John Sunderland - Academia.edu (original) (raw)
Papers by John Sunderland
Tomography
For multicenter clinical studies, characterizing the robustness of image-derived radiomics featur... more For multicenter clinical studies, characterizing the robustness of image-derived radiomics features is essential. Features calculated on PET images have been shown to be very sensitive to image noise. The purpose of this work was to investigate the efficacy of a relatively simple harmonization strategy on feature robustness and agreement. A purpose-built texture pattern phantom was scanned on 10 different PET scanners in 7 institutions with various different image acquisition and reconstruction protocols. An image harmonization technique based on equalizing a contrast-to-noise ratio was employed to generate a “harmonized” alongside a “standard” dataset for a reproducibility study. In addition, a repeatability study was performed with images from a single PET scanner of variable image noise, varying the binning time of the reconstruction. Feature agreement was measured using the intraclass correlation coefficient (ICC). In the repeatability study, 81/93 features had a lower ICC on th...
Physics in Medicine & Biology, 2021
In recent years the use of beta-emitting radiopharmaceuticals for cancer therapy has expanded rap... more In recent years the use of beta-emitting radiopharmaceuticals for cancer therapy has expanded rapidly following development of therapeutics for neuroendocrine tumors, prostate cancer, and other oncologic malignancies. One emerging beta-emitting radioisotope of interest for therapy is 67Cu (t1/2: 2.6 d) due to its chemical equivalency with the widely-established positron-emitting isotope 64Cu (t1/2: 12.7 h). In this work we evaluate both the imaging and dosimetric characteristics of 67Cu, as well as producing the first report of SPECT/CT imaging using 67Cu. To this end, 67Cu was produced by photon-induced reactions on isotopically-enriched 68Zn at the Low-Energy Accelerator Facility (LEAF) of Argonne National Laboratory, followed by bulk separation of metallic 68Zn by sublimation and radiochemical purification by column chromatography. Gamma spectrometry was performed by efficiency-calibrated high-purity germanium (HPGe) analysis to verify absolute activity calibration and establish ...
The Journal of Nuclear Medicine, 2019
The Journal of Nuclear Medicine, 2018
Journal of Nuclear Medicine, 2021
Positron emission tomography and magnetic resonance imaging (PET/MRI) scanners cannot be qualifie... more Positron emission tomography and magnetic resonance imaging (PET/MRI) scanners cannot be qualified in the manner adopted for hybrid PET and computed tomography (CT) devices. The main hurdle with qualification in PET/MRI is that attenuation correction (AC) cannot be adequately measured in conventional PET phantoms due to the difficulty in converting the MRI images of the physical structures (e.g., plastic) into electron density maps. Over the last decade, a plethora of novel MR-based algorithms have been developed to more accurately derive the attenuation properties of the human head, including the skull. Although very promising, none of these techniques has yet emerged as an optimal and universally adopted strategy for AC in PET/MRI. In this work, we propose a path for PET/MRI qualification for multicenter brain imaging studies. Specifically, our solution is to separate the head attenuation correction from the other factors that affect PET data quantification and use a patient as a phantom to assess the former. The emission data collected on the integrated PET/MRI scanner to be qualified should be reconstructed using both MR-and CT-based AC methods and whole-brain qualitative and quantitative (both voxelwise and regional) analyses should be performed. The MR-based approach will be considered satisfactory if the PET quantification bias is within the acceptance criteria specified herein. We have implemented this approach successfully across two PET/MRI scanner manufacturers at two sites.
Journal of Nuclear Medicine, 2021
Background Molecular tumor volume (MTV) is a parameter of interest in advanced prostate cancer fo... more Background Molecular tumor volume (MTV) is a parameter of interest in advanced prostate cancer for assessing total disease burden on prostate-specific membrane antigen (PSMA) PET. Although software segmentation tools can delineate whole-body MTV, a necessary step towards meaningful monitoring of total tumor burden and treatment response through PET is establishing the repeatability of these metrics. The present study assesses the repeatability of total MTV and related metrics for 68 Ga-PSMA-HBED-CC in advanced prostate cancer. Methods Eighteen patients from a prior repeatability study who underwent two test-retest PSMA PET/CT scans within a mean interval of 5 days were reanalyzed. Within subject coefficient of variation and repeatability coefficients (RC) were analyzed on a per lesion and per patient basis. For the per lesion analysis, individual lesions were segmented for analysis by a single reader. For per patient analysis, subgroups of up to 10 lesions (single reader) and the total tumor volume per patient were segmented (independently by two readers). Image parameters were: MTV; maximum, peak, and mean standardized uptake value; total lesion PSMA and the related metric PSMA quotient (which is integrating lesion volume and PSMA avidity). Results In total, 192 segmentations were analyzed for the per lesion analysis and 1662 segmentations for the total tumor volume per patient analysis (combining the 2 readers and 2 scans). The RC of the MTV of single lesions was 77% (95%CI:63-96%). The RC improved after aggregation of up to 10 manually selected lesions into subgroups assessed per patient, 33% (95%CI:25-46%). The RC of 3 the semi-automatic MTVtotal was 35% (95%CI:25-50), the bland-altman bias was-6.70 [95%CI:-14.32-0.93]. Alternating readers between scans led to a comparable RC of 37% (95%CI:28-49%) for MTVtotal meaning that the metric is robust between scanning sessions and between readers. Conclusion 68 Ga-PSMA-HBED-CC PET-derived semi-automatic MTVtotal is repeatable and reader independent with a change of ±35% representing a true change in tumor volume. Volumetry of single manually selected lesions has considerably lower repeatability, and volumetry based on subgroups of these lesions, while showing acceptable repeatability, is less systematic. The semiautomatic analysis of MTVtotal employed in this study offers an efficient and robust means of assessing response to therapy.
