Clinical outcomes and molecular profile of differentiated thyroid cancers with radioiodine-avid distant metastases.

BACKGROUND: Radioiodine (RAI) remains the mainstay of therapy for RAI-avid (RAIA) distant metastatic thyroid carcinoma. We previously demonstrated that RAI-refractory distant metastatic thyroid cancers commonly harbor BRAF mutations. However, the molecular profile of RAIA metastatic thyroid cancer is unknown. Here we describe the mutational profile of thyroid tumors from follicular cell-derived cancer (FCDTC) patients presenting with RAIA distant metastases. In addition, we aimed to correlate clinical outcomes of RAI therapy with clinicopathological factors and tumor mutational status. METHODS: We retrospectively identified 43 patients with FCDTC who had RAI uptake in the lungs and/or bones on their initial ¹³¹I postablation scan. Primary tumors were genotyped for known mutations in thyroid cancer genes. Structural response to RAI was assessed 6-18 months after each administered RAI activity and at the end of follow-up. RESULTS: RAS, BRAF, RET/PTC, and PIK3CA mutations were found in 42, 23, 10, and 2% of tumors, respectively, and the remaining 23% were wild type. None of these patients achieved cure after repeat RAI therapies, and most patients (54%) experienced disease progression despite repeated RAI administration. There was an increased prevalence of RAS mutations in these RAIA tumors. RAS-mutant cancers were more likely to concentrate iodine on diagnostic whole body scans. Despite this, structural response to RAI was not influenced by tumor genotype. CONCLUSIONS: RAIA metastatic FCDTC are overrepresented with RAS mutations, whereas RAI refractory metastatic thyroid cancers are enriched with BRAF mutations. Despite a seemingly preserved ability to concentrate iodine, RAI therapy is ineffective in achieving cure in most patients with RAIA metastatic FCDTC, even in RAS-mutant disease. These poor outcomes may be improved based on recent evidence that pretreatment with MAPK kinase 1/2 inhibitors enhances responses to RAI, particularly in patients with RAS-mutant tumors.

Repeatability of SUV measurements in serial PET.

