JNM Current Issue

This Month in JNM

2019-09-03T10:10:09-07:00

2019 SNMMI Highlights Lecture: Neurosciences

Barthel, H. — 2019-09-03T10:10:09-07:00

SNMMI Newsline

2019-09-03T10:10:09-07:00

Bill Targets Expanded Access to Diagnostic Radiopharmaceuticals

2019-09-03T10:10:09-07:00

Fifth Anniversary of SNMMI Professional Relations Fellowship

Slosky, J., Zukotynski, K. — 2019-09-03T10:10:09-07:00

SNMMI Leadership Update: Focus on International Diversity and Inclusivity

Dilsizian, V. — 2019-09-03T10:10:09-07:00

From the Literature

2019-09-03T10:10:09-07:00

A Conversation Between Joanna Fowler and Johannes Czernin

Fowler, J. S., Czernin, J. — 2019-09-03T10:10:09-07:00

Solid-State Detector SPECT Myocardial Perfusion Imaging

Slomka, P. J., Miller, R. J. H., Hu, L.-H., Germano, G., Berman, D. S. — 2019-09-03T10:10:09-07:00

There has been an evolutionary leap in SPECT imaging with the advent of camera systems that use solid-state crystals and novel collimator designs configured specifically for cardiac imaging. Solid-state SPECT camera systems have facilitated dramatic reductions in both imaging time and radiation dose while maintaining high diagnostic accuracy. These advances are related to simultaneous improvement in photon sensitivity due to the collimator and imaging geometry, as well as image resolution due to the improved energy resolution of the new crystals. Improved photon sensitivity has facilitated fast or low-dose myocardial perfusion imaging (MPI), and early dynamic imaging has emerged as a technique for assessing myocardial blood flow with SPECT. Lastly, general-purpose solid-state camera systems and hybrid SPECT/CT systems have also been developed that may have important clinical roles in cardiac imaging. This review summarizes state-of-the-art solid-state SPECT MPI technology and clinical applications, including emerging techniques for SPECT MPI flow estimation. We also discuss imaging protocols used with the new cameras, potential imaging pitfalls, and the latest data providing large-scale validation of the diagnostic and prognostic value of this new technology.

Training Requirements for Theranostics: A Unique Opportunity for Collaboration

Graham, M. M., Buatti, J. M. — 2019-09-03T10:10:09-07:00

Vascular Calcification: The Evolving Relationship of Vascular Calcification to Major Acute Coronary Events

Strauss, H. W., Nakahara, T., Narula, N., Narula, J. — 2019-09-03T10:10:09-07:00

Calcification in a coronary artery is accepted as definite evidence of coronary atherosclerosis. The extent and density of calcification, as combined in the Agatston score, is associated with the risk of a patient experiencing a major acute coronary event. Atherosclerosis occurs because damaged endothelial cells allow low-density lipoprotein cholesterol (LDLc) to leak into subintimal tissue. Proteoglycans in subendothelial collagen have a high affinity for LDLc, retaining the lipoprotein cholesterol complex. As the endothelial damage is repaired, the subintimal LDLc is trapped. Retained LDLc induces an inflammatory response in the overlying endothelium, causing the endothelium to express chemotactic peptides. Chemotactic peptides attract circulating monocytes, which follow the concentration gradient, enter the tissue, and become tissue macrophages to phagocytize and digest the irritating LDLc in the atheroma. In the process of digesting LDLc, enzymes in the macrophages oxidize the LDLc complex. Oxidized LDL is toxic to macrophages; when present in sufficient quantity, it may cause death of macrophages, contributing to inflammation in the atheroma. In a necrotic inflammatory lesion, the regulatory mechanisms that control tissue concentrations of calcium and phosphorus are lost, allowing the solubility product of calcium phosphate to be exceeded, resulting in the formation of microscopic calcium-phosphate crystals. With ongoing inflammation, additional calcium-phosphate crystals are formed, which may aggregate. When these aggregated calcium phosphate crystals exceed 1 mm, the lesions become visible on clinical CT as coronary calcifications. Serial gated CT scans of the heart have demonstrated that once formed, CT-visible calcifications do not decrease significantly in size but may increase.

Early Phase I Study of a 99mTc-Labeled Anti-Programmed Death Ligand-1 (PD-L1) Single-Domain Antibody in SPECT/CT Assessment of PD-L1 Expression in Non-Small Cell Lung Cancer

2019-09-03T10:10:09-07:00

Immunotherapy with checkpoint inhibitor programmed cell death 1 (PD-1)/programmed death ligand-1 (PD-L1) antibodies demonstrates improvements in treatment of advanced non–small cell lung cancer. Treatment stratification depends on immunohistochemical PD-L1 measurement of biopsy material, an invasive method that does not account for spatiotemporal heterogeneity. Using a single-domain antibody, NM-01, against PD-L1, radiolabeled site-specifically with ^99mTc for SPECT imaging, we aimed to assess the safety, radiation dosimetry, and imaging characteristics of this radiopharmaceutical and correlate tumor uptake with PD-L1 immunohistochemistry results. Methods: Sixteen patients (mean age, 61.7 y; 11 men) with non–small cell lung cancer were recruited. Primary tumor PD-L1 expression was measured by immunohistochemistry. NM-01 was radiolabeled with [^99mTc(OH₂)₃(CO)₃]⁺ complex binding to its C-terminal hexahistidine tag. Administered activity was 3.8–10.4 MBq/kg, corresponding to 100 μg or 400 μg of NM-01. Whole-body planar and thoracic SPECT/CT scans were obtained at 1 and 2 h after injection in all patients, and 5 patients underwent additional imaging at 10 min, 3 h, and 24 h for radiation dosimetry calculations. All patients were monitored for adverse events. Results: No drug-related adverse events occurred in this study. The mean effective dose was 8.84 x 10^–3 ± 9.33 x 10^–4 mSv/MBq (3.59 ± 0.74 mSv per patient). Tracer uptake was observed in the kidneys, spleen, liver, and bone marrow. SPECT primary tumor–to–blood-pool ratios (T:BP) varied from 1.24 to 2.3 (mean, 1.79) at 1 h and 1.24 to 3.53 (mean, 2.22) at 2 h (P = 0.005). Two-hour primary T:BP ratios correlated with PD-L1 immunohistochemistry results (r = 0.68, P = 0.014). Two-hour T:BP was lower in tumors with ≤1% PD-L1 expression (1.89 vs. 2.49, P = 0.048). Nodal and bone metastases showed tracer uptake. Heterogeneity (>20%) between primary tumor and nodal T:BP was present in 4 of 13 patients. Conclusion: This first-in-human study demonstrates that ^99mTc-labeled anti–PD-L1-single-domain antibody SPECT/CT imaging is safe and associated with acceptable dosimetry. Tumor uptake is readily visible against background tissues, particularly at 2 h when the T:BP ratio correlates with PD-L1 immunohistochemistry results.

