Kenneth L. Gage

Biodistribution, Tumor Detection, and Radiation Dosimetry of 18F-DCFBC, a Low-Molecular-Weight Inhibitor of Prostate-Specific Membrane Antigen, in Patients with Metastatic Prostate Cancer

Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-l-cysteine (18F-DCFBC) could image an experimental model of PSMA-positive PCa using PET. Here, we describe the initial clinical experience and radiation dosimetry of 18F-DCFBC in men with metastatic PCa. Methods: Five patients with radiologic evidence of metastatic PCa were studied after the intravenous administration of 370 MBq (10 mCi) of 18F-DCFBC. Serial PET was performed until 2 h after administration. Time–activity curves were generated for selected normal tissues and metastatic foci. Radiation dose estimates were calculated using OLINDA/EXM 1.1. Results: Most vascular organs demonstrated a slow decrease in radioactivity concentration over time consistent with clearance from the blood pool, with primarily urinary radiotracer excretion. Thirty-two PET-positive suspected metastatic sites were identified, with 21 concordant on both PET and conventional imaging for abnormal findings compatible with metastatic disease. Of the 11 PET-positive sites not identified on conventional imaging, most were within the bone and could be considered suggestive for the detection of early bone metastases, although further validation is needed. The highest mean absorbed dose per unit administered radioactivity (μGy/MBq) was in the bladder wall (32.4), and the resultant effective dose was 19.9 ± 1.34 μSv/MBq (mean ± SD). Conclusion: Although further studies are needed for validation, our findings demonstrate the potential of 18F-DCFBC as a new positron-emitting imaging agent for the detection of metastatic PCa. This study also provides dose estimates for 18F-DCFBC that are comparable to those of other PET radiopharmaceuticals such as 18F-FDG.

18F-DCFBC PET/CT for PSMA-Based Detection and Characterization of Primary Prostate Cancer

We previously demonstrated the ability to detect metastatic prostate cancer using N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-l-cysteine (18F-DCFBC), a low-molecular-weight radiotracer that targets the prostate-specific membrane antigen (PSMA). PSMA has been shown to be associated with higher Gleason grade and more aggressive disease. An imaging biomarker able to detect clinically significant high-grade primary prostate cancer reliably would address an unmet clinical need by allowing for risk-adapted patient management. Methods: We enrolled 13 patients with primary prostate cancer who were imaged with 18F-DCFBC PET before scheduled prostatectomy, with 12 of these patients also undergoing pelvic prostate MR imaging. Prostate 18F-DCFBC PET was correlated with MR imaging and histologic and immunohistochemical analysis on a prostate-segment (12 regions) and dominant-lesion basis. There were no incidental extraprostatic findings on PET suggestive of metastatic disease. Results: MR imaging was more sensitive than 18F-DCFBC PET for detection of primary prostate cancer on a per-segment (sensitivities of up to 0.17 and 0.39 for PET and MR imaging, respectively) and per-dominant-lesion analysis (sensitivities of 0.46 and 0.92 for PET and MR imaging, respectively). However, 18F-DCFBC PET was more specific than MR imaging by per-segment analysis (specificities of 0.96 and 0.89 for PET and MR imaging for corresponding sensitivity, respectively) and specific for detection of high-grade lesions (Gleason 8 and 9) greater than 1.0 mL in size (4/4 of these patients positive by PET). 18F-DCFBC uptake in tumors was positively correlated with Gleason score (ρ = 0.64; PSMA expression, ρ = 0.47; and prostate-specific antigen, ρ = 0.52). There was significantly lower 18F-DCFBC uptake in benign prostatic hypertrophy than primary tumors (median maximum standardized uptake value, 2.2 vs. 3.5; P = 0.004). Conclusion: Although the sensitivity of 18F-DCFBC for primary prostate cancer was less than MR imaging, 18F-DCFBC PET was able to detect the more clinically significant high-grade and larger-volume tumors (Gleason score 8 and 9) with higher specificity than MR imaging. In particular, there was relatively low 18F-DCFBC PET uptake in benign prostatic hypertrophy lesions, compared with cancer in the prostate, which may allow for more specific detection of primary prostate cancer by 18F-DCFBC PET. This study demonstrates the utility of PSMA-based PET, which may be used in conjunction with MR imaging to identify clinically significant prostate cancer.