Background Simultaneous PET/MRIs vary in their quantitative PET performance due to inherent diffe... more Background Simultaneous PET/MRIs vary in their quantitative PET performance due to inherent differences in the physical systems and differences in the image reconstruction implementation. This variability in quantitative accuracy confounds the ability to meaningfully combine and compare data across scanners. In this work, we define image reconstruction parameters that lead to comparable contrast recovery curves across simultaneous PET/MRI systems. Method: The NEMA NU-2 image quality phantom was imaged on the GE Signa and on the Siemens mMR PET/MRI scanners. The phantom was imaged at 9.8:1 contrast with standard spheres (diameter 10, 13, 17, 22, 28, 37 mm) and with custom spheres (diameter: 8.5, 11.5, 15, 25, 32.5, 44 mm) using a standardized methodology. Analysis was performed on a 30 minute data acquisition and on a subset of 5 minutes of data acquisition. Images were reconstructed with the manufacturer provided iterative image reconstruction algorithms with and without point sprea...
Medical Physics, 2020
Purpose: To develop bone material analogues that can be used in construction of phantoms for simu... more Purpose: To develop bone material analogues that can be used in construction of phantoms for simultaneous PET/MRI systems. Methods: Plaster was used as the basis for the bone material analogues tested in this study. It was mixed with varying concentrations of an iodinated CT contrast, a gadolinium-based MR contrast agent, and copper sulfate to modulate the attenuation properties and MRI properties (T1 and T2*). Attenuation was measured with CT and 68Ge transmission scans, and MRI properties were measured with quantitative ultrashort echo time pulse sequences. A proof-of-concept skull was created by plaster casting. Results: Undoped plaster has a 511 keV attenuation coefficient (~0.14 cm-1) similar to cortical bone (0.10-0.15 cm-1), but slightly longer T1 (~500 ms) and T2* (~1.2 ms) MR parameters compared to bone (T1 ~ 300 ms, T2* ~ 0.4 ms). Doping with the iodinated agent resulted in increased attenuation with minimal perturbation to the MR parameters. Doping with a gadolinium chelate greatly reduced T1 and T2*, resulting in extremely short T1 values when the target T2* values were reached, while the attenuation coefficient was unchanged. Doping with copper sulfate was more selective for T2* shortening and achieved comparable T1 and T2* values to bone (after 1 week of drying), while the attenuation coefficient was unchanged. Conclusions: Plaster doped with copper sulfate is a promising bone material analogue for a PET/MRI phantom, mimicking the MR properties (T1 and T2*) and 511 keV attenuation coefficient of human cortical bone.
The Laryngoscope, 2012
The early detection of persistent/recurrent disease of head and neck squamous cell carcinoma (HNS... more The early detection of persistent/recurrent disease of head and neck squamous cell carcinoma (HNSCC) after treatment can be challenging. The currently used radioisotope (18)F-fluorodeoxyglucose (FDG) is a nonspecific tracer for cancer cells as it detects all metabolically active cells including inflammation. (18)F-fluorodeoxythymidine (FLT) is a radioactive tracer for rapidly proliferating cells, and therefore is more specific for detecting cancer. Our aim was to compare FLT and FDG microPET (positron-emission tomography) to the gold standard in vivo bioluminescence imaging for serial assessment of neoplastic growth in a minimal residual disease in vivo model. Prospective outcomes research. In order to mimic the postsurgical environment of HNSCC patients FaDu cells transfected with a luciferase-expressing retrovirus were inoculated into the skin flap of Balb/c nu/nu mice. Three days later before tumors formed, mice were randomized into (18)F-FLT or (18) F-FDG groups, and microPET imaging was performed on days 3, 6, 10, 18, and 24 after tumor cell inoculation. (18)F-FLT detected tumors as early as day 3 even before tumors were palpable, whereas (18)F-FDG only detected palpable tumors. The average overall normalized radioactivity in the FLT group was significantly higher than the FDG group (P = .025). (18)F-FLT identified tumor cells before tumors were palpable and can potentially be used for early detection of persistence/recurrence of HNSCC. In addition, this radioisotope can be used to monitor adjuvant therapy with novel targeted therapeutics in preclinical models of persistent disease.
