[11C]-methionine positron emission tomography in the evaluation of pediatric low-grade gliomas.

Background: [11C]-Methionine positron emission tomography (PET; [11C]-MET-PET) is principally used for the evaluation of brain tumors in adults. Although amino acid PET tracers are more commonly used in the evaluation of pediatric brain tumors, data on [11C]-MET-PET imaging of pediatric low-grade gliomas (pLGG) is scarce. This study aimed to investigate the roles of [11C]-MET-PET in the evaluation of pLGGs. Methods: Eighteen patients with newly diagnosed pLGG and 26 previously treated pLGG patients underwent [11C]-MET-PET met the inclusion and exclusion criteria. Tumor-to-brain uptake ratio (TBR) and metabolic tumor volumes were assessed for diagnostic performances (newly diagnosed, 15; previously treated 26), change with therapy (newly diagnosed, 9; previously treated 7), and variability among different histology (n = 12) and molecular markers (n = 7) of pLGGs. Results: The sensitivity of [11C]-MET-PET for diagnosing pLGG, newly diagnosed, and previously treated combined was 93% for both TBRmax and TBRpeak, 76% for TBRmean, and 95% for qualitative evaluation. TBRmax showed a statistically significant reduction after treatment, while other PET parameters showed a tendency to decrease. Median TBRmax, TBRpeak, and TBRmean values were slightly higher in the BRAFV600E mutated tumors compared to the BRAF fused tumors. Median TBRmax, and TBRpeak in diffuse astrocytomas were higher compared to pilocytic astrocytomas, but median TBRmean, was slightly higher in pilocytic astrocytomas. However, formal statistical analysis was not done due to the small sample size. Conclusions: Our study shows that [11C]-MET-PET reliably characterizes new and previously treated pLGGs. Our study also shows that quantitative parameters tend to decrease with treatment, and differences may exist between various pLGG types.

Estimating the synaptic density deficit in Alzheimer's disease using multi-contrast CEST imaging.

In vivo noninvasive imaging of neurometabolites is crucial to improve our understanding of the underlying pathophysiological mechanism in neurodegenerative diseases. Abnormal changes in synaptic organization leading to synaptic degradation and neuronal loss is considered as one of the primary factors driving Alzheimer's disease pathology. Magnetic resonance based molecular imaging techniques such as chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) can provide neurometabolite specific information which may relate to underlying pathological and compensatory mechanisms. In this study, CEST and short echo time single voxel MRS was performed to evaluate the sensitivity of cerebral metabolites to beta-amyloid (Aß) induced synaptic deficit in the hippocampus of a mouse model of Alzheimer's disease. The CEST based spectra (Z-spectra) were acquired on a 9.4 Tesla small animal MR imaging system with two radiofrequency (RF) saturation amplitudes (1.47 µT and 5.9 µT) to obtain creatine-weighted and glutamate-weighted CEST contrasts, respectively. Multi-pool Lorentzian fitting and quantitative T1 longitudinal relaxation maps were used to obtain metabolic specific apparent exchange-dependent relaxation (AREX) maps. Short echo time (TE = 12 ms) single voxel MRS was acquired to quantify multiple neurometabolites from the right hippocampus region. AREX contrasts and MRS based metabolite concentration levels were examined in the ARTE10 animal model for Alzheimer's disease and their wild type (WT) littermate counterparts (age = 10 months). Using MRS voxel as a region of interest, group-wise analysis showed significant reduction in Glu-AREX and Cr-AREX in ARTE10, compared to WT animals. The MRS based results in the ARTE10 mice showed significant decrease in glutamate (Glu) and glutamate-total creatine (Glu/tCr) ratio, compared to WT animals. The MRS results also showed significant increase in total creatine (tCr), phosphocreatine (PCr) and glutathione (GSH) concentration levels in ARTE10, compared to WT animals. In the same ROI, Glu-AREX and Cr-AREX demonstrated positive associations with Glu/tCr ratio. These results indicate the involvement of neurotransmitter metabolites and energy metabolism in Aß-mediated synaptic degradation in the hippocampus region. The study also highlights the feasibility of CEST and MRS to identify and track multiple competing and compensatory mechanisms involved in heterogeneous pathophysiology of Alzheimer's disease in vivo.

Hybrid 18F-Fluoroethyltyrosine PET and MRI with Perfusion to Distinguish Disease Progression from Treatment-Related Change in Malignant Brain Tumors: The Quest to Beat the Toughest Cases.

