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ABSTRACT: The Genisys4 is a small bench-top preclinical PET scanner designed to enable imaging in biology, biochemistry, and pharmacology laboratories and imaging centers. Here, we compare its performance with that of a well-established preclinical PET scanner. METHODS: Subcutaneous and lung tumor xenografts were used to compare lesion detectability and treatment responses to chemotherapy (gemcitabine) using (18)F-FDG PET. The size of subcutaneous xenografts (L1210 and L1210-10K leukemia cells) and lung metastases (B-16 melanoma cells) was measured on small-animal CT images. Tumor (18)F-FDG uptake was expressed as percentage injected dose per gram. Using list-mode data, serial images of the left ventricular blood pool were used to generate time-activity curves. RESULTS: Subcutaneous xenografts (range, 4-12 mm; mean ± SD, 6.1 ± 1.7 mm) and lung metastases (range, 1-5 mm; mean, 2.1 ± 1.2 mm) were detected equally well with both scanners. Tumor (18)F-FDG uptake measured with both scanners was highly correlated for subcutaneous xenografts (r(2) = 0.93) and lung metastases (r(2) = 0.83). The new Genisys4 scanner and the established scanner provided comparable treatment response information (r(2) = 0.93). Dynamic imaging sequences permitted the generation of left ventricular blood-pool time-activity curves with both scanners. CONCLUSION: Using subcutaneous and lung xenografts, a novel and an established preclinical PET scanner provided equivalent information with regard to lesion detection, tumor (18)F-FDG uptake, tumor response to treatment, and generation of time-activity curves. Thus, the Genisys4 provides a small, efficient bench-top preclinical PET alternative for quantitatively studying murine tumor models in biology, biochemistry, and pharmacology laboratories and preclinical imaging centers.
Journal of Nuclear Medicine 04/2013; · 6.38 Impact Factor
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Daniel S Berman,
Jamshid Maddahi,
B K Tamarappoo, Johannes Czernin,
Raymond Taillefer,
James E Udelson,
C Michael Gibson,
Marybeth Devine,
Joel Lazewatsky,
Gajanan Bhat,
Dana Washburn
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ABSTRACT: OBJECTIVES: This was a phase II trial to assess flurpiridaz F 18 for safety and compare its diagnostic performance for positron emission tomography (PET) myocardial perfusion imaging (MPI) with Tc-99m single-photon emission computed tomography (SPECT) MPI with regard to image quality, interpretative certainty, defect magnitude, and detection of coronary artery disease (CAD) (≥50% stenosis) on invasive coronary angiography (ICA). BACKGROUND: In pre-clinical and phase I studies, flurpiridaz F 18 has shown characteristics of an essentially ideal MPI tracer. METHODS: One hundred forty-three patients from 21 centers underwent rest-stress PET and Tc-99m SPECT MPI. Eighty-six patients underwent ICA, and 39 had low-likelihood of CAD. Images were scored by 3 independent, blinded readers. RESULTS: A higher percentage of images were rated as excellent/good on PET versus SPECT on stress (99.2% vs. 88.5%, p < 0.01) and rest (96.9% vs. 66.4, p < 0.01) images. Diagnostic certainty of interpretation (percentage of cases with definitely abnormal/normal interpretation) was higher for PET versus SPECT (90.8% vs. 70.9%, p < 0.01). In 86 patients who underwent ICA, sensitivity of PET was higher than SPECT (78.8% vs. 61.5%, respectively, p = 0.02). Specificity was not significantly different (PET: 76.5% vs. SPECT: 73.5%). Receiver-operating characteristic curve area was 0.82 ± 0.05 for PET and 0.70 ± 0.06 for SPECT (p = 0.04). Normalcy rate was 89.7% with PET and 97.4% with SPECT (p = NS). In patients with CAD on ICA, the magnitude of reversible defects was greater with PET than SPECT (p = 0.008). Extensive safety assessment revealed that flurpiridaz F 18 was safe in this cohort. CONCLUSIONS: In this phase 2 trial, PET MPI with flurpiridaz F 18 was safe and superior to SPECT MPI for image quality, interpretative certainty, and overall CAD diagnosis.