The Journal of Thoracic and Cardiovascular Surgery, 1996
We compared the abilities of positron emission tomography and computed tomography to detect N2 or... more We compared the abilities of positron emission tomography and computed tomography to detect N2 or N3 lymph node metastases (N2 or N3) in patients with lung cancer. Positron emission tomography detects increased rates of glucose uptake, characteristic of malignant cells. Patients with peripheral tumors smaller than 2 cm and a normal mediastinum were ineligible. All patients underwent computed tomography, positron emission tomography, and surgical staging. The American Thoracic Society lymph node map was used. Computed and positron emission tomographic scans were read by separate radiologists blinded to surgical staging results. Lymph nodes were "positive" by computed tomography if larger than 1.0 cm in short-axis diameter. Standardized uptake values were recorded from areas on positron emission tomography corresponding to those from which biopsy specimens were taken; if greater than 4.2, they were called "positive." Seventy-five lymph node stations (2.8 per patient) were analyzed in 27 patients. Computed tomography incorrectly staged the mediastinum as positive for metastases in three patients and as negative for metastases in three patients. Sensitivity and specificity of computed tomographic scans were 67% and 83%, respectively. Positron emission tomography correctly staged the mediastinum in all 27 patients. When analyzed by individual node station, there were four false positive and four false negative results by computed tomography (sensitivity = 60%, specificity = 93%, positive predictive value = 60%). Positron emission tomography mislabeled one node station as positive (100% sensitive, 98% specific, positive predictive value 91%). The differences were significant when the data were analyzed both for individual lymph node stations (p = 0.039) and for patients (p = 0.031) (McNemar test). Positron emission tomography and computed tomography are more accurate than computed tomography alone in detecting mediastinal lymph node metastases from non-small-cell lung cancer.
The Journal of Pain, 2007
IEEE Transactions on Nuclear Science, 2011
In human emission tomography, an additional transmission scan (x-ray CT or external gamma-source)... more In human emission tomography, an additional transmission scan (x-ray CT or external gamma-source) is often required to obtain accurate attenuation maps for attenuation correction (AC) and scatter correction (SC). These transmis- sion-based correction methods have been translated to small animal imaging although the impact of photon interactions on the mouse/rat-reconstructed images is substantially less than that in human imaging. Considering
Genes, Brain and Behavior, 2013
ADAR2 transgenic mice misexpressing the RNA editing enzyme ADAR2 (Adenosine Deaminase that act on... more ADAR2 transgenic mice misexpressing the RNA editing enzyme ADAR2 (Adenosine Deaminase that act on RNA) show characteristics of overeating and experience adult onset obesity. Behavioral patterns and brain changes related to a possible addictive overeating in these transgenic mice were explored as transgenic mice display chronic hyperphagia. ADAR2 transgenic mice were assessed in their food preference and motivation to overeat in a competing reward environment with ad lib access to a running wheel and food. Metabolic activity of brain and peripheral tissue were assessed with [ 18 F] fluorodeoxyglucose positron emission tomography (FDG-PET) and RNA expression of feeding related genes, ADAR2, dopamine and opiate receptors from the hypothalamus and striatum were examined. The results indicate that ADAR2 transgenic mice exhibit, (1) a food preference for diets with higher fat content, (2) significantly increased food intake that is non-distractible in a competing reward environment, (3) significantly increased mRNA expressions of ADAR2, serotonin 2C receptor (5HT 2C R), D1, D2, and mu opioid receptors and no change in CRH mRNAs and significantly reduced ADAR2 protein expression in the hypothalamus, (4) significantly increased D1 receptor and altered bioamines with no change in ADAR2, mu opioid and D2 receptor mRNA expression in the striatum, and (5) significantly greater glucose metabolism in the hypothalamus, brain stem, right hippocampus, left and right mid brain regions and suprascapular peripheral tissue than controls. These results suggest that highly motivated and goal-oriented overeating behaviors of ADAR2 transgenic mice are associated with altered feeding, reward-related mRNAs, and hyperactive brain mesolimbic region.