Conventional MRI has important limitations when assessing for progression of disease (POD) versus treatment-related changes (TRC) in patients with malignant brain tumors. We describe the observed impact and pitfalls of implementing 18F-fluoroethyltyrosine (18F-FET) perfusion PET/MRI into routine clinical practice. Methods: Through expanded-access investigational new drug use of 18F-FET, hybrid 18F-FET perfusion PET/MRI was performed during clinical management of 80 patients with World Health Organization central nervous system grade 3 or 4 gliomas or brain metastases of 6 tissue origins for which the prior brain MRI results were ambiguous. The diagnostic performance with 18F-FET PET/MRI was dually evaluated within routine clinical service and for retrospective parametric evaluation. Various 18F-FET perfusion PET/MRI parameters were assessed, and patients were monitored for at least 6 mo to confirm the diagnosis using pathology, imaging, and clinical progress. Results: Hybrid 18F-FET perfusion PET/MRI had high overall accuracy (86%), sensitivity (86%), and specificity (87%) for difficult diagnostic cases for which conventional MRI accuracy was poor (66%). 18F-FET tumor-to-brain ratio static metrics were highly reliable for distinguishing POD from TRC (area under the curve, 0.90). Dynamic tumor-to-brain intercept was more accurate (85%) than SUV slope (73%) or time to peak (73%). Concordant PET/MRI findings were 89% accurate. When PET and MRI conflicted, 18F-FET PET was correct in 12 of 15 cases (80%), whereas MRI was correct in 3 of 15 cases (20%). Clinical management changed after 88% (36/41) of POD diagnoses, whereas management was maintained after 87% (34/39) of TRC diagnoses. Conclusion: Hybrid 18F-FET PET/MRI positively impacted the routine clinical care of challenging malignant brain tumor cases at a U.S. institution. The results add to a growing body of literature that 18F-FET PET complements MRI, even rescuing MRI when it fails.

Use of multimodality imaging, histology, and treatment feasibility to characterize a transgenic Rag2-null rat model of glioblastoma.

Many drugs that show potential in animal models of glioblastoma (GBM) fail to translate to the clinic, contributing to a paucity of new therapeutic options. In addition, animal model development often includes histologic assessment, but multiparametric/multimodality imaging is rarely included despite increasing utilization in patient cancer management. This study developed an intracranial recurrent, drug-resistant, human-derived glioblastoma tumor in Sprague-Dawley Rag2-Rag2 tm1Hera knockout rat and was characterized both histologically and using multiparametric/multimodality neuroimaging. Hybrid 18F-fluoroethyltyrosine positron emission tomography and magnetic resonance imaging, including chemical exchange saturation transfer (18F-FET PET/CEST MRI), was performed for full tumor viability determination and characterization. Histological analysis demonstrated human-like GBM features of the intracranially implanted tumor, with rapid tumor cell proliferation (Ki67 positivity: 30.5 ± 7.8%) and neovascular heterogeneity (von Willebrand factor VIII:1.8 to 5.0% positivity). Early serial MRI followed by simultaneous 18F-FET PET/CEST MRI demonstrated consistent, predictable tumor growth, with exponential tumor growth most evident between days 35 and 49 post-implantation. In a second, larger cohort of rats, 18F-FET PET/CEST MRI was performed in mature tumors (day 49 post-implantation) for biomarker determination, followed by evaluation of single and combination therapy as part of the model development and validation. The mean percentage of the injected dose per mL of 18F-FET PET correlated with the mean %CEST (r = 0.67, P < 0.05), but there was also a qualitative difference in hot spot location within the tumor, indicating complementary information regarding the tumor cell demand for amino acids and tumor intracellular mobile phase protein levels. Finally, the use of this glioblastoma animal model for therapy assessment was validated by its increased overall survival after treatment with combination therapy (temozolomide and idasanutlin) (P < 0.001). Our findings hold promise for a more accurate tumor viability determination and novel therapy assessment in vivo in a recently developed, reproducible, intracranial, PDX GBM.

11C-Methionine PET for Identification of Pediatric High-Grade Glioma Recurrence.