PURPOSE: The standardized uptake value (SUV) is a quantitative measure of FDG tumor uptake frequently used as a tool to monitor therapeutic response. This study aims to (i) assess the reproducibility and uncertainty of SUV max and SUV mean, due to purely statistical, i.e., nonbiological, effects and (ii) to establish the minimum uncertainty below which changes in SUV cannot be expected to be an indicator of physiological changes. METHODS: Three sets of measurements were made using a GE Discovery STE PET/CT Scanner in 3D mode: (1) A uniform 68Ge 20 cm diameter cylindrical phantom was imaged. Thirty serial frames were acquired for durations of 3, 6, 10, 15, and 30 min. (2) Esser flangeless phantom (Data Spectrum, approximately 6.1 L) with fillable thin-walled cylinders inserts (diameters: 8, 12, 16, and 25 mm; height: approximately 3.8 mm) was scanned for five consecutive 3 min runs. The cylinders were filled with 18FDG with a 37 kBq/cc concentration, and with a target-to-background ratio (T/BKG) of 3/1. (3) Eight cancer patients with healthy livers were scanned approximately 1.5 h post injection. Three sequential 3 min scans were performed for one bed position covering the liver, with the patient and bed remaining at the same position for the entire length of the scan. Volumes of interest were drawn on all images using the corresponding CT and then transferred to the PET images. For each study (1-3), the average percent change in SUV mean and SUV max were determined for each run pair. Moreover, the repeatability coefficient was calculated for both the SUV mean and SUV max for each pair of runs. Finally, the overall ROI repeatability coefficient was determined for each pair of runs. RESULTS: For the 68Ge phantom the average percent change in SUV max and SUV mean decrease as a function of increasing acquisition time from 4.7 +/- 3.1 to 1.1 +/- 0.6%, and from 0.14 +/- 0.09 to 0.04 +/- 0.03%, respectively. Similarly, the coefficients of repeatability also decrease between the 3 and 30 min acquisition scans, in the range of 10.9 +/- 3.9% - 2.6 +/- 0.9%, and 0.3 +/- 0.1% - 0.10 +/- 0.04%, for the SUV max and SUV mean, respectively. The overall ROI repeatability decreased from 18.9 +/- 0.2 to 6.0 +/- 0.1% between the 3 and 30 min acquisition scans. For the l8FDG phantom, the average percent change in SUV max and SUV mean decreases with target diameter from 3.6 +/- 2.0 to 1.5 +/- 0.8% and 1.5 +/- 1.3 to 0.26 +/- 0.15%, respectively, for targets from 8-25 mm in diameter and for a region in the background (BKG). The coefficients of repeatability for SUV max and SUV mean also decrease as a function of target diameter from 7.1 +/- 2.5 to 2.4 +/- 0.9 and 4.2 +/- 1.5 to 0.6 +/- 0.2, respectively, for targets from 8 mm to BKG in diameter. Finally, overall ROI repeatability decreased from 12.0 +/- 4.1 to 13.4 +/- 0.5 targets from 8 mm to BKG in diameter. Finally, for the measurements in healthy livers the average percent change in SUVmax and SUV mean were in the range of 0.5 +/- 0.2% - 6.2 +/- 3.9% and 0.4 +/- 0.1 and 1.6 +/- 1%, respectively. The coefficients of repeatability for SUV max and SUV men are in the range of 0.6 +/- 0.7% - 9.5 +/- 12% and 0.6 +/- 0.7% - 2.9 +/- 3.6%, respectively. The overall target repeatability varied between 27.9 +/- 0.5% and 41.1 +/- 1.0%. CONCLUSIONS: The statistical fluctuations of the SUV mean are half as large as those of the SUV max in the absence of biological or physiological effects. In addition, for clinically applicable scan durations (i.e., approximately 3 min) and FDG concentrations, the SUV max and SUV mean have similar amounts of statistical fluctuation for small regions. However, the statistical fluctuations of the SUVmean rapidly decrease with respect tothe SUVmax as the statistical power of the data grows either due to longer scanning times or as the target regions encompass a larger volume.

Five-year survival is similar in thyroid cancer patients with distant metastases prepared for radioactive iodine therapy with either thyroid hormone withdrawal or recombinant human TSH.

CONTEXT: Elevated levels of TSH markedly enhance the effectiveness of radioiodine (RAI) therapy in metastatic thyroid cancer. OBJECTIVE: The objective of the study was to compare short-term overall survival in thyroid cancer patients with RAI-avid distant metastases prepared for RAI therapy with either traditional thyroid hormone withdrawal (THW) or recombinant human TSH (rhTSH) stimulation. DESIGN: This was a retrospective chart review. SETTING: The study was conducted at a tertiary care comprehensive cancer center. PATIENTS: Patients included 175 patients with RAI avid metastatic disease to lung and/or bone. INTERVENTIONS: In 58 patients, all RAI treatments (remnant ablation and therapy of metastatic disease) were done with rhTSH stimulation. In 35 patients, all RAI treatments were done after THW. In 82 patients, THW was used for initial RAI treatment(s) with subsequent administered activities given after rhTSH stimulation. MAIN OUTCOME MEASURE: Overall survival was measured. RESULTS: After a median follow-up of 5.5 yr, there were no significant differences in overall survival between patients prepared for RAI therapy with rhTSH alone, THW alone, or THW followed by rhTSH (Kaplan-Meier analysis, P = 0.80). In a multivariate analysis that included clinicopathological features and method of preparation (rhTSH or TWH), only age at diagnosis was an independent predictor of overall survival. CONCLUSIONS: Preparation for RAI therapy using either THW or rhTSH stimulation was associated with similar 5-yr overall survival rates in patients with RAI avid thyroid cancer metastases to lung or bone.

A novel respiratory tracking system for smart-gated PET acquisition.