Journal of Nuclear Medicine, 2020
recently completed a 4-y expedition into the uncharted waters of the Food and Drug Administration... more recently completed a 4-y expedition into the uncharted waters of the Food and Drug Administration (FDA) newdrug application (NDA) process that ultimately resulted in approval of 68 Ga-DOTATOC in August 2019. The journey was enlightening, revealing a highly structured, arcane, but rigorous regulatory approval process. The FDA proved to be an efficient, reasonable, and communicative regulatory body that achieved balance between support of the initiative and its mission-bound, process-bound duty to ensure that the application met the expected safety and efficacy standards of the agency. With several clinically valuable PET radiopharmaceuticals without intellectual property residing in regulatory limbo, without industry champions to bring them to marketing approval, there may be justification for a more concerted effort from the molecular imaging community into generating better understanding, support, and perhaps even infrastructure for the academic NDA. As a first step, this article briefly describes the start-to-finish story for 68 Ga-DOTATOC, including a description of the clinical trials, a broad overview of the structured content of the NDA document, and the distilled experiences associated with the 68 Ga-DOTATOC NDA process. It is anticipated that with sustained free sharing of information relating to the FDA drug registration process, it will prove less daunting and more efficient in future academically sponsored NDA filings for PET imaging agents.
The AAPS journal, Jan 7, 2017
To evaluate the role of nucleoside transporters in the nose-to-brain uptake of [F]fluorothymidine... more To evaluate the role of nucleoside transporters in the nose-to-brain uptake of [F]fluorothymidine (FLT), an equilibrative nucleoside transporter (ENT1,2) and concentrative nucleoside transporter (CNT1-3) substrate, using PET to measure local tissue concentrations. Anesthetized Sprague-Dawley rats were administered FLT by intranasal (IN) instillation or tail-vein injection (IV). NBMPR (nitrobenzylmercaptopurine riboside), an ENT1 inhibitor, was administered either IN or intraperitoneally (IP). Dynamic PET imaging was performed for up to 40 min. A CT was obtained for anatomical co-registration and attenuation correction. Time-activity curves (TACs) were generated for the olfactory bulb (OB) and remaining brain, and the area-under-the-curve (AUC) for each TAC was calculated to determine the total tissue exposure of FLT. FLT concentrations were higher in the OB than in the rest of the brain following IN administration. IP administration of NBMPR resulted in increased OB and brain FLT ex...
Journal of Instrumentation, 2010
The borosilica, a very common PMT window and envelope material, contains 5% Boron (1% 10 B). The ... more The borosilica, a very common PMT window and envelope material, contains 5% Boron (1% 10 B). The high cross section for 10 B capturing thermal neutrons (3980 barn), is a concern for LHC experiments using borosilica window PMTs. This study investigates the rate and the size of the signals generated by thermal neutron boron interaction in borosilica window PMTs; Hamamatsu R7525-HA and R7600U-200-M4. Although virtually all of the thermal neutrons incident on the borosilicate glass are absorbed, probability of generating a PMT signal was measured to be 3 × 10 −4 and 3 × 10 −6 for R7525-HA and R7600U-200-M4 PMTs, respectively. For these signals the average pulse size was found to be between 20-30 photoelectrons. We also discuss that four anode PMTs allow the elimination of these events with an offline algorithm.
PLoS ONE, 2010
Background: Complex but common maternal diseases such as diabetes and obesity contribute to adver... more Background: Complex but common maternal diseases such as diabetes and obesity contribute to adverse fetal outcomes. Understanding of the mechanisms involved is hampered by difficulty in isolating individual elements of complex maternal states in vivo. We approached this problem in the context of maternal diabetes and sought an approach to expose the developing fetus in vivo to isolated hyperglycemia in the pregnant rat. Methodology and Principal Findings: We hypothesized that glucose infused into the arterial supply of one uterine horn would more highly expose fetuses in the ipsilateral versus contralateral uterine horn. To test this, the glucose tracer [ 18 F]fluorodeoxyglucose (FDG) was infused via the left uterine artery. Regional glucose uptake into maternal tissues and fetuses was quantified using positron emission tomography (PET). Upon infusion, FDG accumulation began in the left-sided placentae, subsequently spreading to the fetuses. Over two hours after completion of the infusion, FDG accumulation was significantly greater in left compared to right uterine horn fetuses, favoring the left by 1.960.1 and 2.860.3 fold under fasted and hyperinsulinemic conditions (p,10 211 n = 32-35 and p,10 212 n = 27-45) respectively. By contrast, centrally administered [ 3 H]-2-deoxyglucose accumulated equally between the fetuses of the two uterine horns. Induction of significant hyperglycemia (10 3 mg/dL) localized to the left uterine artery was sustained for at least 48 hours while maternal euglycemia was maintained. Conclusions and Significance: This approach exposes selected fetuses to localized hyperglycemia in vivo, minimizing exposure of the mother and thus secondary effects. Additionally, a set of less exposed internal control fetuses are maintained for comparison, allowing direct study of the in vivo fetal effects of isolated hyperglycemia. Broadly, this approach can be extended to study a variety of maternal-sided perturbations suspected to directly affect fetal health.