Differentiating tumor recurrence or progression from pseudoprogression during surveillance of pediatric high-grade gliomas (PHGGs) using MRI, the primary imaging modality for evaluation of brain tumors, can be challenging. The aim of this study was to evaluate whether 11C-methionine PET, a molecular imaging technique that detects functionally active tumors, is useful for further evaluating MRI changes concerning for tumor recurrence during routine surveillance. Methods: Using 11C-methionine PET during follow-up visits, we evaluated 27 lesions in 26 patients with new or worsening MRI abnormalities for whom tumor recurrence was of concern. We performed quantitative and qualitative assessments of both 11C-methionine PET and MRI data to predict the presence of tumor recurrence. Further, to assess for an association with overall survival (OS), we plotted the time from development of the imaging changes against survival. Results: Qualitative evaluation of 11C-methionine PET achieved 100% sensitivity, 60% specificity, and 93% accuracy to correctly predict the presence of tumors in 27 new or worsening MRI abnormalities. Qualitative MRI evaluation achieved sensitivity ranging from 86% to 95%, specificity ranging from 40% to 60%, and accuracy ranging from 85% to 89%. The interobserver agreement for 11C-methionine PET assessment was 100%, whereas the interobserver agreement was only 50% for MRI (P < 0.01). Quantitative MRI and 11C-methionine PET evaluation using receiver-operating characteristics demonstrated higher specificity (80%) than did qualitative evaluations (40%-60%). Postcontrast enhancement volume, metabolic tumor volume, tumor-to-brain ratio, and presence of tumor as determined by consensus MRI assessment were inversely associated with OS. Conclusion:11C-methionine PET has slightly higher sensitivity and accuracy for correctly predicting tumor recurrence, with excellent interobserver agreement, than does MRI. Quantitative 11C-methionine PET can also predict OS. These findings suggest that 11C-methionine PET can be useful for further evaluation of MRI changes during surveillance of previously treated PHGGs.

Positron Emission Tomography Detects In Vivo Expression of Disialoganglioside GD2 in Mouse Models of Primary and Metastatic Osteosarcoma.

The cell membrane glycolipid GD2 is expressed by multiple solid tumors, including 88% of osteosarcomas and 98% of neuroblastomas. However, osteosarcomas are highly heterogeneous, with many tumors exhibiting GD2 expression on <50% of the individual cells, while some tumors are essentially GD2-negative. Anti-GD2 immunotherapy is the current standard of care for high-risk neuroblastoma, but its application to recurrent osteosarcomas, for which no effective therapies exist, has been extremely limited. This is, in part, because the standard assays to measure GD2 expression in these heterogeneous tumors are not quantitative and are subject to tissue availability and sampling bias. To address these limitations, we evaluated a novel, sensitive radiotracer [64Cu]Cu-Bn-NOTA-hu14.18K322A to detect GD2 expression in osteosarcomas (six patient-derived xenografts and one cell line) in vivo using positron emission tomography (PET). Tumor uptake of the radiolabeled, humanized anti-GD2 antibody [64Cu]Cu-Bn-NOTA-hu14.18K322A was 7-fold higher in modestly GD2-expressing osteosarcomas (32% GD2-positive cells) than in a GD2-negative tumor (9.8% vs. 1.3% of the injected dose per cc, respectively). This radiotracer also identified lesions as small as 29 mm3 in a 34% GD2-positive model of metastatic osteosarcoma of the lung. Radiolabeled antibody accumulation in patient-derived xenografts correlated with GD2 expression as measured by flow cytometry (Pearson r = 0.88, P = 0.01), distinguishing moderately GD2-expressing osteosarcomas (32%-69% GD2-positive cells) from high GD2 expressors (>99%, P < 0.05). These results support the utility of GD2 imaging with PET to measure GD2 expression in osteosarcoma and thus maximize the clinical impact of anti-GD2 immunotherapy. SIGNIFICANCE: In situ assessment of all GD2-positive osteosarcoma sites with a novel PET radiotracer could significantly impact anti-GD2 immunotherapy patient selection and enable noninvasive probing of correlations between target expression and therapeutic response.

Evaluation of 11C-Methionine PET and Anatomic MRI Associations in Diffuse Intrinsic Pontine Glioma.