Assessment of Simplified Methods for Quantification of 18F-FDHT Uptake in Patients with Metastatic Castration-Resistant Prostate Cancer

2019-09-03T10:10:09-07:00

¹⁸F-fluorodihydrotestosterone (¹⁸F-FDHT) PET/CT potentially provides a noninvasive method for assessment of androgen receptor expression in patients with metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to assess simplified methods for quantifying ¹⁸F-FDHT uptake in mCRPC patients and to assess effects of tumor perfusion on these ¹⁸F-FDHT uptake metrics. Methods: Seventeen mCRPC patients were included in this prospective observational multicenter study. Test and retest 30-min dynamic ¹⁸F-FDHT PET/CT scans with venous blood sampling were performed in 14 patients. In addition, arterial blood sampling and dynamic ¹⁵O-H₂O scans were obtained in a subset of 6 patients. Several simplified methods were assessed: Patlak plots; SUV normalized to body weight (SUV_BW), lean body mass (SUV_LBM), whole blood (SUV_WB), parent plasma activity concentration (SUV_PP), area under the parent plasma curve (SUV_AUC,PP), and area under the whole-blood input curve (SUV_AUC,WB); and SUV_BW corrected for sex hormone–binding globulin levels (SUV_SHBG). Results were correlated with parameters derived from full pharmacokinetic ¹⁸F-FDHT and ¹⁵O-H₂O. Finally, the repeatability of individual quantitative uptake metrics was assessed. Results: Eighty-seven ¹⁸F-FDHT–avid lesions were evaluated. ¹⁸F-FDHT uptake was best described by an irreversible 2-tissue-compartment model. Replacing the continuous metabolite-corrected arterial plasma input function with an image-derived input function in combination with venous sample data provided similar K_i results (R² = 0.98). Patlak K_i and SUV_AUC,PP showed an excellent correlation (R² > 0.9). SUV_BW showed a moderate correlation to K_i (R² = 0.70, presumably due to fast ¹⁸F-FDHT metabolism. When calculating SUV_SHBG, correlation to K_i improved (R² = 0.88). The repeatability of full kinetic modeling parameters was inferior to that of simplified methods (repeatability coefficients > 36% vs. < 28%, respectively). ¹⁸F-FDHT uptake showed minimal blood flow dependency. Conclusion: ¹⁸F-FDHT kinetics in mCRPC patients are best described by an irreversible 2-tissue-compartment model with blood volume parameter. SUV_AUC,PP showed a near-perfect correlation with the irreversible 2-tissue-compartment model analysis and can be used for accurate quantification of ¹⁸F-FDHT uptake in whole-body PET/CT scans. In addition, SUV_SHBG could potentially be used as an even simpler method to quantify ¹⁸F-FDHT uptake when less complex scanning protocols and accuracy are required.

Frequency, Determinants, and Costs of Recommendations for Additional Imaging in Clinical 18F-FDG PET/CT Reports

Alesawi, H. M., Yakar, D., Glaudemans, A. W. J. M., Kwee, T. C. — 2019-09-03T10:10:09-07:00

Our purpose was to determine the frequency, determinants, and costs of recommendations for additional imaging (RAIs) in clinical ¹⁸F-FDG PET/CT reports. Methods: This retrospective study included a random sample of 2,643 ¹⁸F-FDG PET/CT scans that were performed for various clinical reasons at a tertiary-care academic medical center without financial incentives for self-referral, within a 1.5-y period. Results: Ninety-eight (3.7%) of 2,643 ¹⁸F-FDG PET/CT reports contained an RAI. None of the investigated variables (patient age, hospital status [inpatient or outpatient], indication for ¹⁸F-FDG PET/CT scanning [oncologic, infection/inflammation, or miscellaneous], type of ¹⁸F-FDG PET/CT scan [low-dose ¹⁸F-FDG PET/CT or low-dose ¹⁸F-FDG PET/CT combined with diagnostic CT of any body region], or years of experience of the [most senior] signing author) was univariately associated with the presence of an RAI in the ¹⁸F-FDG PET/CT report. The hypothesis that RAIs more frequently occur when the anatomic area to which the RAI relates is not covered by a diagnostic CT scan (as part of the ¹⁸F-FDG PET/CT examination) was also rejected (P = 0.419). The total costs of all RAIs (regardless of whether they were actually performed by the referring clinicians) were 23,922.21 ($27,065.47), which corresponds to an average of 9.08 ($10.27) RAI costs per ¹⁸F-FDG PET/CT exam. The total costs of all RAIs that were actually performed by the referring clinicians were 16,498.62 ($18,666.46), which corresponds to an average of 6.26 ($7.08) RAI costs per ¹⁸F-FDG PET/CT exam. Conclusion: RAIs in ¹⁸F-FDG PET/CT reports in a European tertiary-care academic medical center without financial incentives for self-referral are infrequent, cannot be anticipated, and result in relatively low overall costs.

