Analysis of capecitabine metabolites in conjunction with digital autoradiography in a murine model of pancreatic cancer suggests extensive drug penetration through the tumor.

Previously published digital autoradiography of 3 H-labeled capecitabine reveals a near-uniform distribution of activity throughout a murine pancreatic model. This is in contrast both to 14 C-labeled gemcitabine, and established expectations, as the dense stroma of pancreatic cancer is understood to inhibit drug penetration. Capecitabine is a pro-drug for 5 FU. The positioning of the radiolabel on capecitabine leaves open the possibility that much of the autoradiographic signal is generated by nontoxic compounds. Studies were performed on tumors derived via organoid culture from a murine KPC tumor. As before, we performed autoradiography comparing 3 H capecitabine to the gemcitabine analog 18 F-FAC. The metabolism of capecitabine in this model was studied through LC-MS of tumor tissue. The autoradiographs confirmed that the 3 H label from capecitabine was much more uniformly distributed through the tumor than the 18 F from the gemcitabine analog. LC-MS revealed that approximately 75% of the molar mass of capecitabine had been converted into 5 FU or pre-5 FU compounds. The remainder had been converted into nontoxic species. Therapeutically relevant capecitabine metabolites achieve a relatively even distribution in this pancreatic cancer model, in contrast to the gemcitabine analog 18 F-FAC. In a human xenograft model, (BxPC3), the 3 H label from capecitabine was also uniformly spread across the tumor autoradiographs. However, at 2 h post-administration the metabolism of capecitabine had proceeded further and the bulk of the agent was in the form of nontoxic species.

Optimizing reconstruction parameters for quantitative 124I-PET in the presence of therapeutic doses of 131I.

BACKGROUND: The goal of this work was to determine the quantitative accuracy and optimal reconstruction parameters for 124I-PET imaging in the presence of therapeutic levels of 131I. In this effort, images were acquired on a GE D710 PET/CT scanner using a NEMA IEC phantom with spheres containing 124I and increasing amounts of 131I activity in the background. At each activity level, two scans were acquired, one with the phantom centered in the field of view (FOV) and one 11.2 cm off-center. Reconstructions used an ordered subset expectation maximization algorithm with up to 100 iterations of 16 subsets, with and without time-of-flight (TOF) information. Results were evaluated visually and by comparing the 124I activity relative to the scan performed in the absence of 131I. RESULTS: 131I within the FOV added to the randoms rate, to dead time, and to pile-up within the detectors. Using our standard clinical reconstruction parameters, the image quality and quantitative accuracy suffered at 131I activities above 1.4 GBq. Convergence rates slowed progressively in the presence of increasing amounts of 131I for both TOF and nonTOF reconstructions. TOF reconstructions converged more quickly than nonTOF but often towards erroneous concentrations. Iterating nonTOF reconstructions to convergence produced quantitatively accurate images except for the off-center phantom at the very highest level of background 131I tested. CONCLUSIONS: This study shows that quantitative PET is feasible in the presence of large amounts of 131I. The high randoms fractions resulted in slow reconstruction convergence and negatively impacted TOF corrections and/or the accuracy of TOF information. Therefore, increased iterations and nonTOF reconstructions are recommended.

Advanced Monte Carlo simulations of emission tomography imaging systems with GATE.

Built on top of the Geant4 toolkit, GATE is collaboratively developed for more than 15 years to design Monte Carlo simulations of nuclear-based imaging systems. It is, in particular, used by researchers and industrials to design, optimize, understand and create innovative emission tomography systems. In this paper, we reviewed the recent developments that have been proposed to simulate modern detectors and provide a comprehensive report on imaging systems that have been simulated and evaluated in GATE. Additionally, some methodological developments that are not specific for imaging but that can improve detector modeling and provide computation time gains, such as Variance Reduction Techniques and Artificial Intelligence integration, are described and discussed.

Comparing the intra-tumoral distribution of Gemcitabine, 5-Fluorouracil, and Capecitabine in a murine model of pancreatic ductal adenocarcinoma.