The role of metabolic imaging in the diagnosis, treatment, and response assessment of diffuse intrinsic pontine glioma (DIPG) is poorly defined. We investigated the uptake of 11C-methionine in pediatric patients with newly diagnosed DIPG and evaluated the associations of 11C-methionine PET metrics with conventional MRI indices and survival outcomes. Methods: Twenty-two patients with newly diagnosed DIPG were prospectively enrolled on an institutional review board-approved investigational study of 11C-methionine PET. All patients underwent baseline 11C-methionine PET/CT, and initial treatment-response scans after chemotherapy or radiation therapy were obtained for 17 patients. Typical and atypical DIPGs were assessed clinically and radiographically and defined by multidisciplinary consensus. Three-dimensional regions of interest, reviewed by consensus between a nuclear medicine physician and a radiation oncologist, were delineated after coregistration of PET and MR images. Associations of 11C-methionine uptake intensity and uniformity with survival, along with associations between 11C-methionine uptake and conventional MRI tumor indices over time, were evaluated. 11C-methionine PET voxel values within regions of interest were assessed as threshold values across proportions of the study population, and 11C-methionine uptake at baseline was assessed relative to MRI-defined tumor progression. Results:11C-methionine uptake above that of uninvolved brain tissue was observed in 18 of 22 baseline scans (82%) and 15 of 17 initial response scans (88%). 11C-methionine avidity within MRI-defined tumor was limited in extent, with 11 of 18 positive baseline 11C-methionine PET scans (61%) showing less than 25% 11C-methionine-avid tumor. The increase in total tumor volume with 11C-methionine PET was relatively limited (17.2%; interquartile range, 6.53%-38.90%), as was the extent of 11C-methionine uptake beyond the MRI-defined tumor (2.2%; interquartile range, 0.55%-10.88%). Although baseline 11C-methionine PET intensity and uniformity metrics did not correlate with survival outcomes, initial 11C-methionine avidity overlapped with recurrent tumor in 100% of cases. A clinical diagnosis of atypical DIPG was associated with borderline significantly prolonged progression-free survival (P = 0.07), yet 11C-methionine PET indices at diagnosis did not differ significantly between atypical and typical DIPGs. Conclusion: Most newly diagnosed DIPGs are successfully visualized by 11C-methionine PET. Baseline 11C-methionine uptake delineates regions at increased risk for recurrence, yet intensity and uniformity metrics did not correlate with treatment outcomes in children with DIPG in this study.

Improved, one-pot synthesis of 6-[18 F]fluorodopamine and quality control testing for use in patients with neuroblastoma.

6-[18 F]Fluorodopamine ([18 F]F-DA) is taken into cells via the norepinephrine transporter (NET). Recent [18 F]F-DA positron emission tomography-computed tomography (PET-CT) imaging of adult neuroendocrine tumors shows a dramatic improvement in sensitivity over the standard-of-care, meta-iodobenzylguanidine (MIBG) single-photon emission computed tomography (SPECT)-CT. A new precursor (ALPdopamine™) allows no-carrier-added synthesis resulting in high-molar activity [18 F]F-DA. Automated synthesis of [18 F]F-DA was performed in a single reactor using a two-step procedure: 1) fluorination via thermolysis of a diaryliodonium salt precursor, followed by 2) acid hydrolysis. Phase transfer agents, Kryptofix 222 and two tetraalkylammonium salts, were investigated. Optimized synthesis of [18 F]F-DA was achieved in 56 to 60 minutes (26% end of synthesis [EOS], nondecay corrected). The product passed all Food and Drug Administration (FDA)-required quality control testing for human use. Accumulation of [18 F]F-DA in SK-N-BE(2)-C (high NET expression) cells was significantly higher than in SH-EP (minimal NET expression) cells (P < 0.0001). ALPdopamine provides an effective scaffold for the routine production of [18 F]F-DA for human use. Validation of uptake by neuroblastoma (NB) cell lines supports the use of [18 F]F-DA for imaging NB patients. A pediatric NB imaging trial using [18 F]F-DA PET has been approved (Investigational New Drug application (IND) no. 138638) based on the methods reported here. We expect [18 F]F-DA will be localized in NB tumors and that high-quality functional images will be obtained within minutes after injection.

Molecular Detection and Analysis of Exosomes Using Surface-Enhanced Raman Scattering Gold Nanorods and a Miniaturized Device.