Preclinical evaluation of an 131I-labeled benzamide for targeted radiotherapy of metastatic melanoma

Radiolabeled benzamides are attractive candidates for targeted radiotherapy of metastatic melanoma as they bind melanin and exhibit high tumor uptake and retention. One such benzamide, N-(2-diethylamino-ethyl)-4-(4-fluoro-benzamido)-5-iodo-2-methoxy-benzamide (MIP-1145), was evaluated for its ability to distinguish melanin-expressing from amelanotic human melanoma cells, and to specifically localize to melanin-containing tumor xenografts. The binding of [(131)I]MIP-1145 to melanoma cells in vitro was melanin dependent, increased over time, and insensitive to mild acid treatment, indicating that it was retained within cells. Cold carrier MIP-1145 did not reduce the binding, consistent with the high capacity of melanin binding of benzamides. In human melanoma xenografts, [(131)I]MIP-1145 exhibited diffuse tissue distribution and washout from all tissues except melanin-expressing tumors. Tumor uptake of 8.82% injected dose per gram (ID/g) was seen at 4 hours postinjection and remained at 5.91% ID/g at 24 hours, with tumor/blood ratios of 25.2 and 197, respectively. Single photon emission computed tomography imaging was consistent with tissue distribution results. The administration of [(131)I]MIP-1145 at 25 MBq or 2.5 GBq/m(2) in single or multiple doses significantly reduced SK-MEL-3 tumor growth, with multiple doses resulting in tumor regression and a durable response for over 125 days. To estimate human dosimetry, gamma camera imaging and pharmacokinetic analysis was performed in cynomolgus monkeys. The melanin-specific binding of [(131)I]MIP-1145 combined with prolonged tumor retention, the ability to significantly inhibit tumor growth, and acceptable projected human dosimetry suggest that it may be effective as a radiotherapeutic pharmaceutical for treating patients with metastatic malignant melanoma.

Regional brain distribution of translocator protein using [11C]DPA-713 PET in individuals infected with HIV

Imaging the brain distribution of translocator protein (TSPO), a putative biomarker for glial cell activation and neuroinflammation, may inform management of individuals infected with HIV by uncovering regional abnormalities related to neurocognitive deficits and enable non-invasive therapeutic monitoring. Using the second-generation TSPO-targeted radiotracer, [11C]DPA-713, we conducted a positron emission tomography (PET) study to compare the brains of 12 healthy human subjects to those of 23 individuals with HIV who were effectively treated with combination antiretroviral therapy (cART). Compared to PET data from age-matched healthy control subjects, [11C]DPA-713 PET of individuals infected with HIV demonstrated significantly higher volume-of-distribution (VT) ratios in white matter, cingulate cortex, and supramarginal gyrus, relative to overall gray matter VT, suggesting localized glial cell activation in susceptible regions. Regional TSPO abnormalities were evident within a sub-cohort of neuro-asymptomatic HIV subjects, and an increase in the VT ratio within frontal cortex was specifically linked to individuals affected with HIV-associated dementia. These findings were enabled by employing a gray matter normalization approach for PET data quantification, which improved test–retest reproducibility, intra-class correlation within the healthy control cohort, and sensitivity of uncovering abnormal regional findings.

ACR Appropriateness Criteria Crohn Disease

Crohn disease is a chronic inflammatory disorder involving the gastrointestinal tract, characterized by episodic flares and times of remission. Underlying structural damage occurs progressively, with recurrent bouts of inflammation. The diagnosis and management of this disease process is dependent on several clinical, laboratory, imaging, endoscopic, and histologic factors. In recent years, with the maturation of CT enterography, and MR enterography, imaging has played an increasingly important role in relation to Crohn Disease. In addition to these specialized examination modalities, ultrasound and routine CT have potential uses. Fluoroscopy, radiography, and nuclear medicine may be less beneficial depending on the clinical scenario. The imaging modality best suited to evaluating this disease may change, depending on the target population, severity of presentation, and specific clinical situation. This document presents seven clinical scenarios (variants) in both the adult and pediatric populations and rates the appropriateness of the available imaging options. They are summarized in a consolidated table, and the underlying rationale and supporting literature are presented in the accompanying narrative. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Differentiating autoimmune pancreatitis from pancreatic adenocarcinoma using dual-phase computed tomography.