Journal of the American College of Cardiology 12/2012; · 14.16 Impact Factor
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ABSTRACT: CA II makes a good PET: Discovering positron emission tomography (PET) probes with high target affinities is challenging. PET probe discovery using in situ click chemistry uses (19) F-bearing fragments as (18) F surrogates. This ensures that the lead hits and PET probes have equivalent chemical or biological characteristics, making PET probe discovery predictable and reliable.
ChemMedChem 12/2012; · 3.15 Impact Factor
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Wayne R Austin,
Amanda L Armijo,
Dean O Campbell,
Arun S Singh,
Terry Hsieh,
David Nathanson,
Harvey R Herschman,
Michael E Phelps,
Owen N Witte, Johannes Czernin,
Caius G Radu
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ABSTRACT: Nucleotide deficiency causes replication stress (RS) and DNA damage in dividing cells. How nucleotide metabolism is regulated in vivo to prevent these deleterious effects remains unknown. In this study, we investigate a functional link between nucleotide deficiency, RS, and the nucleoside salvage pathway (NSP) enzymes deoxycytidine kinase (dCK) and thymidine kinase (TK1). We show that inactivation of dCK in mice depletes deoxycytidine triphosphate (dCTP) pools and induces RS, early S-phase arrest, and DNA damage in erythroid, B lymphoid, and T lymphoid lineages. TK1(-/-) erythroid and B lymphoid lineages also experience nucleotide deficiency but, unlike their dCK(-/-) counterparts, they still sustain DNA replication. Intriguingly, dCTP pool depletion, RS, and hematopoietic defects induced by dCK inactivation are almost completely reversed in a newly generated dCK/TK1 double-knockout (DKO) mouse model. Using NSP-deficient DKO hematopoietic cells, we identify a previously unrecognized biological activity of endogenous thymidine as a strong inducer of RS in vivo through TK1-mediated dCTP pool depletion. We propose a model that explains how TK1 and dCK "tune" dCTP pools to both trigger and resolve RS in vivo. This new model may be exploited therapeutically to induce synthetic sickness/lethality in hematological malignancies, and possibly in other cancers.
Journal of Experimental Medicine 11/2012; · 13.85 Impact Factor
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ABSTRACT: Oncologic (18)F-FDG PET/CT is rapidly gaining acceptance in clinical practice. However, the referring physician's attitude toward the usefulness of this diagnostic modality is unknown. This survey was undertaken to collect information regarding the current perspective of referring physicians on oncologic PET/CT.
We conducted a prospective worldwide, Web-based survey of physicians who manage cancer patients. A total of 963 referring physicians completed a 20-question survey focused on their experience with oncologic (18)F-FDG PET/CT. Attention was directed toward their confidence about indications, their satisfaction with related educational resources, the quality of interaction with interpreting physicians, and practical problems encountered. The respondents included oncologists (38.5%, n = 371), hematologists (16.4%, n = 158), radiation oncologists (9.0%, n = 87), surgeons (30.3%, n = 292), and other physicians (5.7%, n = 55).
Only 25.2% of respondents considered the oncologic (18)F-FDG PET/CT indications to be well established and defined. Frequent uncertainty about the need for a PET scan was indicated by 62.3% of the respondents. High cost and overinterpretation of findings were the most commonly reported concerns (47.0% and 40.9%, respectively). The experience and skill level of the interpreting physician was considered very important by 96.8% of the surveyed physicians.
Referring physicians expressed considerable uncertainty about the appropriate use of oncologic PET/CT. Additional major concerns are procedure costs and quality of interpretation. The responses suggest a strong need for efforts to educate referring and interpreting physicians about the appropriate use of (18)F-FDG PET/CT in oncology.