Early Detection of Multiorgan Light-Chain Amyloidosis by Whole-Body 18F-Florbetapir PET/CT

2019-09-03T10:10:09-07:00

Immunoglobulin light-chain (AL) amyloidosis affects multiple systemic organs. However, determination of the precise extent of organ involvement remains challenging. Targeted amyloid imaging with ¹⁸F-florbetapir PET/CT offers the potential to detect AL deposits in multiple organs. The primary aim of this study was to determine the distribution and frequency of AL deposits in the various organs of subjects with systemic AL amyloidosis using ¹⁸F-florbetapir PET/CT. Methods: This prospective study included 40 subjects with biopsy-proven AL amyloidosis including active AL amyloidosis (n = 30) or AL amyloidosis in hematologic remission for more than 1 y (n = 10). All subjects underwent ¹⁸F-florbetapir PET/CT, skull base to below the kidney scan field, from 60 to 90 min after injection of radiotracer. Volume-of-interest measurements of SUV_max were obtained using Hermes software for the parotid gland, tongue, thyroid, lung, gastric wall, pancreas, spleen, kidney, muscle, abdominal fat, lower thoracic spine, vertebral body, and humeral head. Uptake in each organ was visually compared with that in spine bone marrow. An SUV_max of at least 2.5 was considered abnormal in all organs other than the liver. Results: Compared with the international consensus definition of organ involvement, ¹⁸F-florbetapir PET/CT identified amyloid deposits in substantially higher percentages of subjects for several organ systems, including parotid gland (50% vs. 3%), tongue (53% vs. 10%), and lung (35% vs. 10%). In several organ systems, including kidney (13% vs. 28%) and abdominal wall fat (10% vs. 13%), PET identified involvement in fewer subjects than did international consensus. Quantitative analysis of ¹⁸F-florbetapir PET/CT revealed more frequent organ involvement than did visual analysis in the tongue, thyroid, lung, pancreas, kidney, muscle, and humeral head. Extensive organ amyloid deposits were observed in active AL as well as in AL remission cohorts, and in both cardiac and noncardiac AL cohorts. Conclusion: ¹⁸F-florbetapir PET/CT detected widespread organ amyloid deposition in subjects with both active AL and AL hematologic remission. In most instances, amyloid deposits in the various organs were not associated with clinical symptoms and, thus, were unrecognized. Early recognition of systemic organ involvement may help tailor treatment, and noninvasive monitoring of organ-level disease may guide management with novel fibril-resorbing therapies.

Combination of 5-Fluorouracil with Epigenetic Modifiers Induces Radiosensitization, Somatostatin Receptor 2 Expression, and Radioligand Binding in Neuroendocrine Tumor Cells In Vitro

2019-09-03T10:10:09-07:00

Peptide receptor radionuclide therapy in advanced neuroendocrine tumors (NETs) demonstrates a limited objective response rate. The therapeutic efficacy might be further increased by peptide receptor chemoradionuclide therapy. In this preclinical study, we explored the effects of 5-fluorouracil plus the DNA methyltransferase inhibitor decitabine or the histone deacetylase inhibitor tacedinaline on NET cells in vitro. Methods: Human NET cell lines BON1 and QGP1 were treated with 5-fluorouracil alone or in combination with decitabine or tacedinaline, respectively. Radiosensitivity was tested in combination with -irradiation at doses of 0, 2, 4, or 6 Gy by colony formation assay. Somatostatin receptor type 2 (SSTR2) expression and ⁶⁸Ga-DOTATOC uptake by human NET cell lines were investigated by Western blot analysis and by a radioligand binding assay. Results: Treatment with 5-fluorouracil alone or in combination with decitabine or tacedinaline reduced tumor cell viability and induced apoptosis, enhanced radiosensitivity in BON1 and QGP1 cells, induced SSTR2 expression, and resulted in increased radioligand binding of ⁶⁸Ga-DOTATOC in NET cells. Conclusion: This preclinical study demonstrated that 5-fluorouracil alone or in combination with decitabine or tacedinaline caused radiosensitization of tumor cells, upregulation of SSTR2 expression in tumor cells, and increased radioligand binding of ⁶⁸Ga-DOTATOC to these tumor cells. These preclinical in vitro findings indicate that 5-fluorouracil in combination with epigenetic modifiers might be a putative strategy to improve the treatment efficacy of peptide receptor chemoradionuclide therapy in NET.

18F-Fluoroestradiol PET Imaging of Activating Estrogen Receptor-{alpha} Mutations in Breast Cancer

Kumar, M., Salem, K., Michel, C., Jeffery, J. J., Yan, Y., Fowler, A. M. — 2019-09-03T10:10:09-07:00

The purpose of this study was to determine the effect of estrogen receptor-α gene (ESR1) mutations at the tyrosine (Y) 537 amino acid residue within the ligand binding domain on ¹⁸F-fluoroestradiol (¹⁸F-FES) binding and in vivo tumor uptake compared with wild-type (WT)-estrogen receptor α (ER). Methods: ER-negative MDA-MB-231 breast cancer cells were used to generate stable cell lines that express WT-ER, Y537S, or Y537C mutant ER. Receptor expression and localization were confirmed by Western blot and immunofluorescence, respectively. ER transcriptional function was measured using an estrogen response element-luciferase reporter gene assay and quantitative polymerase chain reaction analysis of ER-regulated endogenous target genes. Saturation binding and competition assays were performed to determine equilibrium dissociation constant (K_d) and half maximal inhibitory concentration (IC50) values. ¹⁸F-FES uptake was measured in tumor xenografts grown in female athymic nude mice by small-animal PET/CT imaging and tissue biodistribution using 5.55 MBq (150 μCi) of ¹⁸F-FES. A 10-fold-lower injected dose of 0.555 MBq (15 μCi) of ¹⁸F-FES was also used for tissue biodistribution. Statistical significance was determined using ANOVA. Results: Y537S and Y537C mutations resulted in increased ER transcriptional activity in the absence of estrogen compared with WT-ER (11.48 ± 2.42 fold; P = 0.0002, and 5.89 ± 0.94 fold; P = 0.04, respectively). Constitutive ER activation of two target genes (PGR and TFF1) in the absence of estrogen was also observed in Y537S- and Y537C-ER cells compared with WT-ER. K_d values for ¹⁸F-FES were 0.98 ± 0.54 nM for Y537S-ER (P = 0.27) and 0.24 ± 0.03 nM for Y537C-ER (P = 0.95) compared with 0.07 ± 0.03 nM for WT-ER. IC50 values were 0.22 ± 0.09 nM for Y537S-ER (P = 0.97), 0.18 ± 0.09 nM for Y537C-ER (P = 0.99), and 0.19 ± 0.11 nM for WT-ER. Tumor xenografts expressing Y537S-ER (mean percentage injected dose per gram, 1.45 ± 0.06; P = 0.77) and Y537C-ER (2.09 ± 0.20; P = 0.21) had similar ¹⁸F-FES uptake compared with WT-ER (1.68 ± 0.12). Comparable ¹⁸F-FES uptake between Y537S-, Y537C-, and WT-ER xenografts was also observed using a 10-fold-lower injected dose with the tissue biodistribution assay. Conclusion: Since tumoral uptake of ¹⁸F-FES is not significantly impacted by Y537S-ER or Y537C-ER mutations, the potential diagnostic utility of ¹⁸F-FES PET imaging is expected to be equally valid for patients with or without these activating ESR1 mutations.

