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Annals of surgical oncology  2014;21(13):4174-4180.
Persistent or recurrent hyperthyroidism after treatment with radioactive iodine (RAI) is common, and many patients require either additional doses or surgery before they are cured. The purpose of this study was to identify patterns and predictors of failure of RAI in patients with hyperthyroidism.
We conducted a retrospective review of patients treated with RAI from 2007–2010. Failure of RAI was defined as receipt of additional dose(s) and/or total thyroidectomy. Using a Cox proportional hazards model, we conducted univariate analysis to identify factors associated with failure of RAI. A final multivariate model was then constructed with significant (p < 0.05) variables from the univariate analysis.
Of the 325 patients analyzed, 74 patients (22.8%) failed initial RAI treatment. 53 (71.6%) received additional RAI, 13 (17.6%) received additional RAI followed by surgery, and the remaining 8 (10.8%) were cured after thyroidectomy. The percentage of patients who failed decreased in a step-wise fashion as RAI dose increased. Similarly, the incidence of failure increased as the presenting T3 level increased. Sensitivity analysis revealed that RAI doses < 12.5 mCi were associated with failure while initial T3 and free T4 levels of at least 4.5 pg/mL and 2.3 ng/dL, respectively, were associated with failure. In the final multivariate analysis, higher T4 (HR 1.13, 95% CI 1.02–1.26, p=0.02) and methimazole treatment (HR 2.55, 95% CI 1.22–5.33, p=0.01) were associated with failure.
Laboratory values at presentation can predict which patients with hyperthyroidism are at risk for failing RAI treatment. Higher doses of RAI or surgical referral may prevent the need for repeat RAI in selected patients.
PMCID: PMC4330099  PMID: 25001092
radioactive iodine; relapse; hyperthyroidism; thyroidectomy
2.  Hypoxia and Exercise Increase the Transpulmonary Passage of 99mTc-Labeled Albumin Particles in Humans 
PLoS ONE  2014;9(7):e101146.
Intrapulmonary arteriovenous anastomoses (IPAVs) are large diameter connections that allow blood to bypass the lung capillaries and may provide a route for right-to-left embolus transmission. These anastomoses are recruited by exercise and catecholamines and hypoxia. Yet, whether IPAVs are recruited via direct, oxygen sensitive regulatory mechanisms or indirect effects secondary to redistribution pulmonary blood flow is unknown. Here, we hypothesized that the addition of exercise to hypoxic gas breathing, which increases cardiac output, would augment IPAVs recruitment in healthy humans. To test this hypothesis, we measured the transpulmonary passage of 99mTc-macroaggregated albumin particles (99mTc-MAA) in seven healthy volunteers, at rest and with exercise at 85% of volitional max, with normoxic (FIO2 = 0.21) and hypoxic (FIO2 = 0.10) gas breathing. We found increased 99mTc-MAA passage in both exercise conditions and resting hypoxia. However, contrary to our hypothesis, we found the greatest 99mTc-MAA passage with resting hypoxia. As an additional, secondary endpoint, we also noted that the transpulmonary passage of 99mTc-MAA was well-correlated with the alveolar-arterial oxygen difference (A-aDO2) during exercise. While increased cardiac output has been proposed as an important modulator of IPAVs recruitment, we provide evidence that the modulation of blood flow through these pathways is more complex and that increasing cardiac output does not necessarily increase IPAVs recruitment. As we discuss, our data suggest that the resistance downstream of IPAVs is an important determinant of their perfusion.
PMCID: PMC4094383  PMID: 25013985
3.  Correlation of PET Images of Metabolism, Proliferation and Hypoxia to Characterize Tumor Phenotype in Patients with Cancer of the Oropharynx 
Spatial organization of tumor phenotype is of great interest to radiotherapy target definition and outcome prediction. We characterized tumor phenotype in patients with cancers of the oropharynx through voxel-based correlation of PET images of metabolism, proliferation, and hypoxia.
Patients with oropharyngeal cancer received 18F-fluorodeoxyglucose (FDG) PET/CT, 18F-fluorothymidine (FLT) PET/CT, and 61Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) PET/CT. Images were co-registered and standardized uptake values (SUV) were calculated for all modalities. Voxel-based correlation was evaluated with Pearson’s correlation coefficient in tumor regions. Additionally, sensitivity studies were performed to quantify the effects of image segmentation, registration, noise, and segmentation on R.