Tomography
For multicenter clinical studies, characterizing the robustness of image-derived radiomics featur... more For multicenter clinical studies, characterizing the robustness of image-derived radiomics features is essential. Features calculated on PET images have been shown to be very sensitive to image noise. The purpose of this work was to investigate the efficacy of a relatively simple harmonization strategy on feature robustness and agreement. A purpose-built texture pattern phantom was scanned on 10 different PET scanners in 7 institutions with various different image acquisition and reconstruction protocols. An image harmonization technique based on equalizing a contrast-to-noise ratio was employed to generate a “harmonized” alongside a “standard” dataset for a reproducibility study. In addition, a repeatability study was performed with images from a single PET scanner of variable image noise, varying the binning time of the reconstruction. Feature agreement was measured using the intraclass correlation coefficient (ICC). In the repeatability study, 81/93 features had a lower ICC on th...
Physics in Medicine & Biology, 2021
In recent years the use of beta-emitting radiopharmaceuticals for cancer therapy has expanded rap... more In recent years the use of beta-emitting radiopharmaceuticals for cancer therapy has expanded rapidly following development of therapeutics for neuroendocrine tumors, prostate cancer, and other oncologic malignancies. One emerging beta-emitting radioisotope of interest for therapy is 67Cu (t1/2: 2.6 d) due to its chemical equivalency with the widely-established positron-emitting isotope 64Cu (t1/2: 12.7 h). In this work we evaluate both the imaging and dosimetric characteristics of 67Cu, as well as producing the first report of SPECT/CT imaging using 67Cu. To this end, 67Cu was produced by photon-induced reactions on isotopically-enriched 68Zn at the Low-Energy Accelerator Facility (LEAF) of Argonne National Laboratory, followed by bulk separation of metallic 68Zn by sublimation and radiochemical purification by column chromatography. Gamma spectrometry was performed by efficiency-calibrated high-purity germanium (HPGe) analysis to verify absolute activity calibration and establish ...
The Journal of Nuclear Medicine, 2019
The Journal of Nuclear Medicine, 2018
Journal of Nuclear Medicine, 2021
Positron emission tomography and magnetic resonance imaging (PET/MRI) scanners cannot be qualifie... more Positron emission tomography and magnetic resonance imaging (PET/MRI) scanners cannot be qualified in the manner adopted for hybrid PET and computed tomography (CT) devices. The main hurdle with qualification in PET/MRI is that attenuation correction (AC) cannot be adequately measured in conventional PET phantoms due to the difficulty in converting the MRI images of the physical structures (e.g., plastic) into electron density maps. Over the last decade, a plethora of novel MR-based algorithms have been developed to more accurately derive the attenuation properties of the human head, including the skull. Although very promising, none of these techniques has yet emerged as an optimal and universally adopted strategy for AC in PET/MRI. In this work, we propose a path for PET/MRI qualification for multicenter brain imaging studies. Specifically, our solution is to separate the head attenuation correction from the other factors that affect PET data quantification and use a patient as a phantom to assess the former. The emission data collected on the integrated PET/MRI scanner to be qualified should be reconstructed using both MR-and CT-based AC methods and whole-brain qualitative and quantitative (both voxelwise and regional) analyses should be performed. The MR-based approach will be considered satisfactory if the PET quantification bias is within the acceptance criteria specified herein. We have implemented this approach successfully across two PET/MRI scanner manufacturers at two sites.
Journal of Nuclear Medicine, 2021
Background Molecular tumor volume (MTV) is a parameter of interest in advanced prostate cancer fo... more Background Molecular tumor volume (MTV) is a parameter of interest in advanced prostate cancer for assessing total disease burden on prostate-specific membrane antigen (PSMA) PET. Although software segmentation tools can delineate whole-body MTV, a necessary step towards meaningful monitoring of total tumor burden and treatment response through PET is establishing the repeatability of these metrics. The present study assesses the repeatability of total MTV and related metrics for 68 Ga-PSMA-HBED-CC in advanced prostate cancer. Methods Eighteen patients from a prior repeatability study who underwent two test-retest PSMA PET/CT scans within a mean interval of 5 days were reanalyzed. Within subject coefficient of variation and repeatability coefficients (RC) were analyzed on a per lesion and per patient basis. For the per lesion analysis, individual lesions were segmented for analysis by a single reader. For per patient analysis, subgroups of up to 10 lesions (single reader) and the total tumor volume per patient were segmented (independently by two readers). Image parameters were: MTV; maximum, peak, and mean standardized uptake value; total lesion PSMA and the related metric PSMA quotient (which is integrating lesion volume and PSMA avidity). Results In total, 192 segmentations were analyzed for the per lesion analysis and 1662 segmentations for the total tumor volume per patient analysis (combining the 2 readers and 2 scans). The RC of the MTV of single lesions was 77% (95%CI:63-96%). The RC improved after aggregation of up to 10 manually selected lesions into subgroups assessed per patient, 33% (95%CI:25-46%). The RC of 3 the semi-automatic MTVtotal was 35% (95%CI:25-50), the bland-altman bias was-6.70 [95%CI:-14.32-0.93]. Alternating readers between scans led to a comparable RC of 37% (95%CI:28-49%) for MTVtotal meaning that the metric is robust between scanning sessions and between readers. Conclusion 68 Ga-PSMA-HBED-CC PET-derived semi-automatic MTVtotal is repeatable and reader independent with a change of ±35% representing a true change in tumor volume. Volumetry of single manually selected lesions has considerably lower repeatability, and volumetry based on subgroups of these lesions, while showing acceptable repeatability, is less systematic. The semiautomatic analysis of MTVtotal employed in this study offers an efficient and robust means of assessing response to therapy.