The Contribution of Multiparametric Pelvic and Whole-Body MRI to Interpretation of 18F-Fluoromethylcholine or 68Ga-HBED-CC PSMA-11 PET/CT in Patients with Biochemical Failure After Radical Prostatectomy

2019-09-03T10:10:09-07:00

Our purpose was to assess whether the addition of data from multiparametric pelvic MRI (mpMR) and whole-body MRI (wbMR) to the interpretation of ¹⁸F-fluoromethylcholine (¹⁸F-FCH) or ⁶⁸Ga-HBED-CC PSMA-11 (⁶⁸Ga-PSMA) PET/CT (=PET) improves the detection of local tumor recurrence or of nodal and distant metastases in patients after radical prostatectomy with biochemical failure. Methods: The current analysis was performed as part of a prospective, multicenter trial on ¹⁸F-FCH or ⁶⁸Ga-PSMA PET, mpMR, and wbMR. Eligible men had an elevated level of prostate-specific antigen (PSA) (>0.2 ng/mL) and high-risk features (Gleason score > 7, PSA doubling time < 10 mo, or PSA > 1.0 ng/mL) with negative or equivocal conventional imaging results. PET was interpreted with mpMR and wbMR in consensus by 2 radiologists and compared with prospective interpretation of PET or MRI alone. Performance measures of each modality (PET, MRI, and PET/mpMR–wbMR) were compared for each radiotracer and each individual patient (for ¹⁸F-FCH, or ⁶⁸Ga-PSMA for patients who had ⁶⁸Ga-PSMA PET) and to a composite reference standard. Results: There were 86 patients with PET (¹⁸F-FCH [n = 76] and/or ⁶⁸Ga-PSMA [n = 26]) who had mpMR and wbMR. Local tumor recurrence was detected in 20 of 76 (26.3%) on ¹⁸F-FCH PET/mpMR, versus 11 of 76 (14.5%) on ¹⁸F-FCH PET (P = 0.039), and in 11 of 26 (42.3%) on ⁶⁸Ga-PSMA PET/mpMR, versus 6 of 26 (23.1%) on ⁶⁸Ga-PSMA PET (P = 0.074). Per patient, PET/mpMR was more often positive for local tumor recurrence than PET (P = 0.039) or mpMR (P = 0.019). There were 20 of 86 patients (23.3%) with regional nodal metastases on both PET/wbMR and PET (P = 1.0) but only 12 of 86 (14%) on wbMR (P = 0.061). Similarly, there were more nonregional metastases detected on PET/wbMR than on PET (P = 0.683) or wbMR (P = 0.074), but these differences did not reach significance. Compared with the composite reference standard for the detection of disease beyond the prostatic fossa, PET/wbMR, PET, and wbMR had sensitivity of 50%, 50%, and 8.3%, respectively, and specificity of 97.1%, 97.1%, and 94.1%, respectively. Conclusion: Interpretation of PET/mpMR resulted in a higher detection rate for local tumor recurrence in the prostatic bed in men with biochemical failure after radical prostatectomy. However, the addition of wbMR to ¹⁸F-FCH or ⁶⁸Ga-PSMA PET did not improve detection of regional or distant metastases.

Parameters to Predict Progression-Free and Overall Survival After Peptide Receptor Radionuclide Therapy: A Multivariate Analysis in 782 Patients

2019-09-03T10:10:09-07:00

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for patients with neuroendocrine neoplasms. The aim of this study was to identify clinical and treatment parameters associated with progression-free survival (PFS) and overall survival (OS). Methods: All patients treated from October 2002 until March 2016 at the Zentralklinik Bad Berka with at least 3 administrations of PRRT (maximal interval of 6 mo between consecutive administrations) were included. Data were collected in 5 categories: general patient characteristics, tumor characteristics, prior treatments, radioisotope used for PRRT, and blood chemistry. Survival was analyzed using Kaplan–Meier curves. Univariate and multivariate Cox regression analyses were performed to identify parameters associated with PFS and OS. Results: In total, 782 patients were included, with a median follow-up of 36 mo. The median PFS and OS were 22 and 53 mo, respectively. Parameters associated with lower PFS in the multivariate analysis were a Ki-67 of more than 5%, previous treatment with interferon-α and chemotherapy, presence of diabetes, and chromogranin-A (CgA) levels higher than 336 μg/L. Parameters associated with lower OS were a Ki-67 of more than 10%, performance status of at least 1, previous chemotherapy and ablation, and CgA levels higher than 112 μg/L. Conclusion: Higher Ki-67 values, as well as higher CgA levels and previous chemotherapy, had a negative outcome on both PFS and OS. Furthermore, PFS was negatively associated with previous interferon-α treatment and diabetes, whereas lower OS was related to prior ablation and higher performance status.