Exosomes are a potential source of cancer biomarkers. Probing tumor-derived exosomes can offer a potential non-invasive way to diagnose cancer, assess cancer progression, and monitor treatment responses. Novel molecular methods would facilitate exosome analysis and accelerate basic and clinical exosome research. Methods: A standard gold-coated glass microscopy slide was used to develop a miniaturized affinity-based device to capture exosomes in a target-specific manner with the assistance of low-cost 3-D printing technology. Gold nanorods coated with QSY21 Raman reporters were used as the label agent to quantitatively detect the target proteins based on surface enhanced Raman scattering spectroscopy. The expressions of several surface protein markers on exosomes from conditioned culture media of breast cancer cells and from HER2-positive breast cancer patients were quantitatively measured. The data was statistically analyzed and compared with healthy controls. Results: A miniaturized 17 × 5 Au array device with 2-mm well size was fabricated to capture exosomes in a target-specific manner and detect the target proteins on exosomes with surface enhanced Raman scattering gold nanorods. This assay can specifically detect exosomes with a limit of detection of 2×106 exosomes/mL and analyze over 80 purified samples on a single device within 2 h. Using the assay, we have showed that exosomes derived from MDA-MB-231, MDA-MB-468, and SKBR3 breast cancer cells give distinct protein profiles compared to exosomes derived from MCF12A normal breast cells. We have also showed that exosomes in the plasma from HER2-positive breast cancer patients exhibit significantly (P ≤ 0.01) higher level of HER2 and EpCAM than those from healthy donors. Conclusion: We have developed a simple, inexpensive, highly efficient, and portable Raman exosome assay for detection and protein profiling of exosomes. Using the assay and model exosomes from breast cancer cells, we have showed that exosomes exhibit diagnostic surface protein markers, reflecting the protein profile of their donor cells. Through proof-of-concept studies, we have identified HER2 and EpCAM biomarkers on exosomes in plasma from HER2-positive breast cancer patients, suggesting the diagnostic potential of these markers for breast cancer diagnostics. This assay would accelerate exosome research and pave a way to the development of novel cancer liquid biopsy for cancer detection and monitoring.

18F-FDG Uptake During Early Adjuvant Chemotherapy Predicts Histologic Response in Pediatric and Young Adult Patients with Osteosarcoma.

The purpose of this study was to determine the relationship of 18F-FDG uptake in the primary tumor at diagnosis, during therapy, and after therapy with a histologic response and event-free survival in pediatric and young adult patients with osteosarcoma (OS). Methods: Serial (baseline and 5 and 10 wk after start of therapy) 18F-FDG PET/CT imaging was performed in patients with newly diagnosed OS treated uniformly in a therapeutic trial at a single institution. Whole-body images were obtained approximately 1 h after injection of 18F-FDG. Logistic regression was used to study the association of tumor uptake and changes in SUVmax between 0, 5, and 10 wk for both clinical endpoints. Results: Thirty-four patients (17 males; median age, 12.2 y; age range, 6.8-19.1 y) underwent PET imaging; 25 (74%) had localized disease. Primary tumor locations included the femur (n = 17; 50%), tibia (n = 9; 26%), and humerus (n = 5; 15%). Logistic regression showed that SUVmax at 5 wk (P = 0.034) and 10 wk (P = 0.022) and percentage change from baseline at 10 wk (P = 0.021) were highly predictive of a histologic response. Using SUVmax of 4.04 at week 5, SUVmax of 3.15 at week 10, and 60% decrease from baseline at week 10 as cutoff values, we determined that the respective sensitivities were 0.93, 0.93, and 0.79 and that the respective specificities were 0.53, 0.71, and 0.76. Conclusion: SUVmax on routine images at 5 or 10 wk and percentage change in SUVmax from baseline to week 10 were metabolic predictors of a histologic response in OS. These findings may be useful in the early identification of patients who are responding poorly to therapy and may benefit from a change in treatment.

Thermolysis and radiofluorination of diaryliodonium salts derived from anilines.

Aniline-derived diaryliodonium salts were synthesized and functionalized in good to excellent yields by judicious utilization of electron-withdrawing protecting groups. This simple approach opens another route to radiolabeling amino arenes in relatively complex molecules, such as flutemetamol.

11C-Methionine positron emission tomography delineates non-contrast enhancing tumor regions at high risk for recurrence in pediatric high-grade glioma.