Background Simultaneous PET/MRIs vary in their quantitative PET performance due to inherent diffe... more Background Simultaneous PET/MRIs vary in their quantitative PET performance due to inherent differences in the physical systems and differences in the image reconstruction implementation. This variability in quantitative accuracy confounds the ability to meaningfully combine and compare data across scanners. In this work, we define image reconstruction parameters that lead to comparable contrast recovery curves across simultaneous PET/MRI systems. Method: The NEMA NU-2 image quality phantom was imaged on the GE Signa and on the Siemens mMR PET/MRI scanners. The phantom was imaged at 9.8:1 contrast with standard spheres (diameter 10, 13, 17, 22, 28, 37 mm) and with custom spheres (diameter: 8.5, 11.5, 15, 25, 32.5, 44 mm) using a standardized methodology. Analysis was performed on a 30 minute data acquisition and on a subset of 5 minutes of data acquisition. Images were reconstructed with the manufacturer provided iterative image reconstruction algorithms with and without point sprea...
Medical Physics, 2020
Purpose: To develop bone material analogues that can be used in construction of phantoms for simu... more Purpose: To develop bone material analogues that can be used in construction of phantoms for simultaneous PET/MRI systems. Methods: Plaster was used as the basis for the bone material analogues tested in this study. It was mixed with varying concentrations of an iodinated CT contrast, a gadolinium-based MR contrast agent, and copper sulfate to modulate the attenuation properties and MRI properties (T1 and T2*). Attenuation was measured with CT and 68Ge transmission scans, and MRI properties were measured with quantitative ultrashort echo time pulse sequences. A proof-of-concept skull was created by plaster casting. Results: Undoped plaster has a 511 keV attenuation coefficient (~0.14 cm-1) similar to cortical bone (0.10-0.15 cm-1), but slightly longer T1 (~500 ms) and T2* (~1.2 ms) MR parameters compared to bone (T1 ~ 300 ms, T2* ~ 0.4 ms). Doping with the iodinated agent resulted in increased attenuation with minimal perturbation to the MR parameters. Doping with a gadolinium chelate greatly reduced T1 and T2*, resulting in extremely short T1 values when the target T2* values were reached, while the attenuation coefficient was unchanged. Doping with copper sulfate was more selective for T2* shortening and achieved comparable T1 and T2* values to bone (after 1 week of drying), while the attenuation coefficient was unchanged. Conclusions: Plaster doped with copper sulfate is a promising bone material analogue for a PET/MRI phantom, mimicking the MR properties (T1 and T2*) and 511 keV attenuation coefficient of human cortical bone.
The Laryngoscope, 2012
The early detection of persistent/recurrent disease of head and neck squamous cell carcinoma (HNS... more The early detection of persistent/recurrent disease of head and neck squamous cell carcinoma (HNSCC) after treatment can be challenging. The currently used radioisotope (18)F-fluorodeoxyglucose (FDG) is a nonspecific tracer for cancer cells as it detects all metabolically active cells including inflammation. (18)F-fluorodeoxythymidine (FLT) is a radioactive tracer for rapidly proliferating cells, and therefore is more specific for detecting cancer. Our aim was to compare FLT and FDG microPET (positron-emission tomography) to the gold standard in vivo bioluminescence imaging for serial assessment of neoplastic growth in a minimal residual disease in vivo model. Prospective outcomes research. In order to mimic the postsurgical environment of HNSCC patients FaDu cells transfected with a luciferase-expressing retrovirus were inoculated into the skin flap of Balb/c nu/nu mice. Three days later before tumors formed, mice were randomized into (18)F-FLT or (18) F-FDG groups, and microPET imaging was performed on days 3, 6, 10, 18, and 24 after tumor cell inoculation. (18)F-FLT detected tumors as early as day 3 even before tumors were palpable, whereas (18)F-FDG only detected palpable tumors. The average overall normalized radioactivity in the FLT group was significantly higher than the FDG group (P = .025). (18)F-FLT identified tumor cells before tumors were palpable and can potentially be used for early detection of persistence/recurrence of HNSCC. In addition, this radioisotope can be used to monitor adjuvant therapy with novel targeted therapeutics in preclinical models of persistent disease.