On average, FDG PET and FLT PET images were most highly correlated (RFDG:FLT=0.76, range 0.53–0.85), while Cu-ATSM PET showed greater heterogeneity in correlation to other tracers (RFDG:Cu-ATSM=0.64, range 0.51–0.79; RFLT:Cu-ATSM=0.61, range 0.21–0.80). Of the tested parameters, correlation was most sensitive to image registration. Misregistration of one voxel lead to ΔRFDG=0.25, ΔRFLT=0.39, and ΔRCu-ATSM=0.27. Image noise and reconstruction also had quantitative effects on correlation. No significant quantitative differences were found between GTV, expanded GTV, or CTV regions.
Voxel-based correlation represents a first step into understanding spatial organization of tumor phenotype. These results have implications for radiotherapy target definition and provide a framework to test outcome prediction based on pretherapy distribution of phenotype.
PMCID: PMC3494460  PMID: 23068711
Correlation; FDG; FLT; Cu-ATSM; PET
4.  Impact of the Definition of Peak Standardized Uptake Value on Quantification of Treatment Response 
Journal of Nuclear Medicine  2012;53(1):4-11.
PET-based treatment response assessment typically measures the change in maximum standardized uptake value (SUVmax), which is adversely affected by noise. Peak SUV (SUVpeak) has been recommended as a more robust alternative, but its associated region of interest (ROIpeak) is not uniquely defined. We investigated the impact of different ROIpeak definitions on quantification of SUVpeak and tumor response.
Seventeen patients with solid malignancies were treated with a multitargeted receptor tyrosine kinase inhibitor resulting in a variety of responses. Using the cellular proliferation marker 3′-deoxy-3′-18F-fluorothymidine (18F-FLT), whole-body PET/CT scans were acquired at baseline and during treatment. 18F-FLT–avid lesions (~2/patient) were segmented on PET images, and tumor response was assessed via the relative change in SUVpeak. For each tumor, 24 different SUVpeaks were determined by changing ROIpeak shape (circles vs. spheres), size (7.5–20 mm), and location (centered on SUVmax vs. placed in highest-uptake region), encompassing different definitions from the literature. Within each tumor, variations in the 24 SUVpeaks and tumor responses were measured using coefficient of variation (CV), standardized deviation (SD), and range. For each ROIpeak definition, a population average SUVpeak and tumor response were determined over all tumors.
A substantial variation in both SUVpeak and tumor response resulted from changing the ROIpeak definition. The variable ROIpeak definition led to an intratumor SUVpeak variation ranging from 49% above to 46% below the mean (CV, 17%) and an intratumor SUVpeak response variation ranging from 49% above to 35% below the mean (SD, 9%). The variable ROIpeak definition led to a population average SUVpeak variation ranging from 24% above to 28% below the mean (CV, 14%) and a population average SUVpeak response variation ranging from only 3% above to 3% below the mean (SD, 2%). The size of ROIpeak caused more variation in intratumor response than did the location or shape of ROIpeak. Population average tumor response was independent of size, shape, and location of ROIpeak.
Quantification of individual tumor response using SUVpeak is highly sensitive to the ROIpeak definition, which can significantly affect the use of SUVpeak for assessment of treatment response. Clinical trials are necessary to compare the efficacy of SUVpeak and SUVmax for quantification of response to therapy.
PMCID: PMC3308343  PMID: 22213818
PET; SUVpeak; treatment response
5.  18F-DOPA PET with and without MRI fusion, a receiver operator characteristics comparison 
This study is a retrospective analysis of the diagnostic accuracy of FDOPA PET with MRI fusion to FDOPA PET without MRI fusion. Clinical FDOPA PET scans obtained between 2000 and 2008 at the University of Wisconsin Hospital and Clinics were assessed using measures derived from regions of interest (ROI) generated with fused MRI (fused group) and again with ROIs derived solely from PET data (non-fused groups). The ROIs were used to calculate ratios (Striatum/Occipital cortex, Striatum/Cerebellum) pertinent to Parkinson’s disease (PD) pathology. The clinical records were assessed for demographic data, follow-up length, and diagnosis. Receiver Operator Characteristics with area under the curve (AUC) measures were calculated and compared using confidence intervals and hypothesis testing. 27 patients had FDOPA PET with median clinical follow-up of 4 years. Of these, 17 patients had FDOPA PET with a fusible MR image. Seven of the 27 had a non-PD movement disorder. AUCs for the ratio measures ranged from 0.97-1.0 (fused), 0.73-0.83 (non-fused), and 0.63-0.82 (matched non-fused). The fused images had improved accuracy compared to the matched non-fused and all non-fused groups for the striatum to occipital group (p=0.04, p=0.03), while the striatum to cerebellum ratio had improvement over the non-fused all group (p=0.041). MR fusion to FDOPA PET improves the accuracy of at least some measures (Striatum/Occiput, Striatum/Cerebellum) in the diagnosis of PD.