We assessed the prognostic utility of 11C-Methionine positron emission tomography (MET-PET) in pediatric high-grade glioma (HGG). Thirty-one children had 62 MET-PET studies. Segmented tumor volumes from co-registered magnetic resonance studies were assessed for concordance with MET-PET uptake using Boolean operations. The tumor volume at diagnosis and treatment failure was assessed relative to MET-PET avid volume. The prognostic impact of MET-PET-delineated non-contrast enhancing tumor (NCET) was assessed. NCET was defined as the region of tumor defined by defined by FLAIR which did not enhance but showed MET-PET avidity. MET-PET concordance varied according to magnetic resonance sequence. MET-PET rarely added to the tumor volume in most cases. The volume of MET-PET with standardized uptake value >3.0 was differentially distributed at diagnosis, post treatment, and at recurrence. The initial MET-PET region overlapped with recurrent tumor in 90% of the cases. When the proportion of tumor which was NCET was >10%, an earlier time to progression (5.8 months; 95% CI, 1-8.2 vs. 10.5 months; 95% CI, 0.9-NR; p = 0.035) was noted. MET-PET delineates regions at increased risk for recurrence and may improve the definition of failure, prognostic assessment, and target definition for radiotherapy.

Comparison of 11C-Methionine and 18F-FDG PET/CT for Staging and Follow-up of Pediatric Lymphoma.

Methionine transport across plasma membranes occurs via the large amino acid transporter, which is overexpressed in malignant cells, leading to tracer accumulation within tumors. We investigated the uptake of 11C-methionine (11C-MET) in children and young adults with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) and compared the biodistribution of 11C-MET PET/CT with that of 18F-FDG PET/CT. Methods: Conducted under an investigational new drug authorization, we prospectively enrolled patients with newly diagnosed HL (n = 19) and NHL (n = 2) onto the Institutional Review Board-approved investigation of 11C-MET PET/CT. After a minimum 4-h fast, patients received 740 MBq/1.7 m2 (maximum, 740 MBq [20 mCi/1.7 m2; maximum, 20 mCi]) of 11C-methionine intravenously. PET/CT was performed 5 min after injection from the vertex to thighs at 3 min per bed position. In a separate session, patients received 5.5 MBq/kg (maximum, 485 MBq [0.15 mCi/kg; maximum, 12 mCi]) of 18F-FDG with imaging initiated approximately 1 h after radiopharmaceutical administration. All studies were reviewed by consensus of 2 senior imaging specialists. The presence of metabolic activity on baseline studies was compared among 17 nodal groups. Results: Eighteen patients (11 male; median age, 15.2 y; age range, 9.5-22.6 y) comprised the study cohort. All had paired 11C-MET PET/CT and 18F-FDG PET/CT studies at diagnosis. At baseline, 3 nodal groups demonstrating discordant metabolic activity by both 18F-FDG PET/CT and 11C-MET PET/CT were Waldeyer's ring, paraaortic region, and the liver. All others were found to have concordant metabolic activity. Normal intense 11C-MET uptake in the pancreas and liver reduced sensitivity for disease detection in these regions. At follow-up, 14 of 15 study pairs had concordant results. Conclusion:11C-MET uptake is elevated in most regions involved with lymphoma at diagnosis and follow-up. Its utility in the abdomen is limited by uptake in normal structures.

Enhancing both CT imaging and natural killer cell-mediated cancer cell killing by a GD2-targeting nanoconstruct.

Although nanomaterials have been widely investigated for drug delivery, imaging and immunotherapy, their potential roles in triggering innate cellular immune responses while simultaneously serving as imaging enhancer remain unexplored. In this work, gold nanoparticles (GNPs) conjugated to the tumor-targeting anti-GD2 antibody hu14.18K322A, namely HGNPs, were designed and synthesized to specifically enhance computerized tomography (CT) imaging contrast and to stimulate the attack of neuroblastoma and melanoma cells by natural killer (NK) cells. The HGNPs specifically targeted GD2-positive neuroblastoma (NB1691) and melanoma (M21) cells, with an enhancement of CT contrast images of the HGNP-labeled cell pellets by 5.27- and 7.66-fold, respectively, compared to images of unlabeled cell pellets. The HGNPs also triggered NK-mediated antibody-dependent cellular cytotoxicity (ADCC) in NB1691 and M21 cells with a two-fold higher efficacy compared to that elicited by hu14.18K322A alone, with no adverse effect to GD2-negative PC-3 cells. These results suggest that HGNPs are promising theranostic agents for neuroblastoma and melanoma cancers.

Efficient automated syntheses of high specific activity 6-[18F]fluorodopamine using a diaryliodonium salt precursor.