111In-Pentetreotide Scintigraphy Versus 68Ga-DOTATATE PET: Impact on Krenning Scores and Effect of Tumor Burden

Hope, T. A., Calais, J., Zhang, L., Dieckmann, W., Millo, C. — 2019-09-03T10:10:09-07:00

Eligibility for somatostatin receptor (SSTR) radionuclide therapy uses the qualitative Krenning score based on ¹¹¹In-pentetreotide planar scintigraphy as was performed in the NETTER-1 trial. The purpose of this study was to determine the effect of using SSTR PET–based Krenning score in comparison to ¹¹¹In-pentetreotide. Methods: This was a post hoc head-to-head comparison of ⁶⁸Ga-DOTATATE–based and ¹¹¹In-pentetreotide–based Krenning scores in 150 patients included in a prospective phase 2 study (NCT01967537). Patients were imaged using ⁶⁸Ga-DOTATATE PET/CT, ¹¹¹In-pentetreotide planar scintigraphy, and SPECT/CT within 1 wk. SSTR ligand uptake was graded using the Krenning score independently by 3 readers. Results: The detection rate of SSTR-expressing disease (Krenning scores 2–4) was 23%, 38%, and 72% with planar imaging, SPECT, and SSTR PET, respectively. The Krenning score was higher with SSTR PET (2.71 ± 1.74) than with planar imaging (0.75 ± 1.37; P < 0.001) or SPECT (1.23 ± 1.57; P < 0.001). In patients with a Krenning score of at least 3 on SSTR PET, the detection rate of planar imaging and SPECT was lower for lesions smaller than 2 cm than lesions 2 cm or larger: 15% and 24% versus 78% and 89%, respectively (P < 0.001). For lesions larger than 5 cm, Krenning scores between SSTR PET and ¹¹¹In-pentetreotide were nearly equivalent. Lesion size did not have an impact on SSTR PET Krenning scores. Interreader agreement was higher for SSTR PET than for planar imaging or SPECT (0.79 vs. 0.67 and 0.50, respectively). Conclusion: SSTR PET results in higher Krenning scores than ¹¹¹In-pentetreotide, particularly when lesions measured 2 cm or less. Small lesion size resulted in low Krenning scores using ¹¹¹In-pentetreotide, but lesion size did not affect SSTR PET–based Krenning scores. The results of the NETTER-1 trial cannot be directly applied to patients with small lesions. Further study of peptide receptor radionuclide therapy in patients with small lesions negative on ¹¹¹In-pentetreotide imaging and positive on SSTR PET is warranted.

First Clinicopathologic Evidence of a Non-PSMA-Related Uptake Mechanism for 68Ga-PSMA-11 in Salivary Glands

2019-09-03T10:10:09-07:00

The intense accumulation of prostate-specific membrane antigen (PSMA) radioligands in salivary glands is still not well understood. It is of concern for therapeutic applications of PSMA radioligands, because therapeutic radiation will damage these glands. A better understanding of the uptake mechanism is, therefore, crucial to find solutions to reduce toxicity. The aim of this study was to investigate whether the accumulation of PSMA-targeting radioligands in submandibular glands (SMGs) can be explained with PSMA expression levels using autoradiography (ARG) and immunohistochemistry (IHC). Methods: All patients gave written informed consent for further utility of the biologic material. The SMG of 9 patients, pancreatic tissue of 4 patients, and prostate cancer (PCA) lesions of 9 patients were analyzed. Tissue specimens were analyzed by means of PSMA-IHC (using an anti–PSMA-antibody and an immunoreactivity score system [IRS]) and ARG using ¹⁷⁷Lu-PSMA-617 (with quantification of the relative signal intensity compared with a PSMA-positive standard). The SUV_max in salivary glands, pancreas, and PCA tissues were quantified in 60 clinical ⁶⁸Ga-PSMA-11 PET scans for recurrent disease as well as the 9 primary tumors selected for ARG and IHC. Results: PCA tissue samples revealed a wide range of PSMA staining intensity on IHC (IRS = 70–300) as well as in ARG (1.3%–22% of standard). This variability on PCA tissue could also be observed in ⁶⁸Ga-PSMA-11 PET (SUV_max, 4.4–16) with a significant correlation between ARG and SUV_max (P < 0.001, R² = 0.897). On IHC, ARG, and ⁶⁸Ga-PSMA-11 PET, the pancreatic tissue was negative (IRS = 0, ARG = 0.1% ± 0.05%, SUV_max of 3.1 ± 1.1). The SMG tissue displayed only focal expression of PSMA limited to the intercalated ducts on IHC (IRS = 10–15) and a minimal signal on ARG (1.3% ± 0.9%). In contrast, all SMG showed a high ⁶⁸Ga-PSMA-11 accumulation on PET scans (SUV_max 23.5 ± 5.2). Conclusion: Our results indicate that the high accumulation of PSMA radioligands in salivary glands does not correspond to high PSMA expression levels determined using ARG and IHC. These findings provide evidence, that the significant accumulation of PSMA radioligands in SMG is not primarily a result of PSMA-mediated uptake.

qPSMA: Semiautomatic Software for Whole-Body Tumor Burden Assessment in Prostate Cancer Using 68Ga-PSMA11 PET/CT