PURPOSE: In this study, the authors validated a novel respiratory tracking device, the multidimensional respiratory tracking (MDRT) system, that was designed to assist in correcting for respiratory motion in PET/CT images. The authors also investigated a novel PET acquisition technique, smart gating (SG), that enables to acquire motion-free PET data prospectively, with minimum user interference and with no additional postprocessing of the PET data. METHODS: MDRT uses visual tracking techniques to track simultaneously the two-dimensional (in the vertical plane) motion of multiple fiducial markers using a standard video camera. A threshold window is set at the breathing amplitude of interest using the MDRT GUI. A trigger is generated at a rate of 250 Hz as long as the breathing signal is within the threshold window. The triggers are fed into the PET scanner to initialize one single bin of a gated acquisition every 4 ms. No triggers are delivered as the breathing signal drifts outside the threshold window. Consequently, PET data are acquired only whenever the breathing signal is confined within the amplitude threshold window, thus resulting into a motion-free image set. The accuracy of MDRT in tracking the breathing signal was assessed (1) by comparing the period of an oscillating phantom, as measured by MDRT, to that measured with a photogate timer and (2) by comparing the MDRT output to that of the real-time position management (RPM) in ten patients. The SG PET/CT acquisition was validated in phantoms and in two stereotactic body radiosurgery (SBRS) lung DIBH-PET/CT patients. RESULTS: MDRT was in agreement with the photogate timer in determining the period of motion to less than 2%. The percent errors between MDRT and RPM in the positions of the peaks and troughs of the ten patients' breathing signals were within 10%. In phantoms, SG technique enables to correct for motion-induced artifacts in the PET images and improve the accuracy of PET quantitation. For the SBRS application, in one patient, the patient's CT lesion was not detected in the corresponding clinical PET images, while it exhibited an SUV of 1.8 in the DIBH image set. In the second patient, DIBH-PET images showed an improved PET-to-CT spatial matching and a 52% increase in the lesion SUV. CONCLUSIONS: MDRT has been shown to be accurate in tracking breathing motion and assisted in implementing a smart-gating PET acquisition technique that allowed to acquire prospectively motion-free PET images.

Renal uptake of bismuth-213 and its contribution to kidney radiation dose following administration of actinium-225-labeled antibody.

Clinical therapeutic studies using (225)Ac-labeled antibodies have begun. Of major concern is renal toxicity that may result from the three alpha-emitting progeny generated following the decay of (225)Ac. The purpose of this study was to determine the amount of (225)Ac and non-equilibrium progeny in the mouse kidney after the injection of (225)Ac-huM195 antibody and examine the dosimetric consequences. Groups of mice were sacrificed at 24, 96 and 144 h after injection with (225)Ac-huM195 antibody and kidneys excised. One kidney was used for gamma ray spectroscopic measurements by a high-purity germanium (HPGe) detector. The second kidney was used to generate frozen tissue sections which were examined by digital autoradiography (DAR). Two measurements were performed on each kidney specimen: (1) immediately post-resection and (2) after sufficient time for any non-equilibrium excess (213)Bi to decay completely. Comparison of these measurements enabled estimation of the amount of excess (213)Bi reaching the kidney (γ-ray spectroscopy) and its sub-regional distribution (DAR). The average absorbed dose to whole kidney, determined by spectroscopy, was 0.77 (SD 0.21) Gy kBq(-1), of which 0.46 (SD 0.16) Gy kBq(-1) (i.e. 60%) was due to non-equilibrium excess (213)Bi. The relative contributions to renal cortex and medulla were determined by DAR. The estimated dose to the cortex from non-equilibrium excess (213)Bi (0.31 (SD 0.11) Gy kBq(-1)) represented ∼46% of the total. For the medulla the dose contribution from excess (213)Bi (0.81 (SD 0.28) Gy kBq(-1)) was ∼80% of the total. Based on these estimates, for human patients we project a kidney-absorbed dose of 0.28 Gy MBq(-1) following administration of (225)Ac-huM195 with non-equilibrium excess (213)Bi responsible for approximately 60% of the total. Methods to reduce renal accumulation of radioactive progeny appear to be necessary for the success of (225)Ac radioimmunotherapy.

An iterative technique to segment PET lesions using a Monte Carlo based mathematical model.