Journal of Nuclear Medicine 08/2012; 53(10):1499-505. · 6.38 Impact Factor
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ABSTRACT: The current study examined the use of voxel-wise changes in (18)F-FDOPA and (18)F-FLT PET uptake, referred to as parametric response maps (PRMs), to determine whether they were predictive of response to bevacizumab in patients with recurrent malignant gliomas. Twenty-four patients with recurrent malignant gliomas who underwent bevacizumab treatment were analyzed. Patients had MR and PET images acquired before and at 2 time points after bevacizumab treatment. PRMs were created by examining the percentage change in tracer uptake between time points in each image voxel. Voxel-wise increase in PET uptake in areas of pretreatment contrast enhancement defined by MRI stratified 3-month progression-free survival (PFS) and 6-month overall survival (OS) according to receiver-operating characteristic curve analysis. A decrease in PET tracer uptake was associated with longer PFS and OS, whereas an increase in PET uptake was associated with short PFS and OS. The volume fraction of increased (18)F-FDOPA PET uptake between the 2 posttreatment time points also stratified long- and short-term PFS and OS (log-rank, P < .05); however, (18)F-FLT uptake did not stratify OS. This study suggests that an increase in FDOPA or FLT PET uptake on PRMs after bevacizumab treatment may be a useful biomarker for predicting PFS and that FDOPA PET PRMs are also predictive of OS in recurrent gliomas treated with bevacizumab.
Neuro-Oncology 06/2012; 14(8):1079-89. · 5.72 Impact Factor
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Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 06/2012; 14(4):399-401. · 2.47 Impact Factor
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ABSTRACT: Squamous papilloma is one of the most common benign neoplasms of the oral cavity and oropharynx. The (18)F-FDG PET/CT metabolic phenotype of this entity has not been described. We document the incidental finding of a hypermetabolic lesion at the right base of the tongue on an FDG PET/CT that proved to be squamous papilloma. The maximum standard uptake value was high at 7.0 g/ml. We conclude that oral cavity squamous papilloma can present with an intensely hypermetabolic phenotype on (18)F- FDG PET/CT. This benign entity should be included in the differential diagnosis of FDG-positive oral and oropharyngeal lesions.
Clinical nuclear medicine 05/2012; 37(5):e98-9. · 3.92 Impact Factor
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ABSTRACT: Serum prostate-specific antigen (PSA) levels are used to monitor the development of prostate cancer, recurrence after surgery, and response to subsequent therapy. However, the clinical implications often are difficult to interpret. Ulmert and colleagues report use of a positron-emitting labeled monoclonal antibody directed to a unique PSA epitope to noninvasively image PSA-positive prostate cancer xenografts and to measure both androgen-stimulated PSA expression and androgen therapy-responsive PSA decreases.
Cancer discovery. 04/2012; 2(4):301-3.
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ABSTRACT: We investigated the impact of (18)F-DOPA brain PET/CT on the clinical management of patients with known or suspected brain tumors.
A prospective survey of referring physicians was conducted. A pre-PET questionnaire inquired about indication, tumor histology or grade, level of suspicion for tumor recurrence, and planned management. Early post-PET questionnaires asked referring physicians to categorize PET findings as negative, equivocal, or positive; assessed the level of suspicion for primary or recurrent brain tumor; and recorded intended management changes prompted by PET findings. A late follow-up questionnaire 6 mo after the scan aimed at determining patient outcome (recurrence, survival). In addition, all referring physicians were contacted to determine whether management changes intended after (18)F-DOPA PET/CT were implemented.
Fifty-eight consecutive patients were included. The clinical suspicion for recurrence increased in 33%, remained unchanged in 50%, and decreased in 17% of patients after adding the PET/CT result to the available diagnostic data. The late post-PET questionnaire confirmed recurrence in 26 patients whereas 32 had stable disease or remained disease-free. (18)F-DOPA PET/CT resulted in intended management changes in 41% of patients. Changes in intended management from wait and watch to chemotherapy (6 patients [25%]) and from chemotherapy to wait and watch (4 patients [17%]) occurred most frequently. Clinical follow-up revealed that 75% of intended treatment changes were implemented.
(18)F-DOPA PET/CT changed the intended management of 41% of patients with brain tumors, and intended management changes were implemented in 75% of these. These changes suggest a potentially important clinical role of imaging amino acid transport in the management of brain tumor patients.