PURPOSE: To develop a technique to compare the intra-tumoral distribution of the drug gemcitabine, its surrogate [18F]-fluoroarabinocytosine ([18F]-FAC) and related chemotherapeutics 5-FU and capecitabine in a pre-clinical model of pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN: Using a KPC-organoid derived model of PDAC, we obtained autoradiographic images of the tumor distribution of, [14C]-gemcitabine, [14C]-5-FU, [3H]-capecitabine. These were compared indirectly by co-administering [18F]-FAC, a close analog of gemcitabine with a proven equivalent intra-tumor distribution. The short half-life of 18F allows for clean separation of 3H/14C labeled drugs in specimens by dual isotope digital autoradiography. Autoradiographic images of [14C]-gemcitabine, [3H]-capecitabine and [14C]-5-FU were each correlated to [18F]-FAC on a pixel-by-pixel basis. The tumor drug penetration was compared using cumulative histograms. RESULTS: Gemcitabine distribution correlated strongly with FAC as expected. 5-FU also gave a similar microdistribution to that of FAC, whereas no correlation was found between capecitabine or its metabolic products and FAC distribution. Accumulation of Gemcitabine and 5-FU was lower in hypoxic regions of the tumor, whereas no such correlation was observed for capecitabine and its metabolites. CONCLUSIONS: Gemcitabine and 5-FU target the same regions of the tumor, leaving hypoxic cells untreated. Capecitabine metabolites penetrate further into the tumor but it is yet to be determined whether these metabolites are the active form of the drug.

18F-fluoromisonidazole predicts evofosfamide uptake in pancreatic tumor model.

BACKGROUND: Quantitative imaging can facilitate patient stratification in clinical trials. The hypoxia-activated prodrug evofosfamide recently failed a phase III trial in pancreatic cancer. However, the study did not attempt to select for patients with hypoxic tumors. We tested the ability of 18F-fluoromisonidazole to predict evofosfamide uptake in an orthotopic xenograft model (BxPC3). METHODS: Two forms of evofosfamide were used: (1) labeled on the active moiety (3H) and (2) on the hypoxia targeting nitroimidazole group (14C). Tumor uptake of evofosfamide and 18F-fluoromisonidazole was counted ex vivo. Autoradiography of 14C and 18F coupled with pimonidazole immunohistochemistry revealed the spatial distributions of prodrug, radiotracer, and hypoxia. RESULTS: There was significant individual variation in 18F-fluoromisonidazole uptake, and a significant correlation between normalized 18F-fluoromisonidazole and both 3H-labeled and 14C-labeled evofosfamide. 18F-fluoromisonidazole and 14C-evofosfamide both localized in hypoxic regions as identified by pimonidazole. CONCLUSION: 18F-fluoromisonidazole predicts evofosfamide uptake in a preclinical pancreatic tumor model.

Technical Note: Scintillation well counters and particle counting digital autoradiography devices can be used to detect activities associated with genomic profiling adequacy of biopsy specimens obtained after a low activity 18 F-FDG injection.

PURPOSE: Genomic profiling of biopsied tissue is the basis for precision cancer therapy. However, biopsied materials may not contain sufficient amounts of tumor deoxyribonucleonic acid needed for the analysis. We propose a method to determine the adequacy of specimens for performing genomic profiling by quantifying their metabolic activity. METHODS: We estimated the average density of tumor cells in biopsy specimens needed to successfully perform genomic analysis following the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) protocol from the minimum amount of deoxyribonucleonic acid needed and the volume of tissue typically used for analysis. The average 18 F-FDG uptake per cell was assessed by incubating HT-29 adenocarcinoma tumor cells in 18 F-FDG containing solution and then measuring their activity with a scintillation well counter. Consequently, we evaluated the response of two devices around the minimum expected activities which would indicate genomic profiling adequacy of biopsy specimens obtained under 18 F-FDG PET/CT guidance. Surrogate samples obtained using 18G core needle biopsies of gels containing either 18 F-FDG-loaded cells in the expected concentrations or the corresponding activity were measured using autoradiography and a scintillation well counter. Autoradiography was performed using a CCD-based device with real-time image display as well as with digital autoradiography imaging plates following a 30-min off-line protocol for specimen activity determination against previously established calibration. RESULTS: Cell incubation experiments and estimates obtained from quantitative autoradiography of biopsy specimens (QABS) indicate that specimens acquired under 18 F-FDG PET/CT guidance that contained the minimum amount of cells needed for genomic profiling would have an average activity concentration in the range of about 3 to about 9 kBq/mL. When exposed to specimens with similar activity concentration, both a CCD-based autoradiography device and a scintillation well counter produced signals with sufficient signal-to-background ratio for specimen genomic adequacy identification in less than 10 min, which is short enough to allow procedure guidance. CONCLUSION: Scintillation well counter measurements and CCD-based autoradiography have adequate sensitivity to detect the tumor burden needed for genomic profiling during 18 F-FDG PET/CT-guided 18G core needle biopsies of liver adenocarcinoma metastases.

Evaluation of the tumor registration error in biopsy procedures performed under real-time PET/CT guidance.

