG, correlated better with CT-derived tumor volume than did FDG PET volume alone.Conclusion: Using CT volume as a gold standard, the optimal PET-based estimate of total tumor burden in patients with metastatic renal cancer is the sum over all lesions of the total lesion glycolysis.     

A stereotactic method for the three-dimensional registration of multi-modality biologic images in animals: NMR, PET, histology, and autoradiography

The objective of this work was to develop and then validate a stereotactic fiduciary marker system for tumor xenografts in rodents which could be used to co-register magnetic resonance imaging (MRI), PET, tissue histology, autoradiography, and measurements from physiologic probes. A Teflon fiduciary template has been designed which allows the precise insertion of small hollow Teflon rods (0.71 mm diameter) into a tumor. These rods can be visualized by MRI and PET as well as by histology and autoradiography on tissue sections. The methodology has been applied and tested on a rigid phantom, on tissue phantom material, and finally on tumor bearing mice. Image registration has been performed between the MRI and PET images for the rigid Teflon phantom and among MRI, digitized microscopy images of tissue histology, and autoradiograms for both tissue phantom and tumor-bearing mice. A registration accuracy, expressed as the average Euclidean distance between the centers of three fiduciary markers among the registered image sets, of 0.2 +/- 0.06 mm was achieved between MRI and microPET image sets of a rigid Teflon phantom. The fiduciary template allows digitized tissue sections to be co-registered with three-dimensional MRI images with an average accuracy of 0.21 and 0.25 mm for the tissue phantoms and tumor xenografts, respectively. Between histology and autoradiograms, it was 0.19 and 0.21 mm for tissue phantoms and tumor xenografts, respectively. The fiduciary marker system provides a coordinate system with which to correlate information from multiple image types, on a voxel-by-voxel basis, with sub-millimeter accuracy--even among imaging modalities with widely disparate spatial resolution and in the absence of identifiable anatomic landmarks.     

Reproducibility of intratumor distribution of (18)F-fluoromisonidazole in head and neck cancer

PURPOSE: Hypoxia is one of the main causes of the failure to achieve local control using radiotherapy. This is due to the increased radioresistance of hypoxic cells. (18)F-fluoromisonidazole ((18)F-FMISO) positron emission tomography (PET) is a noninvasive imaging technique that can assist in the identification of intratumor regions of hypoxia. The aim of this study was to evaluate the reproducibility of (18)F-FMISO intratumor distribution using two pretreatment PET scans. METHODS AND MATERIALS: We enrolled 20 head and neck cancer patients in this study. Of these, 6 were excluded from the analysis for technical reasons. All patients underwent an (18)F-fluorodeoxyglucose study, followed by two (18)F-FMISO studies 3 days apart. The hypoxic volumes were delineated according to a tumor/blood ratio >or=1.2. The (18)F-FMISO tracer distributions from the two (18)F-FMISO studies were co-registered on a voxel-by-voxel basis using the computed tomography images from the PET/computed tomography examinations. A correlation between the (18)F-FMISO intensities of the corresponding spatial voxels was derived. RESULTS: A voxel-by-voxel analysis of the (18)F-FMISO distributions in the entire tumor volume showed a strong correlation in 71% of the patients. Restraining the correlation to putatively hypoxic zones reduced the number of patients exhibiting a strong correlation to 46%. CONCLUSION: Variability in spatial uptake can occur between repeat (18)F-FMISO PET scans in patients with head and neck cancer. Blood data for one patient was not available. Of 13 patients, 6 had well-correlated intratumor distributions of (18)F-FMISO-suggestive of chronic hypoxia. More work is required to identify the underlying causes of changes in intratumor distribution before single-time-point (18)F-FMISO PET images can be used as the basis of hypoxia-targeting intensity-modulated radiotherapy.     

Radiation Dose Assessment for I-131 Therapy of Thyroid Cancer Using I-124 PET Imaging

The goal for this work was to develop a method to determine the feasibility of estimating absorbed dose distribution of I-131 thyroid therapy using I-124 PET images of residual thyroid lesions with the dose constraint of 200 cGy to blood, that is a surrogate for bone marrow toxicity. A dose response study has been carried out on 3 patients with papillary thyroid carcinoma. Those patients were given 15-37 MBq of I-124 along with 74-185 MBq of I-131. PET imaging was performed 2-4 hour and then at 24 hour and either 48 hour, or 72 hour post-infusion. Lesion masses were computed from PET images using an adaptive thresholding technique. The definition of the boundary enabled determination of the iodine activity within the lesion. Time-activity curves were fitted to estimate the cumulated activity and therefore the absorbed dose per MBq administered. Daily blood and total body counts were performed on the patients using a multichannel analyzer with windows set for both I-131 (364 keV) and I-124 (511 keV). Cross-talk corrections from one isotope into the alternate window was determined using a standard of each respective isotope. At maximum-tolerated-activity (MTA) that delivers 200 cGy radiation dose to the blood, the dose to lesions from I-131 varied from 0.04 to 2.44 cGy/MBq (1.57-90.48 rads/mCi) with effective half-lives for I-124 ranging from 0.58 to 1.86 days. The three-dimensional absorbed dose distribution in the thyroid lesions was calculated by convolving the activity values with an I-131 point-source kernel using a Fast Hartley Transform. The calculated mean absorbed dose distribution was displayed as isodose lines on PET images that can be used to refine the amount of administered activity. PET with I-124 may improve the absorbed dose estimates from radioiodine therapy with I-131 in the treatment of thyroid cancer. The capability of estimating I-131 mean absorbed dose distributions from serial I-124 PET images can lead to patient-specific treatment planning for thyroid therapy.     