The Journal of Thoracic and Cardiovascular Surgery, 1996
We compared the abilities of positron emission tomography and computed tomography to detect N2 or... more We compared the abilities of positron emission tomography and computed tomography to detect N2 or N3 lymph node metastases (N2 or N3) in patients with lung cancer. Positron emission tomography detects increased rates of glucose uptake, characteristic of malignant cells. Patients with peripheral tumors smaller than 2 cm and a normal mediastinum were ineligible. All patients underwent computed tomography, positron emission tomography, and surgical staging. The American Thoracic Society lymph node map was used. Computed and positron emission tomographic scans were read by separate radiologists blinded to surgical staging results. Lymph nodes were "positive" by computed tomography if larger than 1.0 cm in short-axis diameter. Standardized uptake values were recorded from areas on positron emission tomography corresponding to those from which biopsy specimens were taken; if greater than 4.2, they were called "positive." Seventy-five lymph node stations (2.8 per patient) were analyzed in 27 patients. Computed tomography incorrectly staged the mediastinum as positive for metastases in three patients and as negative for metastases in three patients. Sensitivity and specificity of computed tomographic scans were 67% and 83%, respectively. Positron emission tomography correctly staged the mediastinum in all 27 patients. When analyzed by individual node station, there were four false positive and four false negative results by computed tomography (sensitivity = 60%, specificity = 93%, positive predictive value = 60%). Positron emission tomography mislabeled one node station as positive (100% sensitive, 98% specific, positive predictive value 91%). The differences were significant when the data were analyzed both for individual lymph node stations (p = 0.039) and for patients (p = 0.031) (McNemar test). Positron emission tomography and computed tomography are more accurate than computed tomography alone in detecting mediastinal lymph node metastases from non-small-cell lung cancer.
The Journal of Pain, 2007
IEEE Transactions on Nuclear Science, 2011
In human emission tomography, an additional transmission scan (x-ray CT or external gamma-source)... more In human emission tomography, an additional transmission scan (x-ray CT or external gamma-source) is often required to obtain accurate attenuation maps for attenuation correction (AC) and scatter correction (SC). These transmis- sion-based correction methods have been translated to small animal imaging although the impact of photon interactions on the mouse/rat-reconstructed images is substantially less than that in human imaging. Considering
Genes, Brain and Behavior, 2013
ADAR2 transgenic mice misexpressing the RNA editing enzyme ADAR2 (Adenosine Deaminase that act on... more ADAR2 transgenic mice misexpressing the RNA editing enzyme ADAR2 (Adenosine Deaminase that act on RNA) show characteristics of overeating and experience adult onset obesity. Behavioral patterns and brain changes related to a possible addictive overeating in these transgenic mice were explored as transgenic mice display chronic hyperphagia. ADAR2 transgenic mice were assessed in their food preference and motivation to overeat in a competing reward environment with ad lib access to a running wheel and food. Metabolic activity of brain and peripheral tissue were assessed with [ 18 F] fluorodeoxyglucose positron emission tomography (FDG-PET) and RNA expression of feeding related genes, ADAR2, dopamine and opiate receptors from the hypothalamus and striatum were examined. The results indicate that ADAR2 transgenic mice exhibit, (1) a food preference for diets with higher fat content, (2) significantly increased food intake that is non-distractible in a competing reward environment, (3) significantly increased mRNA expressions of ADAR2, serotonin 2C receptor (5HT 2C R), D1, D2, and mu opioid receptors and no change in CRH mRNAs and significantly reduced ADAR2 protein expression in the hypothalamus, (4) significantly increased D1 receptor and altered bioamines with no change in ADAR2, mu opioid and D2 receptor mRNA expression in the striatum, and (5) significantly greater glucose metabolism in the hypothalamus, brain stem, right hippocampus, left and right mid brain regions and suprascapular peripheral tissue than controls. These results suggest that highly motivated and goal-oriented overeating behaviors of ADAR2 transgenic mice are associated with altered feeding, reward-related mRNAs, and hyperactive brain mesolimbic region.