2019-09-03T10:10:09-07:00

Our aim was to introduce and validate qPSMA, a semiautomatic software package for whole-body tumor burden assessment in prostate cancer patients using ⁶⁸Ga-prostate-specific membrane antigen (PSMA) 11 PET/CT. Methods: qPSMA reads hybrid PET/CT images in DICOM format. Its pipeline was written using Python and C++ languages. A bone mask based on CT and a normal-uptake mask including organs with physiologic ⁶⁸Ga-PSMA11 uptake are automatically computed. An SUV threshold of 3 and a liver-based threshold are used to segment bone and soft-tissue lesions, respectively. Manual corrections can be applied using different tools. Multiple output parameters are computed, that is, PSMA ligand–positive tumor volume (PSMA-TV), PSMA ligand–positive total lesion (PSMA-TL), PSMA SUV_mean, and PSMA SUV_max. Twenty ⁶⁸Ga-PSMA11 PET/CT data sets were used to validate and evaluate the performance characteristics of qPSMA. Four analyses were performed: validation of the semiautomatic algorithm for liver background activity determination, assessment of intra- and interobserver variability, validation of data from qPSMA by comparison with Syngo.via, and assessment of computational time and comparison of PSMA PET–derived parameters with serum prostate-specific antigen. Results: Automatic liver background calculation resulted in a mean relative difference of 0.74% (intraclass correlation coefficient [ICC], 0.996; 95%CI, 0.989;0.998) compared with METAVOL. Intra- and interobserver variability analyses showed high agreement (all ICCs > 0.990). Quantitative output parameters were compared for 68 lesions. Paired t testing showed no significant differences between the values obtained with the 2 software packages. The ICC estimates obtained for PSMA-TV, PSMA-TL, SUV_mean, and SUV_max were 1.000 (95%CI, 1.000;1.000), 1.000 (95%CI, 1.000;1.000), 0.995 (95%CI, 0.992;0.997), and 0.999 (95%CI, 0.999;1.000), respectively. The first and second reads for intraobserver variability resulted in mean computational times of 13.63 min (range, 8.22–25.45 min) and 9.27 min (range, 8.10–12.15 min), respectively (P = 0.001). Highly significant correlations were found between serum prostate-specific antigen value and both PSMA-TV (r = 0.72, P < 0.001) and PSMA-TL (r = 0.66, P = 0.002). Conclusion: Semiautomatic analyses of whole-body tumor burden in ⁶⁸Ga-PSMA11 PET/CT is feasible. qPSMA is a robust software package that can help physicians quantify tumor load in heavily metastasized prostate cancer patients.

Preclinical Evaluation and Pilot Clinical Study of Al18F-PSMA-BCH for Prostate Cancer PET Imaging

2019-09-03T10:10:09-07:00

Prostate-specific membrane antigen (PSMA)–targeted radioligands have played an important role in the diagnosis of prostate cancer. In this study, we developed an Al¹⁸F-labeled radiotracer and evaluated its potential for prostate cancer imaging. Methods: Al¹⁸F-PSMA-BCH (BCH is Beijing Cancer Hospital) was efficiently prepared manually. The binding affinity to PSMA was evaluated in vitro using the 22Rv1 (PSMA-positive) cell line. Small-animal PET imaging, biodistribution studies of Al¹⁸F-PSMA-BCH in mice bearing 22Rv1 and PC-3 (PSMA-negative) xenografted tumors, and a comparison with ⁶⁸Ga-PSMA-617 in mice bearing LNCaP tumors were performed. PET/CT imaging was performed on 11 newly diagnosed prostate cancer patients at 1 and 2 h after injection. Biodistribution and preliminary efficacy were evaluated, and radiation dosimetry was estimated using OLINDA/EXM 2.0 software. Results: Al¹⁸F-PSMA-BCH was prepared within 30 min and was found to bind to PSMA with a dissociation constant of 2.90 ± 0.83 nM. Small-animal PET imaging of Al¹⁸F-PSMA-BCH could clearly differentiate 22Rv1 tumors from PC-3 tumors, as confirmed by ex vivo biodistribution data (7.87% ± 2.37% and 0.54% ± 0.22% injected dose/g at 1 h in 22Rv1 and PC-3 tumors, respectively). The uptake of Al¹⁸F-PSMA-BCH in 22Rv1 tumors could be substantially blocked by excess ZJ-43, a PSMA inhibitor. High-level accumulation of Al¹⁸F-PSMA-BCH was observed in PSMA-expressing organs, with increased uptake at later time points. Thirty-seven tumor lesions were detected in 11 patients, and the SUV_max in 27 lesions increased between 1 and 2 h after injection (10.60 vs. 14.11). The SUV_max in primary lesions in patients with high-risk prostate cancer was higher than that in patients with intermediate-risk prostate cancer. The kidneys received the highest estimated dose, 0.135 mGy/MBq, and the effective dose was 0.016 mGy/MBq. Conclusion: Al¹⁸F-PSMA-BCH was conveniently prepared with a reasonable yield within 30 min and showed a promising imaging capability for prostate cancer with reasonable radiation exposure. Al¹⁸F-PSMA-BCH can be used for prostate cancer imaging as a novel ¹⁸F PET radiotracer.

Synergistic Effect of a Mesothelin-Targeted 227Th Conjugate in Combination with DNA Damage Response Inhibitors in Ovarian Cancer Xenograft Models

2019-09-03T10:10:09-07:00

Targeted ²²⁷Th conjugates (TTCs) represent a new class of therapeutic radiopharmaceuticals for targeted α-therapy. They comprise the α-emitter ²²⁷Th complexed to a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting monoclonal antibody. The high energy and short range of the α-particles induce antitumor activity, driven by the induction of complex DNA double-strand breaks. We hypothesized that blocking the DNA damage response (DDR) pathway should further sensitize cancer cells by inhibiting DNA repair, thereby increasing the response to TTCs. Methods: This article reports the evaluation of the mesothelin (MSLN)-TTC conjugate (BAY 2287411) in combination with several DDR inhibitors, each of them blocking different DDR pathway enzymes. MSLN is a validated cancer target known to be overexpressed in mesothelioma, ovarian, lung, breast, and pancreatic cancer, with low expression in normal tissue. In vitro cytotoxicity experiments were performed on cancer cell lines by combining the MSLN-TTC with inhibitors of ataxia telangiectasia mutated, ataxia telangiectasia and Rad3-related (ATR), DNA-dependent protein kinase, and poly[adenosine diphosphate ribose] polymerase (PARP) 1/2. Further, we evaluated the antitumor efficacy of the MSLN-TTC in combination with DDR inhibitors in human ovarian cancer xenograft models. Results: Synergistic activity was observed in vitro for all tested inhibitors (inhibitors are denoted herein by the suffix "i") when combined with MSLN-TTC. ATRi and PARPi appeared to induce the strongest increase in potency. Further, in vivo antitumor efficacy of the MSLN-TTC in combination with ATRi or PARPi was investigated in the OVCAR-3 and OVCAR-8 xenograft models in nude mice, demonstrating synergistic antitumor activity for the ATRi combination at doses demonstrated to be nonefficacious when administered as monotherapy. Conclusion: The presented data support the mechanism-based rationale for combining the MSLN-TTC with DDR inhibitors as new treatment strategies in MSLN-positive ovarian cancer.