PURPOSE: The purpose of this study is to quantify tumor displacement during real-time PET/CT guided biopsy and to investigate correlations between tumor displacement and false-negative results. METHODS: 19 patients who underwent real-time 18 F-FDG PET-guided biopsy and were found positive for malignancy were included in this study under IRB approval. PET/CT images were acquired for all patients within minutes prior to biopsy to visualize the FDG-avid region and plan the needle insertion. The biopsy needle was inserted and a post-insertion CT scan was acquired. The two CT scans acquired before and after needle insertion were registered using a deformable image registration (DIR) algorithm. The DIR deformation vector field (DVF) was used to calculate the mean displacement between the pre-insertion and post-insertion CT scans for a region around the tip of the biopsy needle. For 12 patients one biopsy core from each was tracked during histopathological testing to investigate correlations of the mean displacement between the two CT scans and false-negative or true-positive biopsy results. For 11 patients, two PET scans were acquired; one at the beginning of the procedure, pre-needle insertion, and an additional one with the needle in place. The pre-insertion PET scan was corrected for intraprocedural motion by applying the DVF. The corrected PET was compared with the post-needle insertion PET to validate the correction method. RESULTS: The mean displacement of tissue around the needle between the pre-biopsy CT and the postneedle insertion CT was 5.1 mm (min = 1.1 mm, max = 10.9 mm and SD = 3.0 mm). For mean displacements larger than 7.2 mm, the biopsy cores gave false-negative results. Correcting pre-biopsy PET using the DVF improved the PET/CT registration in 8 of 11 cases. CONCLUSIONS: The DVF obtained from DIR of the CT scans can be used for evaluation and correction of the error in needle placement with respect to the FDG-avid area. Misregistration between the pre-biopsy PET and the CT acquired with the needle in place was shown to correlate with false negative biopsy results.

Ga-68 DOTATOC PET/CT-Guided Biopsy and Cryoablation with Autoradiography of Biopsy Specimen for Treatment of Tumor-Induced Osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by small benign tumors of mesenchymal origin also known as phosphaturic mesenchymal tumors mixed connective tissue variant. Excellent prognosis is expected with eradication of the culprit tumor. These small tumors are notoriously difficult to localize with conventional imaging studies; this often leads to an extensive work up and prolonged morbidity. We report a patient with clinical diagnosis of TIO whose culprit tumor was localized with Ga-68 DOTATOC PET/CT and MRI. Biopsy and cryoablation were performed under Ga-68 DOTATOC PET/CT guidance. Autoradiography of the biopsy specimen was performed and showed in situ correlation between Ga-68 DOTATOC uptake and histopathology with millimeter resolution.

Feasibility of in situ, high-resolution correlation of tracer uptake with histopathology by quantitative autoradiography of biopsy specimens obtained under 18F-FDG PET/CT guidance.

UNLABELLED: Core biopsies obtained using PET/CT guidance contain bound radiotracer and therefore provide information about tracer uptake in situ. Our goal was to develop a method for quantitative autoradiography of biopsy specimens (QABS), to use this method to correlate (18)F-FDG tracer uptake in situ with histopathology findings, and to briefly discuss its potential application. METHODS: Twenty-seven patients referred for a PET/CT-guided biopsy of (18)F-FDG-avid primary or metastatic lesions in different locations consented to participate in this institutional review board-approved study, which complied with the Health Insurance Portability and Accountability Act. Autoradiography of biopsy specimens obtained using 5 types of needles was performed immediately after extraction. The response of autoradiography imaging plates was calibrated using dummy specimens with known activity obtained using 2 core-biopsy needle sizes. The calibration curves were used to quantify the activity along biopsy specimens obtained with these 2 needles and to calculate the standardized uptake value, SUVARG. Autoradiography images were correlated with histopathologic findings and fused with PET/CT images demonstrating the position of the biopsy needle within the lesion. Logistic regression analysis was performed to search for an SUVARG threshold distinguishing benign from malignant tissue in liver biopsy specimens. Pearson correlation between SUVARG of the whole biopsy specimen and average SUVPET over the voxels intersected by the needle in the fused PET/CT image was calculated. RESULTS: Activity concentrations were obtained using autoradiography for 20 specimens extracted with 18- and 20-gauge needles. The probability of finding malignancy in a specimen is greater than 50% (95% confidence) if SUVARG is greater than 7.3. For core specimens with preserved shape and orientation and in the absence of motion, one can achieve autoradiography, CT, and PET image registration with spatial accuracy better than 2 mm. The correlation coefficient between the mean specimen SUVARG and SUVPET was 0.66. CONCLUSION: Performing QABS on core-biopsy specimens obtained using PET/CT guidance enables in situ correlation of (18)F-FDG tracer uptake and histopathology on a millimeter scale. QABS promises to provide useful information for guiding interventional radiology procedures and localized therapies and for in situ high-spatial-resolution validation of radiopharmaceutical uptake.