Journal of Nuclear Medicine 03/2012; 53(3):393-8. · 6.38 Impact Factor
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Ken Herrmann,
Matthias R Benz, Johannes Czernin,
Martin S Allen-Auerbach,
William D Tap,
Sarah M Dry,
Tibor Schuster,
Jeff J Eckardt,
Michael E Phelps,
Wolfgang A Weber,
Fritz C Eilber
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ABSTRACT: Neoadjuvant therapy is associated with considerable toxicity and limited survival benefits in patients with soft tissue sarcoma (STS). We prospectively evaluated whether 2[18F]fluoro-2-deoxy-d-glucose ((18)F-FDG)-PET/computed tomographic (CT) imaging after the initial cycle of neoadjuvant therapy could predict overall survival in these patients.
Thirty-nine patients underwent (18)F-FDG-PET/CT before and after one cycle of neoadjuvant therapy. Fifty-six patients underwent end-of-treatment PET. Overall survival was, among others, correlated with changes of SUV(peak) and histopathology.
One-, two-, and five-year survival rates were 95% ± 3.0%, 86% ± 4.6%, and 68% ± 6.6%, respectively. Median time to death was 30.9 months (mean, 27.7; range, 6.9-50.1). Optimal cutoff values for early and late decreases in SUV(peak) (26% and 57%, respectively) were significant predictors of survival in univariate survival analysis [P = 0.041; HR, 0.27; 95% confidence interval (CI), 0.08-0.95 and P = 0.045; HR, 0.31; 95% CI, 0.10-0.98]. Seven of 15 early PET nonresponders but only four of 24 early PET responders died during follow-up (P = 0.068). The only other significant survival predictor was surgical margin positivity (P = 0.041; HR, 3.31; 95% CI, 1.05-10.42). By multivariable analysis, early metabolic response (P = 0.016) and positivity of surgical margins (P = 0.036) remained significant survival predictors.
(18)F-FDG-PET predicted survival after the initial cycle of neoadjuvant chemotherapy in patients with STS and can potentially serve as an intermediate endpoint biomarker in clinical research and patient care.
Clinical Cancer Research 02/2012; 18(7):2024-31. · 7.74 Impact Factor
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ABSTRACT: The ability to measure tumor determinants of response to nucleoside analog (NA) chemotherapy agents such as gemcitabine and related compounds could significantly affect the management of several types of cancer. Previously we showed that the accumulation in tumors of the new PET tracer 1-(2'-deoxy-2'-(18)F-fluoro-β-d-arabinofuranosyl)cytosine ((18)F-FAC) is predictive of responses to gemcitabine. (18)F-FAC retention in cells requires deoxycytidine kinase (dCK), a rate-limiting enzyme in the deoxyribonucleoside salvage metabolism and in gemcitabine conversion from an inactive prodrug to a cytotoxic compound. The objectives of the current study were to determine whether (18)F-FAC tumor uptake is also influenced by cytidine deaminase (CDA), a determinant of resistance to gemcitabine; to develop a new PET assay using (18)F-FAC and the related probe 1-(2'-deoxy-2'-(18)F-fluoro-β-l-arabinofuranosyl)-5-methylcytosine (l-(18)F-FMAC) to profile tumor lesions for both dCK and CDA enzymatic activities; and to determine whether this PET assay can identify the most effective NA chemotherapy against tumors with differential expression of dCK and CDA.
Isogenic murine leukemic cell lines with defined dCK and CDA activities were generated by retroviral transduction. A cell viability assay was used to determine the sensitivity of the isogenic cell lines to the dCK-dependent NA prodrugs gemcitabine and clofarabine. In vitro enzymatic and cell-based tracer uptake assays and in vivo PET with (18)F-FAC and l-(18)F-FMAC were used to predict tumor responses to gemcitabine and clofarabine.
dCK and CDA activities measured by kinase and tracer uptake assays correlated with the sensitivity of isogenic cell lines to gemcitabine and clofarabine. Coexpression of CDA decreased the sensitivity of dCK-positive cells to gemcitabine treatment in vitro by 15-fold but did not affect responses to clofarabine. Coexpression of CDA decreased (18)F-FAC but not l-(18)F-FMAC, phosphorylation, and uptake by dCK-positive cells. (18)F-FAC and l-(18)F-FMAC PET estimates of the enzymatic activities of dCK and CDA in tumor implants in mice were predictive of responses to gemcitabine and clofarabine treatment in vivo.
These findings support the utility of PET-based phenotyping of tumor nucleoside metabolism for guiding the selection of NA prodrugs.