Tumor Treatment Response Based on Visual and Quantitative Changes in Global Tumor Glycolysis Using PET-FDG Imaging. The Visual Response Score and the Change in Total Lesion Glycolysis

"Functional" tumor treatment response parameters have been developed to measure treatment induced biochemical changes in the entire tumor mass, using positron emission tomography (PET) and [F-18] fludeoxyglucose (FDG). These new parameters are intended to measure global changes in tumor glycolysis. The response parameters are determined by comparing the pre- and posttreatment PET-FDG images either visually from the change in image appearance in the region of the tumor, or quantitatively based on features of the calibrated digital PET image. The visually assessed parameters are expressed as a visual response score (VRS), or visual response index (VRI), as the estimated percent response of the tumor. Visual Response Score (VRS) is recorded on a 5 point response scale (0-4): 0: no response or progression; 1: 1-33%; 2: >33%-66%; 3: >66%-99%; and 4: >99%, estimated response, respectively. The quantitative changes are expressed as total lesion glycolysis TLG or as the change in TLG during treatment, also called deltaTLG or Larson-Ginsberg Index (LGI), expressed as percent response. The volume of the lesion is determined from the PET-FDG images by an adaptive thresholding technique. This response index is computed as, deltaTLG (LGI) = {[(SUV(ave))(1) * (Vol)(1) - (SUV(ave))(2) * (Vol)(2)]/[(SUV(ave))(1) * (Vol)(1)]} * 100. Where "1" and "2" denote the pre- and posttreatment PET-FDG, scans respectively. Pre- and posttreatment PET-FDG scans were performed on a group of 41 locally advanced lung (2), rectal (17), esophageal (16) and gastric (6) cancers. These patients were treated before surgery with neoadjuvant chemo-radiation. Four experienced PET readers determined individual VRS and VRI blinded to each other as well as to the clinical history. Consensus VRS was obtained based on a discussion. The interobserver variability captured by intraclass correlation coefficient was 89.7%. In addition, reader reliability was assessed for the categorized VRS using Kendall's coefficient of concordance for ordinal data and was found to be equal to 85% This provided assurance that these response parameters were highly reproducible. The correlation of deltaTLG with % change in SUV(ave) and % change in SUV(max), as widely used parameters of response, were 0.73 and 0.78 (P <.0001) respectively. The corresponding correlation of VRI were 0.63 and 0.64 (P <.0001) respectively. Both deltaTLG and VRI showed greater mean changes than SUV maximum or average (59.7% and 76% vs. 46.9% and 46.8%). We conclude that VRS and deltaTLG are substantially correlated with other response parameters and are highly reproducible. As global measures of metabolic response, VRS, VRI and deltaTLG (LGI) should provide complementary information to more commonly used PET response parameters like the metabolic rate of FDG (MRFDG), or the standardized uptake value (SUV), that are calculated as normalized per gram of tumor. These findings set the stage for validation studies of the VRS and deltaTLG as objective measures of clinical treatment response, through comparison to the appropriate gold standards of posttreatment histopathology, recurrence free survival, and disease specific survival in well characterized populations of patients with locally advanced cancers.     

Theta oscillation-coupled dendritic spiking integrates inputs on a long time scale

Persistent neural activity lasting for seconds after transient stimulation has been observed in several brain areas. This activity has been taken to be indicative of the integration of inputs on long time scales. Passive membrane properties render neural time constants to be on the order of milliseconds. Intense synaptic bombardment, characteristic of in vivo states, was previously shown to further reduce the time scale of effective integration. We explored how long-term integration in single cells could be supported by dendritic spikes coupled with the theta oscillation, a prominent brain rhythm often observed during working memory tasks. We used a two-compartmental conductance-based model of a hippocampal pyramidal cell to study the interplay of intrinsic dynamics with periodic inputs in the theta frequency band. We show that periodic dendritic spiking integrates inputs by shifting the phase relative to an external oscillation, since spiking frequency is quasi-linearly modulated by current injection. The time-constant of this integration process is practically infinite for input intensities above a threshold (the integration threshold) and can be still several hundred milliseconds long below the integration threshold. The somatic compartment received theta frequency stimulation in antiphase with the dendritic oscillation. Consequently, dendritic spikes could only elicit somatic action potentials when they were sufficiently phase-shifted and thus coincided with somatic depolarization. Somatic depolarization modulated the frequency but not the phase of firing, endowing the cell with the capability to code for two different variables at the same time. Inputs to the dendrite shifted the phase of dendritic spiking, while somatic input was modulating its firing rate. This mechanism resulted in firing patterns that closely matched experimental data from hippocampal place cells of freely behaving rats. We discuss the plausibility of our proposed mechanism and its potential to account for the firing pattern of cells outside the hippocampus during working memory tasks.