PURPOSE: The need for an accurate lesion segmentation tool in 18FDG PET is a prerequisite for the estimation of lesion response to therapy, for radionuclide dosimetry, and for the application of 18FDG PET to radiotherapy planning. In this work, the authors have developed an iterative method based on a mathematical fit deduced from Monte Carlo simulations to estimate tumor segmentation thresholds. METHODS: The GATE software, a GEANT4 based Monte Carlo tool, was used to model the GE Advance PET scanner geometry. Spheres ranging between 1 and 6 cm in diameters were simulated in a 10 cm high and 11 cm in diameter cylinder. The spheres were filled with water-equivalent density and simulated in both water and lung equivalent background. The simulations were performed with an infinite, 8/1, and 4/1 target-to-background ratio (T/B). A mathematical fit describing the correlation between the lesion volume and the corresponding optimum threshold value was then deduced through analysis of the reconstructed images. An iterative method, based on this mathematical fit, was developed to determine the optimum threshold value. The effects of the lesion volume and T/B on the threshold value were investigated. This method was evaluated experimentally using the NEMA NU2-2001 IEC phantom, the ACNP cardiac phantom, a randomly deformed aluminum can, and a spheroidal shape phantom implemented artificially in the lung, liver, and brain of patient PET images. Clinically, the algorithm was evaluated in six lesions from five patients. Clinical results were compared to CT volumes. RESULTS: This mathematical fit predicts an existing relationship between the PET lesion size and the percent of maximum activity concentration within the target volume (or threshold). It also showed a dependence of the threshold value on the T/B, which could be eliminated by background subtraction. In the phantom studies, the volumes of the segmented PET targets in the PET images were within 10% of the nominal ones. Clinically, the PET target volumes were also within 10% of those measured from CT images. CONCLUSIONS: This iterative algorithm enabled accurately segment PET lesions, independently of their contrast value.

New PET tracers for evaluation of solid tumor response to therapy.

We take advantage of the special characteristics of human tumors to image tumor response including predicting susceptibility to specific cancer therapies. The metabolic phenotype of malignancy, includes increased glycolysis (2-[(18)F]fluoro-2-D-deoxyglucose [FDG]), increased proliferation (2-[(18)F]fluoro-L-thymidine [FLT]), increased amino acid transport, as well as other functions such as fatty acid synthesis which have yet to be fully exploited. The endocrine dependent malignancies offer rich opportunities for selective imaging, including radioligands that have high affinity for hormone receptors, like androgen receptor (AR) (16Beta-[(18)F]16beta-[(18)F]fluoro-5alpha-dihydrotestoste-rone [FDHT]) and estrogen receptor (ER) ([(18)F]fluoroestradiol [FES]) and tissue specific transporters such as sodium iodide symporter (NIS) ((124)I). As knowledge of cancer biology has grown, it has become possible to develop tracers which image the client proteins involved in response to specific drugs, e.g. Gallium-68-Fab'2 herceptin for HER 2 effected by HSP 90 inhibitor drugs. More and more radiolabeled drugs will be used to explore the pharmacology of anticancer therapies, such as [(18)F]Desatinib. These may or may not be excellent imaging agents, but as analogs or even true tracers for specific anti-cancer drugs, noninvasive imaging through positron emission tomography will provide highly useful information, relating cancer pharmacology within the local tumor, to treatment response.

Phase and amplitude binning for 4D-CT imaging.

We compare the consistency and accuracy of two image binning approaches used in 4D-CT imaging. One approach, phase binning (PB), assigns each breathing cycle 2pi rad, within which the images are grouped. In amplitude binning (AB), the images are assigned bins according to the breathing signal's full amplitude. To quantitate both approaches we used a NEMA NU2-2001 IEC phantom oscillating in the axial direction and at random frequencies and amplitudes, approximately simulating a patient's breathing. 4D-CT images were obtained using a four-slice GE Lightspeed CT scanner operating in cine mode. We define consistency error as a measure of ability to correctly bin over repeated cycles in the same field of view. Average consistency error mue+/-sigmae in PB ranged from 18%+/-20% to 30%+/-35%, while in AB the error ranged from 11%+/-14% to 20%+/-24%. In PB nearly all bins contained sphere slices. AB was more accurate, revealing empty bins where no sphere slices existed. As a proof of principle, we present examples of two non-small cell lung carcinoma patients' 4D-CT lung images binned by both approaches. While AB can lead to gaps in the coronal images, depending on the patient's breathing pattern, PB exhibits no gaps but suffers visible artifacts due to misbinning, yielding images that cover a relatively large amplitude range. AB was more consistent, though often resulted in gaps when no data existed due to patients' breathing pattern. We conclude AB is more accurate than PB. This has important consequences to treatment planning and diagnosis.