Journal of Nuclear Medicine 02/2012; 53(2):275-80. · 6.38 Impact Factor
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ABSTRACT: Knowing the glycolytic phenotype of cancers is important for the appropriate use of F-18 FDG PET/CT imaging. This study was performed to determine the influence of tumor grade and histology on the glycolytic phenotype of epithelial ovarian cancer patients.
Only histopathologically confirmed epithelial ovarian cancer patients, with no other concurrent malignancies, who had F-18 FDG PET/CT either before or at least 3 months after any therapeutic intervention and had confirmed measurable disease of >1 cm were included. The F-18 FDG PET/CT uptake was determined as maximum standard uptake value (SUVmax) at the pathologically confirmed site of disease or in the most active lesion. SUVmax was correlated to tumor grade and histology.
Of 171 ovarian cancer patients, 42 referred for F-18 FDG PET/CT scans between January 2003 and December 2010 were eligible for inclusion. Histologic diagnosis most frequently revealed the serous subtype (n = 32) and grade III (n = 28) epithelial ovarian cancer. Overall, ovarian carcinomas exhibited a strong glycolytic phenotype (average SUVmax, 7.6 g/mL). The SUVmax averaged 7.76 g/mL, 6.76 g/mL, and 7.95 g/mL for Grade I, II, and III, respectively. There was no statistically significant correlation between tumor SUVmax and the histologic tumor grade (P = 0.74). No statistically significant differences were found between the tumor SUVmax of serous and endometrioid subtypes (P = 0.53). For other histology subtypes, no statistic evaluation was possible due to the low number of cases.
The glycolytic phenotype in epithelial ovarian cancer, expressed as SUVmax, is strong. However, tumor FDG uptake is unrelated to tumor grade and histologic subtype implying that F-18 FDG PET/CT cannot be used to predict tumor aggressiveness or histology.
Clinical nuclear medicine 01/2012; 37(1):49-53. · 3.92 Impact Factor
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ABSTRACT: Positron emission tomography (PET) imaging reporter genes (IRGs) and PET reporter probes (PRPs) are amongst the most valuable tools for gene and cell therapy. PET IRGs/PRPs can be used to non-invasively monitor all aspects of the kinetics of therapeutic transgenes and cells in all types of living mammals. This technology is generalizable and can allow long-term kinetics monitoring. In gene therapy, PET IRGs/PRPs can be used for whole-body imaging of therapeutic transgene expression, monitoring variations in the magnitude of transgene expression over time. In cell or cellular gene therapy, PET IRGs/PRPs can be used for whole-body monitoring of therapeutic cell locations, quantity at all locations, survival and proliferation over time and also possibly changes in characteristics or function over time. In this review, we have classified PET IRGs/PRPs into two groups based on the source from which they were derived: human or non-human. This classification addresses the important concern of potential immunogenicity in humans, which is important for expansion of PET IRG imaging in clinical trials. We have then discussed the application of this technology in gene/cell therapy and described its use in these fields, including a summary of using PET IRGs/PRPs in gene and cell therapy clinical trials. This review concludes with a discussion of the future direction of PET IRGs/PRPs and recommends cell and gene therapists collaborate with molecular imaging experts early in their investigations to choose a PET IRG/PRP system suitable for progression into clinical trials.
Theranostics. 01/2012; 2(4):374-91.
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Johannes Schwarzenberg, Johannes Czernin,
Timothy F Cloughesy,
Benjamin M Ellingson,
Whitney B Pope,
Cheri Geist,
Magnus Dahlbom,
Daniel H S Silverman,
Nagichettiar Satyamurthy,
Michael E Phelps,
Wei Chen
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ABSTRACT: With the dismal prognosis for malignant glioma patients, survival predictions become key elements in patient management. This study compares the value of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET and MRI for early outcome predictions in patients with recurrent malignant glioma on bevacizumab therapy.