6-[(18)F]Fluorodopamine (6-[(18) F]F-DA) is a positron emission tomography radiopharmaceutical used to image sympathetic cardiac innervation and neuroendocrine tumors. Imaging with 6-[(18)F]F-DA is constrained, in part, by the bioactivity and neurotoxicity of 6-[(19)F]fluorodopamine. Furthermore, routine access to this radiotracer is limited by the inherent difficulty of incorporation of [(18)F]fluoride into electron-rich aromatic substrates. We describe the simple and direct preparation of high specific activity (SA) 6-[(18)F]F-DA from no-carrier-added (n.c.a.) [(18)F]fluoride. Incorporation of n.c.a. [(18)F]fluoride into a diaryliodonium salt precursor was achieved in 50-75% radiochemical yields (decay corrected to end of bombardment). Synthesis of 6-[(18)F]F-DA on the IBA Synthera® and GE TRACERlab FX-FN automated platforms gave 6-[(18)F]F-DA in >99% chemical and radiochemical purities after HPLC purification. The final non-corrected yields of 6-[(18)F]F-DA were 25 ± 4% (n = 4, 65 min) and 31 ± 6% (n = 3, 75 min) using the Synthera and TRACERlab modules, respectively. Efficient access to high SA 6-[(18)F]F-DA from a diaryliodonium salt precursor and n.c.a. [(18)F]fluoride is provided by a relatively subtle change in reaction conditions - replacement of a polar aprotic solvent (acetonitrile) with a relatively nonpolar solvent (toluene) during the critical radiofluorination reaction. Implementation of this process on common radiochemistry platforms should make 6-[(18)F]F-DA readily available to the wider imaging community.

A practical, automated synthesis of meta-[(18)F]fluorobenzylguanidine for clinical use.

Many neuroendocrine tumors, such as neuroblastoma (NB), arise from neural crest cells of the sympathetic nervous system. This nerve-like phenotype has been exploited for functional imaging using radioactive probes originally designed for neuronal and adrenal medullary applications. NB imaging with meta-[(123)I]iodobenzylguanidine ([(123)I]MIBG) is limited by the emissions of (123)I, which lead to poor image resolution and challenges in quantification of its accumulation in tumors. meta-[(18)F]Fluorobenzylguanidine ([(18)F]MFBG) is a promising alternative to [(123)I]MIBG that could change the standard of practice for imaging neuroendocrine tumors, but interest in this PET radiotracer has suffered due to its complex and inefficient radiosynthesis. Here we report a two-step, automated method for the routine production of [(18)F]MFBG by thermolysis of a diaryliodonium fluoride and subsequent acid deprotection. The synthesis was adapted for use on a commercially available synthesizer for routine production. Full characterization of [(18)F]MFBG produced by this route demonstrated the tracer's suitability for human use. [(18)F]MFBG was prepared in almost 3-fold higher yield than previously reported (31% corrected to end of bombardment, n = 9) in a synthesis time of 56 min with >99.9% radiochemical purity. Other than pH adjustment and dilution of the final product, no reformulation was necessary after purification. This method permits the automated production of multidose batches of clinical grade [(18)F]MFBG. Moreover, if ongoing clinical imaging trials of [(18)F]MFBG are successful, this methodology is suitable for rapid commercialization and can be easily adapted for use on most commercial automated radiosynthesis equipment.

FDG PET/CT imaging of desmoplastic small round cell tumor: findings at staging, during treatment and at follow-up.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a very uncommon soft-tissue tumor of children and young adults. It has an aggressive course with generally poor survival. In general the assessment of tumor burden and response has relied upon CT or MRI. However these tumors are often metabolically active and can be evaluated using FDG PET/CT imaging. OBJECTIVE: The purpose of this study was to determine the metabolic activity of desmoplastic small round cell tumors using FDG PET/CT imaging and the potential utility of FDG PET/CT in this disease. MATERIALS AND METHODS: Eight patients (seven male, one female; ages 2-20 years, median 11 years) with confirmed DSRCT underwent 82 positron emission tomography/computed tomography (PET/CT) scans. PET/CT was used for initial staging (seven patients, eight scans), monitoring response to therapy (eight patients, 37 scans) and for surveillance of DSRCT recurrence (six patients, 37 scans). RESULTS: Each scan performed at diagnosis showed abnormally elevated uptake in the primary tumor. Five patients had abdominal pelvic involvement, and two of those also had thoracic disease. Six patients whose scans showed no abnormal sites of uptake at the end of therapy have had progression-free survivals of 2-10 years. One patient whose scan continued to show uptake during treatment died of disease 1.3 years from diagnosis. Another patient with persistent uptake remained in treatment 3 years after initial diagnosis. One surveillance scan identified recurrent disease. CONCLUSION: FDG PET/CT identified elevated metabolic activity in each patient studied. Despite our small sample size, FDG PET/CT scans appear useful for the management of patients with DSCRT. Patients whose studies become negative during or following treatment may have a prolonged remission.