Molecular imaging of EGFR kinase activity in tumors with 124I-labeled small molecular tracer and positron emission tomography.

Positron emission tomography (PET) with epidermal growth factor receptor (EGFR) kinase-specific radiolabeled tracers could provide the means for noninvasive and repetitive imaging of heterogeneity of EGFR expression and signaling activity in tumors in individual patients before and during therapy with EGFR signaling inhibitors. We developed the synthesis and (124)I-radiolabeling of the (E)-But-2-enedioic acid [4-(3-[(124)I]iodoanilino)-quinazolin-6-yl]-amide-(3-morpholin-4-yl-propyl)-amide (morpholino-[(124)I]-IPQA), which selectively, irreversibly, and covalently binds the adenosine-triphosphate-binding site to the activated (phosphorylated) EGFR kinase, but not to the inactive EGFR kinase. The latter was demonstrated using in silico modeling with crystal structures of the wild type and different gain-of-function mutants of EGFR kinases. Also, this was demonstrated by selective radiolabeling of the EGFR kinase domain with morpholino-[(131)I]-IPQA in A431 human epidermoid carcinoma cells and Western blot autoradiography. In vitro radiotracer accumulation and washout studies demonstrated a rapid accumulation and progressive retention postwashout of morpholino-[(131)I]-IPQA in A431 epidermoid carcinoma and in U87 human glioma cells genetically modified to express the EGFRvIII mutant receptor, but not in the wild-type U87MG glioma cells under serum-starved conditions. Using morpholino-[(124)I]-IPQA, we obtained noninvasive PET images of EGFR activity in A431 subcutaneous tumor xenografts, but not in subcutaneous tumor xenografts grown from K562 human chronic myeloid leukemia cells in immunocompromised rats and mice. Based on these observations, we suggest that PET imaging with morpholino-[(124)I]-IPQA should allow for identification of tumors with high EGFR kinase signaling activity, including brain tumors expressing EGFRvIII mutants and nonsmall-cell lung cancer expressing gain-of-function EGFR kinase mutants. Because of significant hepatobiliary clearance and intestinal reuptake of the morpholino-[(124)I]-IPQA, additional [(124)I]-IPQA derivatives with improved water solubility may be required to optimize the pharmacokinetics of this class of molecular imaging agents.

Quantitation of respiratory motion during 4D-PET/CT acquisition.

We report on the variability of the respiratory motion during 4D-PET/CT acquisition. The respiratory motion for five lung cancer patients was monitored by tracking external markers placed on the abdomen. CT data were acquired over an entire respiratory cycle at each couch position. The x-ray tube status was recorded by the tracking system, for retrospective sorting of the CT data as a function of respiration phase. Each respiratory cycle was sampled in ten equal bins. 4D-PET data were acquired in gated mode, where each breathing cycle was divided into ten 500 ms bins. For both CT and PET acquisition, patients received audio prompting to regularize breathing. The 4D-CT and 4D-PET data were then correlated according to their respiratory phases. The respiratory periods, and average amplitude within each phase bin, acquired in both modality sessions were then analyzed. The average respiratory motion period during 4D-CT was within 18% from that in the 4D-PET sessions. This would reflect up to 1.8% fluctuation in the duration of each 4D-CT bin. This small uncertainty enabled good correlation between CT and PET data, on a phase-to-phase basis. Comparison of the average-amplitude within the respiration trace, between 4D-CT and 4D- PET, on a bin-by-bin basis show a maximum deviation of approximately 15%. This study has proved the feasibility of performing 4D-PET/CT acquisition. Respiratory motion was in most cases consistent between PET and CT sessions, thereby improving both the attenuation correction of PET images, and co-registration of PET and CT images. On the other hand, in two patients, there was an increased partial irregularity in their breathing motion, which would prevent accurately correlating the corresponding PET and CT images.

