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Nuclear Medicine Training: What Now?
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Nuclear Medicine Training: What Now?

J Nucl Med. 2017 Oct;58(10):1536-1538

Authors: Mankoff D, Pryma DA

Abstract
Although the multidisciplinary nature of nuclear medicine (NM) and clinical molecular imaging is a key strength of the specialty, the breadth of disciplines involved in the practice of NM creates challenges for education and training. The evolution of NM science and technology-and the practice of clinical molecular imaging and theranostics-has created a need for changes in the approach to specialty training. The broader U.S. community of imaging physicians has been slow to accept this change, in good part due to historical divides between the NM and nuclear radiology (NR) communities. In this Journal of Nuclear Medicine Hot Topics discussion, we review the historical pathways to training; discuss the training needs for the modern practice of NM, clinical molecular imaging, and radionuclide therapy; and suggest a path forward for an approach to training that matches the needs of the evolving clinical specialty.

PMID: 28818993 [PubMed - indexed for MEDLINE]




(18)F-FDG PET/CT in Lymphoma: Has Imaging-Directed Personalized Medicine Become a Reality?
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(18)F-FDG PET/CT in Lymphoma: Has Imaging-Directed Personalized Medicine Become a Reality?

J Nucl Med. 2017 Oct;58(10):1539-1544

Authors: Barrington SF, Johnson PWM

Abstract
PET/CT using (18)F-FDG is an essential part of the management of patients with lymphoma. Efforts to standardize PET acquisition and reporting, including the 5-point Deauville scale, have enabled PET to become a surrogate for treatment success or failure in common lymphoma subtypes. This review summarizes the key clinical-trial evidence that supports PET-directed personalized approaches in lymphoma. PET-guided therapy has improved outcomes in Hodgkin lymphoma, using less chemotherapy and more selective radiotherapy. Attempts to intensify chemotherapy in aggressive non-Hodgkin lymphomas have, however, proved ineffective in patients treated with rituximab and chemotherapy. Trials are under way to determine whether PET can obviate consolidation radiotherapy in patients with diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma. More recently, PET has been reported to be a reliable predictor of outcome in follicular lymphoma requiring treatment, and prospective trials to test PET-guided therapy in this disease are anticipated.

PMID: 28798034 [PubMed - indexed for MEDLINE]




Pretargeted Imaging and Therapy.
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Pretargeted Imaging and Therapy.

J Nucl Med. 2017 Oct;58(10):1553-1559

Authors: Altai M, Membreno R, Cook B, Tolmachev V, Zeglis BM

Abstract
In vivo pretargeting stands as a promising approach to harnessing the exquisite tumor-targeting properties of antibodies for nuclear imaging and therapy while simultaneously skirting their pharmacokinetic limitations. The core premise of pretargeting lies in administering the targeting vector and radioisotope separately and having the 2 components combine within the body. In this manner, pretargeting strategies decrease the circulation time of the radioactivity, reduce the uptake of the radionuclide in healthy nontarget tissues, and facilitate the use of short-lived radionuclides that would otherwise be incompatible with antibody-based vectors. In this short review, we seek to provide a brief yet informative survey of the 4 preeminent mechanistic approaches to pretargeting, strategies predicated on streptavidin and biotin, bispecific antibodies, complementary oligonucleotides, and bioorthogonal click chemistry.

PMID: 28687600 [PubMed - indexed for MEDLINE]




PSMA Ligands for PET Imaging of Prostate Cancer.
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PSMA Ligands for PET Imaging of Prostate Cancer.

J Nucl Med. 2017 Oct;58(10):1545-1552

Authors: Schwarzenboeck SM, Rauscher I, Bluemel C, Fendler WP, Rowe SP, Pomper MG, Asfhar-Oromieh A, Herrmann K, Eiber M

Abstract
Targeting the prostate-specific membrane antigen (PSMA) with (68)Ga-labeled and (18)F-labeled PET agents has become increasingly important in recent years. Imaging of biochemically recurrent prostate cancer has been established as a widely accepted clinical indication for PSMA ligand PET/CT in many parts of the world because of the results of multiple, primarily retrospective, studies that indicate superior detection efficacy compared with standard-of-care imaging. For high-risk primary prostate cancer, evidence is growing that this modality significantly aids in the detection of otherwise occult nodal and bone metastases. For both clinical indications in recurrent as well as in primary prostate cancer, preliminary data demonstrate a substantial impact on clinical management. Emerging data imply that intraprostatic tumor localization, therapy stratification, and treatment monitoring of advanced disease in specific clinical situations might become future indications. Current criteria for image reporting of PSMA ligand PET are evolving given the expanding body of literature on physiologic and pathologic uptake patterns and pitfalls. This article intends to give an educational overview on the current status of PSMA ligand PET imaging, including imaging procedure and interpretation, clinical indications, diagnostic potential, and impact on treatment planning.