Targeting the DNA repair pathway in Ewing sarcoma.

Ewing sarcoma (EWS) is a tumor of the bone and soft tissue that primarily affects adolescents and young adults. With current therapies, 70% of patients with localized disease survive, but patients with metastatic or recurrent disease have a poor outcome. We found that EWS cell lines are defective in DNA break repair and are sensitive to PARP inhibitors (PARPis). PARPi-induced cytotoxicity in EWS cells was 10- to 1,000-fold higher after administration of the DNA-damaging agents irinotecan or temozolomide. We developed an orthotopic EWS mouse model and performed pharmacokinetic and pharmacodynamic studies using three different PARPis that are in clinical development for pediatric cancer. Irinotecan administered on a low-dose, protracted schedule previously optimized for pediatric patients was an effective DNA-damaging agent when combined with PARPis; it was also better tolerated than combinations with temozolomide. Combining PARPis with irinotecan and temozolomide gave complete and durable responses in more than 80% of the mice.

Evaluation of the biodistribution of 11C-methionine in children and young adults.

UNLABELLED: The purpose of this study was to evaluate the biodistribution of (11)C-labeled methionine in non-tumor-involved organs in pediatric patients studied for malignant diseases. METHODS: Ninety-three children and young adults with known or suspected malignancies underwent (11)C-methionine PET and CT scans. Imaging began 5-15 min after injection of 740 MBq (20 mCi) per 1.7 m(2) of body surface area. Images were acquired from the top of the head through the mid thighs. Standardized uptake values were determined using regions of interest drawn on the CT image and transferred to the corresponding transverse PET slice. RESULTS: The highest concentrations of (11)C-methionine were found in the pancreas and liver. Less intense uptake was seen in other regions, such as the salivary glands, tonsils, and bone marrow. There was little uptake in the lungs, fat (including brown adipose tissue), and muscle. Uptake in bone marrow, parotid glands, and tonsils was slightly but statistically significantly higher in men than women. Testicular, bone marrow, and left ventricular uptake increased with age. There was little variability statistically between comparisons of uptake change and groupings of age, race, sex, and patients studied at the time of diagnosis versus previously treated patients. CONCLUSION: High uptake of (11)C-methionine is reliably found in the pancreas and liver, consistent with the anabolic functions of these organs. Low uptake in the brain, neck, chest, pelvis, and extremities will facilitate tumor localization in those areas. However, intense uptake in the upper abdomen may limit the diagnostic utility of (11)C-methionine in that area.

Evaluation of children with craniopharyngioma using carbon-11 methionine PET prior to proton therapy.

BACKGROUND: Fluorine-18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET) is limited in its evaluation of brain tumors due to the high basal activity of the cerebral cortex and white matter. Carbon-11 methionine ((11)C MET) has little uptake under normal conditions. We prospectively investigated the uptake of (18)F FDG and (11)C MET PET in patients with craniopharyngioma prior to proton therapy. METHODS: Ten patients newly diagnosed with craniopharyngioma underwent PET imaging using (18)F FDG and (11)C MET. PET and MRI studies were registered to help identify tumor volume. Measurements of maximum standardized uptake value (SUV(max)) were taken of the tumor and compared with noninvolved left frontal background white matter using a paired t-test. Uptake was graded using a 4-point scale. RESULTS: Median patient age was 9 years (range 5-19). Seven patients were diagnosed by pathology, 1 by cyst fluid aspiration, and 2 by neuroimaging. Median FDG SUV(max) for tumor and background were 2.65 and 3.2, respectively. Median MET SUV(max) for tumor and background were 2.2 and 1, respectively. There was a significant difference between MET tumor SUV(max) and MET background SUV(max) (P = .0001). The difference between FDG tumor SUV(max) and FDG background SUV(max) was not significant (P = .3672). CONCLUSION: (11)C MET PET uptake is significantly greater within the tumor compared with noninvolved background white matter, making it more useful than FDG PET in identifying active tumor in patients with craniopharyngioma. Future work will focus on using (11)C MET PET to discriminate between active and inactive tumor after irradiation.