Journal of Nuclear Medicine, 2020
recently completed a 4-y expedition into the uncharted waters of the Food and Drug Administration... more recently completed a 4-y expedition into the uncharted waters of the Food and Drug Administration (FDA) newdrug application (NDA) process that ultimately resulted in approval of 68 Ga-DOTATOC in August 2019. The journey was enlightening, revealing a highly structured, arcane, but rigorous regulatory approval process. The FDA proved to be an efficient, reasonable, and communicative regulatory body that achieved balance between support of the initiative and its mission-bound, process-bound duty to ensure that the application met the expected safety and efficacy standards of the agency. With several clinically valuable PET radiopharmaceuticals without intellectual property residing in regulatory limbo, without industry champions to bring them to marketing approval, there may be justification for a more concerted effort from the molecular imaging community into generating better understanding, support, and perhaps even infrastructure for the academic NDA. As a first step, this article briefly describes the start-to-finish story for 68 Ga-DOTATOC, including a description of the clinical trials, a broad overview of the structured content of the NDA document, and the distilled experiences associated with the 68 Ga-DOTATOC NDA process. It is anticipated that with sustained free sharing of information relating to the FDA drug registration process, it will prove less daunting and more efficient in future academically sponsored NDA filings for PET imaging agents.
The AAPS journal, Jan 7, 2017
To evaluate the role of nucleoside transporters in the nose-to-brain uptake of [F]fluorothymidine... more To evaluate the role of nucleoside transporters in the nose-to-brain uptake of [F]fluorothymidine (FLT), an equilibrative nucleoside transporter (ENT1,2) and concentrative nucleoside transporter (CNT1-3) substrate, using PET to measure local tissue concentrations. Anesthetized Sprague-Dawley rats were administered FLT by intranasal (IN) instillation or tail-vein injection (IV). NBMPR (nitrobenzylmercaptopurine riboside), an ENT1 inhibitor, was administered either IN or intraperitoneally (IP). Dynamic PET imaging was performed for up to 40 min. A CT was obtained for anatomical co-registration and attenuation correction. Time-activity curves (TACs) were generated for the olfactory bulb (OB) and remaining brain, and the area-under-the-curve (AUC) for each TAC was calculated to determine the total tissue exposure of FLT. FLT concentrations were higher in the OB than in the rest of the brain following IN administration. IP administration of NBMPR resulted in increased OB and brain FLT ex...
Journal of Instrumentation, 2010
The borosilica, a very common PMT window and envelope material, contains 5% Boron (1% 10 B). The ... more The borosilica, a very common PMT window and envelope material, contains 5% Boron (1% 10 B). The high cross section for 10 B capturing thermal neutrons (3980 barn), is a concern for LHC experiments using borosilica window PMTs. This study investigates the rate and the size of the signals generated by thermal neutron boron interaction in borosilica window PMTs; Hamamatsu R7525-HA and R7600U-200-M4. Although virtually all of the thermal neutrons incident on the borosilicate glass are absorbed, probability of generating a PMT signal was measured to be 3 × 10 −4 and 3 × 10 −6 for R7525-HA and R7600U-200-M4 PMTs, respectively. For these signals the average pulse size was found to be between 20-30 photoelectrons. We also discuss that four anode PMTs allow the elimination of these events with an offline algorithm.
PLoS ONE, 2010
Background: Complex but common maternal diseases such as diabetes and obesity contribute to adver... more Background: Complex but common maternal diseases such as diabetes and obesity contribute to adverse fetal outcomes. Understanding of the mechanisms involved is hampered by difficulty in isolating individual elements of complex maternal states in vivo. We approached this problem in the context of maternal diabetes and sought an approach to expose the developing fetus in vivo to isolated hyperglycemia in the pregnant rat. Methodology and Principal Findings: We hypothesized that glucose infused into the arterial supply of one uterine horn would more highly expose fetuses in the ipsilateral versus contralateral uterine horn. To test this, the glucose tracer [ 18 F]fluorodeoxyglucose (FDG) was infused via the left uterine artery. Regional glucose uptake into maternal tissues and fetuses was quantified using positron emission tomography (PET). Upon infusion, FDG accumulation began in the left-sided placentae, subsequently spreading to the fetuses. Over two hours after completion of the infusion, FDG accumulation was significantly greater in left compared to right uterine horn fetuses, favoring the left by 1.960.1 and 2.860.3 fold under fasted and hyperinsulinemic conditions (p,10 211 n = 32-35 and p,10 212 n = 27-45) respectively. By contrast, centrally administered [ 3 H]-2-deoxyglucose accumulated equally between the fetuses of the two uterine horns. Induction of significant hyperglycemia (10 3 mg/dL) localized to the left uterine artery was sustained for at least 48 hours while maternal euglycemia was maintained. Conclusions and Significance: This approach exposes selected fetuses to localized hyperglycemia in vivo, minimizing exposure of the mother and thus secondary effects. Additionally, a set of less exposed internal control fetuses are maintained for comparison, allowing direct study of the in vivo fetal effects of isolated hyperglycemia. Broadly, this approach can be extended to study a variety of maternal-sided perturbations suspected to directly affect fetal health.