Objective This article aimed to study features on dual-phase computed tomography (CT) that help differentiate autoimmune pancreatitis (AIP) from pancreatic adenocarcinoma (PA). Methods The CTs of 32 patients with AIP were matched with equal number of PA and were independently evaluated by 3 radiologists who assigned a diagnosis of AIP, PA, or unsure. Interobserver agreement between radiologists was evaluated using &kgr; statistics. Results The mean accuracies for diagnosing AIP and PA were 68% and 83%, respectively. There was moderate agreement between radiologists (&kgr;, 0.58; P < 0.0001). The most common findings for AIP were common bile duct (CBD) stricture (63%), bile duct wall hyperenhancement (47%), and diffuse parenchymal enlargement (41%). The most common findings for PA were focal mass (78%; &kgr;, 0.58; P < 0.0001) and pancreatic ductal dilatation (69%; &kgr;, 0.7; P < 0.0001). Findings helpful for diagnosing AIP were diffuse enlargement, parenchymal atrophy as well as absence of pancreatic duct dilatation and focal mass. Findings helpful for diagnosing PA were focal mass and pancreatic ductal dilatation. Misdiagnosis of PA in patients with AIP was due to focal mass, pancreatic duct dilatation, and pancreatic atrophy, whereas misdiagnosis of AIP in patients with PA was due to absence of atrophy, presence of diffuse enlargement, and peripancreatic halo. Conclusions Diffuse enlargement, hypoenhancement, and characteristic peripancreatic halo are strong indicators for a diagnosis of AIP. Radiologists demonstrated moderate agreement in distinguishing AIP from PA on the basis of CT imaging.

Radiation Dosimetry and Biodistribution of the TSPO Ligand 11C-DPA-713 in Humans

Whole-body PET/CT was used to characterize the radiation dosimetry of 11C-DPA-713, a specific PET ligand for the assessment of translocator protein. Methods: Six healthy control subjects, 3 men and 3 women, underwent whole-body dynamic PET scans after bolus injection of 11C-DPA-713. Subjects were scanned from head to mid thigh with 7 passes performed, with a total PET acquisition of approximately 100 min. Time–activity curves were generated in organs with visible tracer uptake, and tissue residence times were calculated. Whole-body dosimetry was calculated using OLINDA 1.1 software, assuming no voiding. Results: The absorbed dose is highest in the lungs, spleen, kidney, and pancreas. The lungs were determined to be the dose-limiting organ, with an average absorbed dose of 2.01 × 10−2 mSv/MBq (7.43 × 10−2 rem/mCi). On the basis of exposure limits outlined in the U.S. Food and Drug Administration Code of Federal Regulations (21CFR361.1), the single-dose limit for 11C-DPA-713 radiotracer injection is 2,487.6 MBq (67.3 mCi). Conclusion: 11C-DPA-713 has an uptake pattern that is consistent with the biodistribution of translocator protein and yields a dose burden that is comparable to that of other 11C-labeled PET tracers.

ACR Appropriateness Criteria® Thoracic Aorta Interventional Planning and Follow-Up

Thoracic endovascular aortic repair (TEVAR) has undergone rapid evolution and is now applied to a range of aortic pathologies. Imaging plays a vital role in the pre- and postintervention assessment of TEVAR patients. Accurate characterization of pathology and evaluation for high-risk anatomic features are necessary in the planning phase, and careful assessment for graft stability, aortic lumen diameter, and presence of endoleak are paramount in the follow-up period. CTA is the imaging modality of choice for pre- and postintervention assessment, and MRA is an acceptable alternative depending on patient stability and graft composition. Lifelong imaging follow-up is necessary in TEVAR patients because endoleaks may develop at any time. The exact surveillance interval is unclear and may be procedure and patient specific. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Suspected Thoracic Aortic Aneurysm

Although the incidence of thoracic aortic aneurysm is on the rise, initial imaging diagnosis can present a challenge for many clinicians. Providers are faced with many imaging choices as part of the initial workup. Considering level of invasiveness, relative radiation level, and quality of associated diagnostic data, CT angiography and MR angiography are believed to be the most appropriate options for radiological diagnosis of suspected thoracic aortic aneurysm. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Vascular Claudication—Assessment for Revascularization

Vascular claudication is a symptom complex characterized by reproducible pain and weakness in an active muscle group due to peripheral arterial disease. Noninvasive hemodynamic tests such as the ankle brachial index, toe brachial index, segmental pressures, and pulse volume recordings are considered the first imaging modalities necessary to reliably establish the presence and severity of arterial obstructions. Vascular imaging is consequently used for diagnosing individual lesions and triaging patients for medical, percutaneous, or surgical intervention. Catheter angiography remains the reference standard for imaging the peripheral arteries, providing a dynamic and accurate depiction of the peripheral arteries. It is particularly useful when endovascular intervention is anticipated. When combined with noninvasive hemodynamic tests, however, noninvasive imaging, including ultrasound, CT angiography, and MR angiography, can also reliably confirm or exclude the presence of peripheral arterial disease. All modalities, however, have their own technical limitations when classifying the location, extent, and severity of disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.