Enhancement of 211At Uptake via the Sodium Iodide Symporter by the Addition of Ascorbic Acid in Targeted {alpha}-Therapy of Thyroid Cancer

2019-09-03T10:10:09-07:00

²¹¹At is an α-emitter that has similar chemical properties to iodine and is used in targeted α-therapy. In the present study, we added ascorbic acid (AA) to ²¹¹At solution to increase the radiochemical purity of astatide and evaluated its efficacy against differentiated thyroid cancer, which is characterized by the expression of sodium/iodide symporter (NIS). Methods: Crude ²¹¹At solution (AA(–)) and ²¹¹At solution treated with AA (AA(+)) were prepared. Uptake by the thyroid was compared between the 2 solutions in normal male Wistar rats (n = 6). Cellular uptake in K1-NIS cells was analyzed under the AA(+) and AA(–) conditions. AA(+) was injected at 3 doses into K1-NIS xenograft mice: 1 MBq (n = 6), 0.4 MBq (n = 6), and 0.1 MBq (n = 6), and vehicle was injected into control mice (n = 6). The treatment effects were compared among the 4 groups. Results: Uptake by the thyroid was significantly enhanced in rats injected with the AA(+) as compared with those injected with AA(–). Cellular uptake analysis showed significantly increased uptake of ²¹¹At by the K1-NIS cells under the AA(+) condition as compared with the AA(–) condition. In the mouse xenograft model, the K1-NIS tumors showed significant accumulation of ²¹¹At at 3 and 24 h after administration (22.5 ± 10.4 and 12.9 ± 6.8 percentage injected dose, respectively). Tumor growth was immediately inhibited in a dose-dependent manner after administration of ²¹¹At. In the survival analysis, the ²¹¹At groups (0.1, 0.4, and 1 MBq) showed significantly better survival than the control group. Conclusion: Uptake of ²¹¹At was enhanced in differentiated thyroid cancer cells as well as the normal thyroid using ²¹¹At solution treated with AA. The method also showed dose-dependent efficacy against the K1-NIS xenografts, suggesting its potential applicability to targeted α-therapy.

In Vivo Translation of the CIRPI System: Revealing Molecular Pathology of Rabbit Aortic Atherosclerotic Plaques

2019-09-03T10:10:09-07:00

Thin-cap fibroatheroma (TCFA) are the unstable lesions in coronary artery disease that are prone to rupture, resulting in substantial morbidity and mortality worldwide. However, their small size and complex morphologic and biologic features make early detection and risk assessment difficult. We tested our newly developed catheter-based Circumferential-Intravascular-Radioluminescence-Photoacoustic-Imaging (CIRPI) system in vivo to enable detection and characterization of vulnerable plaque structure and biology in rabbit abdominal aorta. Methods: The CIRPI system includes a novel optical probe combining circumferential radioluminescence imaging and photoacoustic tomography (PAT). The probe’s CaF₂:Eu-based scintillating imaging window captures radioluminescence images (360° view) of plaques by detecting β-particles during ¹⁸F-FDG decay. A tunable laser-based PAT characterizes tissue constituents of plaque at 7 different wavelengths—540 and 560 nm (calcification), 920 nm (cholesteryl ester), 1040 nm (phospholipids), 1180 nm (elastin/collagen), 1210 nm (cholesterol), and 1235 nm (triglyceride). A single B-scan is concatenated from 330 A-lines captured during a 360° rotation. The abdominal aorta was imaged in vivo in both atherosclerotic rabbits (Watanabe Heritable Hyper Lipidemic [WHHL], 13-mo-old male, n = 5) and controls (New Zealand White, n = 2). Rabbits were fasted for 6 h before 5.55 x 10⁷ Bq (1.5 mCi) of ¹⁸F-FDG were injected 1 h before the imaging procedure. Rabbits were anesthetized, and the right or left common carotid artery was surgically exposed. An 8 French catheter sheath was inserted into the common carotid artery, and a 0.035-cm (0.014-in) guidewire was advanced to the iliac artery, guided by x-ray fluoroscopy. A bare metal stent was implanted in the dorsal abdominal aorta as a landmark, followed by the 7 French imaging catheters that were advanced up to the proximal stent edge. Our CIRPI and clinical optical coherence tomography (OCT) were performed using pullback and nonocclusive flushing techniques. After imaging with the CIRPI system, the descending aorta was flushed with contrast agent, and OCT images were obtained with a pullback speed of 20 mm/s, providing images at 100 frames/s. Results were verified with histochemical analysis. Results: Our CIRPI system successfully detected the locations and characterized both stable and vulnerable aortic plaques in vivo among all WHHL rabbits. Calcification was detected from the stable plaque (540 and 560 nm), whereas TCFA exhibited phospholipids/cholesterol (1040 nm, 1210 nm). These findings were further verified with the clinical OCT system showing an area of low attenuation filled with lipids within TCFA. PAT images illustrated broken elastic fiber/collagen that could be verified with the histochemical analysis. All WHHL rabbits exhibited sparse to severe macrophages. Only 4 rabbits showed both moderate-to-severe level of calcifications and cholesterol clefts. However, all rabbits exhibited broken elastic fibers and collagen deposition. Control rabbits showed normal wall thickness with no presence of plaque tissue compositions. These findings were verified with OCT and histochemical analysis. Conclusion: Our novel multimodality hybrid system has been successfully translated to in vivo evaluation of atherosclerotic plaque structure and biology in a preclinical rabbit model. This system proposed a paradigm shift that unites molecular and pathologic imaging technologies. Therefore, the system may enhance the clinical evaluation of TCFA, as well as expand our understanding of coronary artery disease.