PMCID: PMC3484423  PMID: 23145363
18F-Fluorodopa; positron emission tomography; image fusion; receiver operator characteristics; Parkinson’s
6.  Surgical decision making in Temporal Lobe Epilepsy (TLE): a comparison of 18Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET), MRI, and EEG 
Epilepsy & behavior : E&B  2011;22(2):293-297.
(1) Determine the effect of 18Fluorodeoxyglucose Positron Emission Tomography (FDG-PET), magnetic resonance imaging (MRI), and electroencephalogram (EEG) on the decision for temporal lobe epilepsy (TLE) surgery. (2) Determine if FDG-PET, MRI, or EEG predict surgical outcome.
All PET scans ordered (2000–2010) for epilepsy or seizure were tabulated. Medical records were investigated to determine eligibility and collect data. Statistical analysis included odds ratios, kappa statistics, univariate analysis, and logistic regression.
186 patients had an FDG-PET, 124 patients had TLE, 50 were surgical candidates, and 27 had operations with > 6 months follow-up. Median length of follow-up was 24 months. MRI, FDG-PET, and EEG were significant predictors of surgical candidacy (p<0.001) with odds ratio of 42.8, 20.4, and 6.3 respectively. PET was the only significant predictor of post-operative outcome. (p<0.01)
MRI had a trend toward most influence on surgical candidacy, but only FDG-PET predicted the surgical outcome.
PMCID: PMC3260654  PMID: 21798813
temporal lobe epilepsy; medication refractory epilepsy; epilepsy surgery; fluorodeoxyglucose (FDG); positron emission tomography (PET); magnetic resonance imaging (MRI); Electroencephalogram (EEG)
7.  Impact of expectation-maximization reconstruction iterations on the diagnosis of temporal lobe epilepsy with PET 
There is a well known tradeoff between image noise and image sharpness that is dependent on the number of iterations performed in ordered subset expectation maximization (OSEM) reconstruction of PET data. We aim to evaluate the impact of this tradeoff on the sensitivity and specificity of 18F-FDG PET for the diagnosis of temporal lobe epilepsy. A retrospective blinded reader study was performed on two OSEM reconstructions, using either 2 or 5 iterations, of 32 18F-FDG PET studies acquired at our institution for the diagnosis of temporal lobe epilepsy. The sensitivity and specificity of each reconstruction for identifying patients who were ultimately determined to be surgical candidates was assessed using an ROC analysis. The sensitivity of each reconstruction for identifying patients who showed clinical improvement following surgery was also assessed. Our results showed no significant difference between the two reconstructions studied for either the sensitivity and specificity of 18F-FDG PET for predicting surgical candidacy, or its sensitivity for predicting positive surgical outcomes. This implies that the number of iterations performed during OSEM reconstruction will have little impact on a reader based interpretation of 18F-FDG PET scans acquired for the diagnosis of temporal lobe epilepsy, and can be determined by physician and institutional preference.
PMCID: PMC3477742  PMID: 23133820
18F-FDG PET; temporal lobe epilepsy; OSEM reconstruction; ROC analysis
8.  Early assessment of treatment response in patients with AML using [18F]FLT PET imaging 
Leukemia Research  2010;35(3):310-316.
Assessment of treatment response in acute leukemia is routinely performed after therapy via bone marrow biopsy. We investigated the use of positron emission tomography (PET) for early assessment of treatment response in patients with acute myeloid leukemia (AML), using the proliferation marker 3′-deoxy-3′-[18F]fluoro-l-thymidine (FLT). Eight adult AML patients receiving induction chemotherapy underwent whole-body FLT PET/CT scans acquired at different time points during therapy. Patients who entered complete remission (CR) exhibited significantly lower FLT uptake in bone marrow than those patients with resistant disease (RD). In bone marrow, mean and maximum standardized uptake values were 0.8, 3.6 for CR and 1.6, 11.4 for RD, p < 0.001. FLT PET results for CR and RD patients were independent of assessment time point, suggesting that FLT PET scans acquired as early as 2 days after chemotherapy initiation may be predictive of clinical response. This pilot study suggests that FLT PET imaging during induction chemotherapy may serve as an early biomarker of treatment response in AML.
PMCID: PMC3319294  PMID: 20832860
Positron emission tomography (PET); Acute myeloid leukemia (AML); FLT; [18F]FLT; 3′-Deoxy-3′-fluorothymidine; Treatment response; Radionuclide imaging

Results 1-8 (8)