Thirty patients treated with bevacizumab combination therapy underwent (18)F-FLT PET immediately before and at 2 and 6 wk after the start of treatment. A metabolic treatment response was defined as a decrease of equal to or greater than 25% in tumor (18)F-FLT uptake (standardized uptake values) from baseline using receiver-operating-characteristic analysis. MRI treatment response was assessed at 6 wk according to the Response Assessment in Neurooncology criteria. (18)F-FLT responses at different times were compared with MRI response and correlated with progression-free survival and overall survival using Kaplan-Meier analysis. Metabolic response based on (18)F-FLT was further compared with other outcome predictors using Cox regression analysis.
Early and late changes in tumor (18)F-FLT uptake were more predictive of overall survival than MRI criteria (P < 0.001 and P = 0.01, respectively). (18)F-FLT uptake changes were also predictive of progression-free survival (P < 0.001). The median overall survival for responders was 3.3 times longer than for nonresponders based on (18)F-FLT PET criteria (12.5 vs. 3.8 mo, P < 0.001) but only 1.4 times longer using MRI assessment (12.9 vs. 9.0 mo, P = 0.05). On the basis of the 6-wk (18)F-FLT PET response, there were 16 responders (53%) and 14 nonresponders (47%), whereas MRI identified 9 responders (7 partial response, 2 complete response, 31%) and 20 nonresponders (13 stable disease, 7 progressive disease, 69%). In 7 of the 8 discrepant cases between MRI and PET, (18)F-FLT PET was able to demonstrate response earlier than MRI. Among various outcome predictors, multivariate analysis identified (18)F-FLT PET changes at 6 wk as the strongest independent survival predictor (P < 0.001; hazard ratio, 10.051).
Changes in tumor (18)F-FLT uptake were highly predictive of progression-free and overall survival in patients with recurrent malignant glioma on bevacizumab therapy. (18)F-FLT PET seems to be more predictive than MRI for early treatment response.
Journal of Nuclear Medicine 12/2011; 53(1):29-36. · 6.38 Impact Factor
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Journal of Nuclear Medicine 12/2011; 52 Suppl 2:1S-2S. · 6.38 Impact Factor
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ABSTRACT: Many children with sarcomas undergo whole body 2-deoxy-2-((18)F)fluoro-D-glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) and technetium methylene diphosphonate ((99)Tc-MDP) studies. It is unknown whether the combination of both tests results in more accurate detection of bone lesions than (18)F-FDG- PET/CT alone.
(99)Tc-MDP bone and (18)F-FDG PET/CT scans were each read by 2 "blinded" observers and then reviewed side-by-side by 3 readers. Bone lesions were graded qualitatively on a 5-point scale (from benign to malignant). Clinical and imaging follow-up (n = 21) and bone biopsy results (n = 8) served as reference standard.
A total of 39 paired (99)Tc-MDP and (18)F-FDG-PET/CT studies (cases) performed at a mean interval 4 ± 7 days, were performed on 29 patients (mean age 12 ± 5 y). Of these, 21 patients (72%) had bone sarcoma, whereas 8 patients (28%) had soft tissue sarcoma. By patient and case-based analysis, (18)F-FDG PET/CT had an accuracy of 100%. Tc-MDP had accuracies of 90% and 82% by patient and case-based analysis. The combined interpretation had an accuracy of 97%.
In this study, (99)Tc-MDP bone imaging does not provide an added diagnostic value for bone involvement over (18)F-FDG-PET/CT.
Journal of Pediatric Hematology/Oncology 11/2011; 34(2):131-6. · 1.16 Impact Factor
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ABSTRACT: Positron emission tomography (PET) reporter gene imaging can be used to non-invasively monitor cell-based therapies. Therapeutic cells engineered to express a PET reporter gene (PRG) specifically accumulate a PET reporter probe (PRP) and can be detected by PET imaging. Expanding the utility of this technology requires the development of new non-immunogenic PRGs. Here we describe a new PRG-PRP system that employs, as the PRG, a mutated form of human thymidine kinase 2 (TK2) and 2'-deoxy-2'-18F-5-methyl-1-β-L-arabinofuranosyluracil (L-18F-FMAU) as the PRP. We identified L-18F-FMAU as a candidate PRP and determined its biodistribution in mice and humans. Using structure-guided enzyme engineering, we generated a TK2 double mutant (TK2-N93D/L109F) that efficiently phosphorylates L-18F-FMAU. The N93D/L109F TK2 mutant has lower activity for the endogenous nucleosides thymidine and deoxycytidine than wild type TK2, and its ectopic expression in therapeutic cells is not expected to alter nucleotide metabolism. Imaging studies in mice indicate that the sensitivity of the new human TK2-N93D/L109F PRG is comparable with that of a widely used PRG based on the herpes simplex virus 1 thymidine kinase. These findings suggest that the TK2-N93D/L109F/L-18F-FMAU PRG-PRP system warrants further evaluation in preclinical and clinical applications of cell-based therapies.