Four-dimensional (4D) PET/CT imaging of the thorax.

We have reported in our previous studies on the methodology, and feasibility of 4D-PET (Gated PET) acquisition, to reduce respiratory motion artifact in PET imaging of the thorax. In this study, we expand our investigation to address the problem of respiration motion in PET/CT imaging. The respiratory motion of four lung cancer patients were monitored by tracking external markers placed on the thorax. A 4D-CT acquisition was performed using a "step-and-shoot" technique, in which computed tomography (CT) projection data were acquired over a complete respiratory cycle at each couch position. The period of each CT acquisition segment was time stamped with an "x-ray ON" signal, which was recorded by the tracking system. 4D-CT data were then sorted into 10 groups, according to their corresponding phase of the breathing cycle. 4D-PET data were acquired in the gated mode, where each breathing cycle was divided into ten 0.5 s bins. For both CT and PET acquisitions, patients received audio prompting to regularize breathing. The 4D-CT and 4D-PET data were then correlated according to respiratory phase. The effect of 4D acquisition on improving the co-registration of PET and CT images, reducing motion smearing, and consequently increase the quantitation of the SUV, were investigated. Also, quantitation of the tumor motions in PET, and CT, were studied and compared. 4D-PET with matching phase 4D-CTAC showed an improved accuracy in PET-CT image co-registration of up to 41%, compared to measurements from 4D-PET with clinical-CTAC. Gating PET data in correlation with respiratory motion reduced motion-induced smearing, thereby decreasing the observed tumor volume, by as much as 43%. 4D-PET lesions volumes showed a maximum deviation of 19% between clinical CT and phase- matched 4D-CT attenuation corrected PET images. In CT, 4D acquisition resulted in increasing the tumor volume in two patients by up to 79%, and decreasing it in the other two by up to 35%. Consequently, these corrections have yielded an increase in the measured SUV by up to 16% over the clinical measured SUV, and 36% over SUV's measured in 4D-PET with clinical-CT Attenuation Correction (CTAC) SUV's. Quantitation of the maximum tumor motion amplitude, using 4D-PET and 4D-CT, showed up to 30% discrepancy between the two modalities. We have shown that 4D PET/CT is clinically a feasible method, to correct for respiratory motion artifacts in PET/CT imaging of the thorax. 4D PET/CT acquisition can reduce smearing, improve the accuracy in PET-CT co-registration, and increase the measured SUV. This should result in an improved tumor assessment for patients with lung malignancies.

Cytoreduction with iodine-131-anti-CD33 antibodies before bone marrow transplantation for advanced myeloid leukemias.

The monoclonal antibodies M195 and HuM195 target CD33, a glycoprotein found on myeloid leukemia cells. When labeled with iodine-131 ((131)I), these antibodies can eliminate large disease burdens and produce prolonged myelosuppression. We studied whether (131)I-labeled M195 and HuM195 could be combined safely with busulfan and cyclophosphamide (BuCy) as conditioning for allogeneic BMT. A total of 31 patients with relapsed/refractory acute myeloloid leukemia (AML) (n=16), accelerated/myeloblastic chronic myeloid leukemia (CML) (n=14), or advanced myelodysplastic syndrome (n=1) received (131)I-M195 or (131)I-HuM195 (122-437 mCi) plus busulfan (16 mg/kg) and cyclophosphamide (90-120 mg/kg) followed by infusion of related-donor bone marrow (27 first BMT; four second BMT). Hyperbilirubinemia was the most common extramedullary toxicity, occurring in 69% of patients during the first 28 days after BMT. Gamma camera imaging showed targeting of the radioisotope to the bone marrow, liver, and spleen, with absorbed radiation doses to the marrow of 272-1470 cGy. The median survival was 4.9 months (range 0.3-90+ months). Three patients with relapsed AML remain in complete remission 59+, 87+, and 90+ months following bone marrow transplantation (BMT). These studies show the feasibility of adding CD33-targeted radioimmunotherapy to a standard BMT preparative regimen; however, randomized trials will be needed to prove a benefit to intensified conditioning with radioimmunotherapy.