Small-Animal PET/CT Imaging of Local and Systemic Immune Response Using 64Cu-{alpha}CD11b

Cao, Q., Huang, Q., Mohan, C., Li, C. — 2019-09-03T10:10:09-07:00

Current noninvasive imaging methods for monitoring immune response were largely developed for interrogation of the local reaction. This study developed the radiotracer ⁶⁴Cu-labeled anti-CD11b (⁶⁴Cu-αCD11b) for longitudinal assessment of local and systemic immune response involving mobilization of CD11b⁺ myeloid cells by small-animal PET/CT. Methods: Acute or chronic inflammation in the ears of BALB/c mice was induced by 12-o-tetradecanoylphorbol-13-acetate. Acute lung inflammation was induced by intratracheal lipopolysaccharide inoculation. αCD11b was conjugated with p-SCN-Bn-DOTA followed by labeling with ⁶⁴Cu. PET/CT and biodistribution were evaluated at different times after intravenous injection of ⁶⁴Cu-αCD11b. Cell populations from bone marrow (BM) and spleen were analyzed by flow cytometry. Results: ⁶⁴Cu-αCD11b was primarily taken up by BM and spleen in control mice. In comparison, ⁶⁴Cu-αCD11b uptake was significantly reduced in the BM and spleen of CD11b-knockout mice, indicating that ⁶⁴Cu-αCD11b selectively homed to CD11b⁺ myeloid cells in vivo. In mice with ear inflammation, for the local inflammatory response, ⁶⁴Cu-αCD11b PET/CT revealed significantly higher ⁶⁴Cu-αCD11b uptake in the inflamed ears in the acute inflammation phase than the chronic phase, consistent with markedly increased infiltration of CD11b⁺ cells into the inflammatory lesions at the acute phase. Moreover, imaging of ⁶⁴Cu-αCD11b also showed the difference in mouse systemic response for different inflammatory stages. Compared with uptake in control mice, BM ⁶⁴Cu-αCD11b uptake in mice with ear inflammation was significantly lower in the acute phase and higher in the chronic phase, reflecting an initial mobilization of CD11b⁺ cells from the BM to the inflammatory foci followed by a compensatory regeneration of CD11b⁺ myeloid cells in the BM. Similarly, in mice with lung inflammation, ⁶⁴Cu-αCD11b PET/CT readily detected acute lung inflammation and recruitment of CD11b⁺ myeloid cells from the BM. Immunohistochemistry staining and flow cytometry results confirmed the noninvasive imaging of PET/CT. Conclusion: ⁶⁴Cu-αCD11b PET/CT successfully tracked ear and pulmonary inflammation in mice and differentiated acute from chronic inflammation at the local and systemic levels. ⁶⁴Cu-αCD11b PET/CT is a robust quantitative method for imaging of local and systemic immune responses.

Molecular Imaging of the Glomerulus via Mesangial Cell Uptake of Radiolabeled Tilmanocept

2019-09-03T10:10:09-07:00

An unmet need for the clinical management of chronic kidney disease is a predictive tool of kidney function during the first decade of the disease, when there is silent loss of glomerular function. The objective of this study was to demonstrate receptor-mediated binding of tilmanocept to CD206 within the kidney and provide evidence of kinetic sensitivity of this binding to renal function. Methods: Rats were positioned in a PET scanner with the liver and kidneys within the field of view. After an intravenous injection of ⁶⁸Ga-IRDye800-tilmanocept, using 1 of 2 scaled molar doses (0.02 nmol/g, n = 5; or 0.10 nmol/g, n = 5), or coinjection (n = 3) of ⁶⁸Ga-IRDye800-tilmanocept (0.10 nmol/g) and unlabeled tilmanocept (5.0 nmol/g), or a negative control, ⁶⁸Ga-IRDye800-DTPA-galactosyl-dextran (0.02 nmol/g, n = 5), each animal was imaged for 20 min followed by a whole-body scan. Frozen kidney sections were stained for podocytes and CD206 using immunofluorescence. Molecular imaging of diabetic db/db mice (4.9 wk, n = 6; 7.3 wk, n = 4; 13.3 wk, n = 6) and nondiabetic db/m mice (n = 6) was performed with fluorescence-labeled ^99mTc-tilmanocept (18.5 MBq, 2.6 nmol). Thirty minutes after injection, blood, liver, kidneys, and urine were assayed for radioactivity. Renal time–activity curves were generated. Results: Rat PET whole-body images and time–activity curves of ⁶⁸Ga-IRDye800-tilmanocept demonstrated receptor-mediated renal accumulation with evidence of glomerular uptake. Activity within the renal cortex persisted during the 40-min study. Histologic examination demonstrated colocalization of CD206 and IRDye800-tilmanocept within the glomerulus. The glomerular accumulation of the coinjection and the negative control studies were significantly less than the CD206-targeted agent. The db/db mice displayed a multiphasic renal time–activity curve with high urinary bladder accumulation; the nondiabetic mice exhibited renal uptake curves dominated by a single phase with low bladder accumulation. Conclusion: This study demonstrated receptor-mediated binding to the glomerular mesangial cells and kinetic sensitivity of tilmanocept to chronic renal disease. Given the role of mesangial cells during the progression of diabetic nephropathy, PET or SPECT renal imaging with radiolabeled tilmanocept may provide a noninvasive quantitative assessment of glomerular function.

Also Human: The Inner Lives of Doctors

Tadepalli, V. R., Matthews, R. — 2019-09-03T10:10:09-07:00

Improved Scatter Correction to Eliminate Halo Artifacts for 68Ga-Labeled Radiopharmaceuticals in PET Imaging

Wangerin, K., Iagaru, A. — 2019-09-03T10:10:09-07:00

Reply to: Improved Scatter Correction to Eliminate Halo Artifacts for 68Ga-Labeled Radiopharmaceuticals in PET Imaging

Lindemann, M. E., Quick, H. H. — 2019-09-03T10:10:09-07:00

The Martinique Principles

2019-09-03T10:10:09-07:00