Journal of Biological Chemistry 11/2011; 287(1):446-54. · 4.77 Impact Factor
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ABSTRACT: Response rates of unselected non-small cell lung cancer (NSCLC) patients to the epidermal growth factor receptor inhibitor erlotinib are low and range from 10% to 20%. Early response assessments are needed to avoid costs and side effects of inefficient treatments. Here we determined whether early changes in tumor uptake of (18)F-FDG can predict progression-free and overall survival in NSCLC patients who are treated with erlotinib.
Twenty-two patients (6 men, 16 women; mean age ± SD, 64 ± 13 y) with stage III or stage IV NSCLC who received erlotinib treatment were enrolled prospectively. (18)F-FDG PET/CT was performed before the initiation of treatment (n = 22), after 2 wk (n = 22), and after 78 ± 21 d (n = 11). Tumor maximum standardized uptake values were measured for a maximum of 5 lesions for each patient. Tumor responses were classified using modified PET Response Criteria in Solid Tumors (use of maximum standardized uptake values). Median overall survival by Kaplan-Meier analysis was compared between groups using a log-rank test.
The overall median time to progression was 52 d (95% confidence interval, 47-57 d). The overall median survival time was 131 d (95% confidence interval, 0-351 d). Patients with progressive metabolic disease on early follow-up PET showed a significantly shorter time to progression (47 vs. 119 d; P < 0.001) and overall survival (87 vs. 828 d; P = 0.01) than patients classified as having stable metabolic disease or partial or complete metabolic response.
These data suggest that (18)F-FDG PET/CT performed early after the start of erlotinib treatment can help to identify patients who benefit from this targeted therapy.
Journal of Nuclear Medicine 11/2011; 52(11):1684-9. · 6.38 Impact Factor
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ABSTRACT: This study sought to determine whether [(18)F]fluorothymidine (FLT) positron emission tomography (PET)/computed tomography (CT) imaging allows assessment of tumor viability and proliferation in patients with soft tissue sarcomas who are treated with neoadjuvant therapy.
Twenty patients with biopsy-proven, resectable, high-grade soft tissue sarcoma underwent [(18)F]FLT PET/CT imaging before and after neoadjuvant therapy. Histologic subtypes included sarcomas not otherwise specified (n = 5), malignant peripheral nerve sheath tumors (n = 3), gastrointestinal stromal tumors (n = 3), leiomyosarcomas (n = 3), angiosarcomas (n = 2), and others (n = 4). Changes in [(18)F]FLT peak standardized uptake value (SUVpeak) were correlated with percent necrosis in excised tissue, whereas posttreatment [(18)F]FLT tumor uptake was correlated with thymidine kinase 1 (TK1) expression and Ki-67 staining indices in excised tumor tissue.
Tumor FLT SUVpeak averaged 7.1 ± 3.7 g/mL (range, 1.9-16.1 g/mL) at baseline and decreased significantly to 2.7 ± 1.6 g/mL (range, 0.8-6.0 g/mL) at follow-up (P < .001); however, marked reductions in SUV were not specific for histopathological response. The posttreatment SUVpeak did not correlate with TK1 (P = .27) or Ki-67 expression (P = .21).
Marked reductions in [(18)F]FLT tumor uptake in response to neoadjuvant treatment were observed in most patients with sarcoma. However, these reductions were not specific for histopathologic response to neoadjuvant therapy. Furthermore, posttreatment [(18)F]FLT tumor uptake was unrelated to tumor proliferation by Ki-67 and TK1 staining. These results question the value of [(18)F]FLT PET imaging for treatment response assessments in patients with soft tissue sarcoma.
Cancer 10/2011; 118(12):3135-44. · 4.77 Impact Factor