Diagnostic and prognostic value of [(18)F]fluorodeoxyglucose positron emission tomography for recurrent head and neck squamous cell carcinoma.

PURPOSE: Patients with recurrent head and neck squamous cell carcinoma (HNSCC) present a diagnostic and therapeutic challenge. We evaluated the diagnostic accuracy and prognostic value of [(18)F]fluorodeoxyglucose positron emission tomography (PET) in this patient population. PATIENTS AND METHODS: We performed a retrospective review of 143 patients with previously treated HNSCC who underwent 181 PET scans at our institution from May 1996 through April 2001 to detect recurrent disease. Disease recurrence within 6 months was used as the gold standard for assessing true disease status at PET. RESULTS: With equivocal sites considered positive, the sensitivity and specificity of PET for detecting recurrence overall were 96% and 72%, respectively. PET was highly sensitive and specific at regional and distant sites. At local sites, sensitivity was high, but specificity was lower because of false-positive findings. One fifth of all false-positive PET scans occurred at sites of known inflammation or infection. The area under the curve for a receiver operator characteristic curve on the basis of standardized uptake value (SUV) was 0.882 +/- 0.025. PET interpretation, SUV, and physical examination were independent predictors of relapse-free and overall survival in a time-dependent, multivariate proportional hazards model. An increase in SUV by one unit increased the relative risk (RR) of relapse by 11% and the RR of death by 14%. A positive PET interpretation increased the RR of relapse by four-fold and the RR of death by seven-fold. CONCLUSION: PET was a highly sensitive method of detecting recurrent HNSCC and provided important prognostic information for relapse-free and overall survival.

Qualitative and quantitative comparison between images obtained with filtered back projection and iterative reconstruction in prostate cancer lesions of (18)F-FDG PET.

BACKGROUND: Recently, iterative reconstruction with segmented attenuation corrections (IRSAC) has been introduced for reconstruction of (18)F-FDG PET images. IRSAC produces images that are more pleasing to the eye, but qualitative and quantitative comparisons between IRSAC and filtered back projection (FBP) have not been reported for metastatic cancer. Since quantitative data has been widely used as an adjunct to interpretation of PET scans, comparison between IRSAC and FBP is needed. The purpose of this study was to compare image quality and the maximum standardized uptake value (SUVmax) obtained with FBP and with IRSAC in metastatic lesions from prostate cancer. METHODS: Twenty (18)F-FDG PET scans (10 baseline and 10 follow-up) were performed in 10 patients with prostate cancer (ages 66-85 yrs, mean 73.6 yrs). Acquisition began 45 min after injection of 370 MBq of (18)F-FDG. Images were reconstructed using FBP and IRSAC, and submitted to visual and quantitative analysis. SUVmax was obtained for all metastases, on FBP and IRSAC. A Jaszczak phantom study was also performed. RESULTS: IRSAC images showed better image quality than FBP especially in regions of high activity concentrations. IRSAC detected 106 lesions on both baseline and follow-up scans, while FBP detected 100 and 95 lesions on baseline and follow-up scans, respectively. Therefore, 17 more lesions were seen on IRSAC. The mean SUVmax values on baseline scans for FBP and IRSAC were systematically different, at 4.46+/-1.99 and 5.13+/-2.67, respectively. On follow-up scans values were 3.89+/-1.72 for FBP and 4.29+/-1.93 for IRSAC. Comparison of FBP with IRSAC on baseline and follow-up scans were statistically significant (baseline: paired "t"-test p=0.0017; follow-up: paired "t"-test p=0.0008). Phantom studies reveal that these differences can be explained by the type of reconstruction filters used, and IRSAC was more accurate than FBP. CONCLUSIONS: IRSAC detects smaller volumes in phantoms, patient images are easier to interpret and more metastatic lesions were detected. In addition, IRSAC provides reproducible quantitative data, comparable to data provided by FBP. IRSAC SUV and FBP SUV are in close agreement but there was a statistically significant difference between the two, and therefore threshold values of SUV will probably need to be re-determined with IRSAC, and are likely to be 10 to 19% higher than currently reported.

Effect of respiratory gating on reducing lung motion artifacts in PET imaging of lung cancer.

Positron emission tomography (PET) has shown an increase in both sensitivity and specificity over computed tomography (CT) in lung cancer. However, motion artifacts in the 18F fluorodioxydoglucose (FDG) PET images caused by respiration persists to be an important factor in degrading PET image quality and quantification. Motion artifacts lead to two major effects: First, it affects the accuracy of quantitation, producing a reduction of the measured standard uptake value (SUV). Second, the apparent lesion volume is overestimated. Both impact upon the usage of PET images for radiation treatment planning. The first affects the visibility, or contrast, of the lesion. The second results in an increase in the planning target volume, and consequently a greater radiation dose to the normal tissues. One way to compensate for this effect is by applying a multiple-frame capture technique. The PET data are then acquired in synchronization with the respiratory motion. Reduction in smearing due to gating was investigated in both phantoms and patient studies. Phantom studies showed a dependence of the reduction in smearing on the lesion size, the motion amplitude, and the number of bins used for data acquisition. These studies also showed an improvement in the target-to-background ratio, and a more accurate measurement of the SUV. When applied to one patient, respiratory gating showed a 28% reduction in the total lesion volume, and a 56.5% increase in the SUV. This study was conducted as a proof of principle that a gating technique can effectively reduce motion artifacts in PET image acquisition.

Standardized uptake value in pediatric patients: an investigation to determine the optimum measurement parameter.

Although the standardized uptake value (SUV) is currently used in fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging, concerns have been raised over its accuracy and clinical relevance. Dependence of the SUV on body weight has been observed in adults and this should be of concern in the pediatric population, since there are significant body changes during childhood. The aim of the present study was to compare SUV measurements based on body weight, body surface area and lean body mass in the pediatric population and to determine a more reliable parameter across all ages. Sixty-eight pediatric FDG-PET studies were evaluated. Age ranged from 2 to 17 years and weight from 11 to 77 kg. Regions of interest were drawn at the liver for physiologic comparison and at FDG-avid malignant lesions. SUV based on body weight (SUV(bw)) varied across different weights, a phenomenon less evident when body surface area (SUV(bsa)) normalization is applied. Lean body mass-based SUV (SUV(lbm)) also showed a positive correlation with weight, which again was less evident when normalized to bsa (SUV(bsa-lbm)). The measured liver SUV(bw) was 1.1+/-0.3, a much lower value than in our adult population (1.9+/-0.3). The liver SUV(bsa) was 7.3+/-1.3. The tumor sites had an SUV(bw) of 4.0+/-2.7 and an SUV(bsa) of 25.9+/-15.4 (65% of the patients had neuroblastoma). The bsa-based SUVs were more constant across the pediatric ages and were less dependent on body weight than the SUV(bw). These results indicate that SUV calculated on the basis of body surface area is a more uniform parameter than SUV based on body weight in pediatric patients and is probably the most appropriate approach for the follow-up of these patients.

Statistical issues in analysis of diagnostic imaging experiments with multiple observations per patient.

Many diagnostic imaging experiments are characterized by the presence of several observations for each patient studied. Evaluation of metastases with different imaging modalities in patients with cancer or examination of multiple artery segments in patients with heart abnormalities are some examples of such studies. Data obtained from multiple observations per patient are cluster correlated and should not be analyzed by using standard statistical methods because of correlations within a subject. In this article, positron emission tomographic studies are used as a framework to review statistical methods for the analysis of clustered data. Some simple statistical methods that account for correlation within a subject and that can be applied to conventional and well-known statistical methods, such as the chi(2) and t tests, are introduced. One of these methods is illustrated by using a brief analysis of data from a positron emission tomographic study, which demonstrates how resulting conclusions may be incorrect if appropriate techniques are not applied. Alternative methods that can handle multiple observations and dependency within a subject for diagnostic imaging studies are discussed.