PMID: 28687599 [PubMed - indexed for MEDLINE]




Doxorubicin Effect on Myocardial Metabolism as a Prerequisite for Subsequent Development of Cardiac Toxicity: A Translational (18)F-FDG PET/CT Observation.
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Doxorubicin Effect on Myocardial Metabolism as a Prerequisite for Subsequent Development of Cardiac Toxicity: A Translational (18)F-FDG PET/CT Observation.

J Nucl Med. 2017 Oct;58(10):1638-1645

Authors: Bauckneht M, Ferrarazzo G, Fiz F, Morbelli S, Sarocchi M, Pastorino F, Ghidella A, Pomposelli E, Miglino M, Ameri P, Emionite L, Ticconi F, Arboscello E, Buschiazzo A, Massimelli EA, Fiordoro S, Borra A, Cossu V, Bozzano A, Ibatici A, Ponzoni M, Spallarossa P, Gallamini A, Bruzzi P, Sambuceti G, Marini C

Abstract
The present translational study aimed to verify whether serial (18)F-FDG PET/CT predicts doxorubicin cardiotoxicity. Methods: Fifteen athymic mice were treated intravenously with saline (n = 5) or with 5 or 7.5 mg of doxorubicin per kilogram (n = 5 each) and underwent dynamic small-animal PET beforehand and afterward to estimate left ventricular (LV) metabolic rate of glucose (MRGlu). Thereafter, we retrospectively identified 69 patients who had been successfully treated with a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine for Hodgkin disease (HD) and had undergone 4 consecutive (18)F-FDG PET/CT scans. Volumes of interest were drawn on LV myocardium to quantify mean SUV. All patients were subsequently interviewed by telephone (median follow-up, 30 mo); 36 of them agreed to undergo electrocardiography and transthoracic echocardiography. Results: In mice, LV MRGlu was 17.9 ± 4.4 nmol × min(-1) × g(-1) at baseline. Doxorubicin selectively and dose-dependently increased this value in the standard-dose (27.9 ± 9 nmol × min(-1) × g(-1), P < 0.05 vs. controls) and high-dose subgroups (37.2 ± 7.8 nmol × min(-1) × g(-1), P < 0.01 vs. controls, P < 0.05 vs. standard-dose). In HD patients, LV SUV showed a progressive increase during doxorubicin treatment that persisted at follow-up. New-onset cardiac abnormalities appeared in 11 of 36 patients (31%). In these subjects, pretherapy LV SUV was markedly lower with respect to the remaining patients (1.53 ± 0.9 vs. 3.34 ± 2.54, respectively, P < 0.01). Multivariate analysis confirmed the predictive value of baseline LV SUV for subsequent cardiac abnormalities. Conclusion: Doxorubicin dose-dependently increases LV MRGlu, particularly in the presence of low baseline (18)F-FDG uptake. These results imply that low myocardial (18)F-FDG uptake before the initiation of doxorubicin chemotherapy in HD patients may predict the development of chemotherapy-induced cardiotoxicity, suggesting that prospective clinical trials are warranted to test this hypothesis.

PMID: 28646013 [PubMed - indexed for MEDLINE]




In Vivo Relationship Between Hypoxia and Angiogenesis in Human Glioblastoma: A Multimodal Imaging Study.
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In Vivo Relationship Between Hypoxia and Angiogenesis in Human Glioblastoma: A Multimodal Imaging Study.

J Nucl Med. 2017 Oct;58(10):1574-1579

Authors: da Ponte KF, Berro DH, Collet S, Constans JM, Emery E, Valable S, Guillamo JS

Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. This aggressiveness is in part attributed to the closely interrelated phenomena tumor hypoxia and angiogenesis, although few in vivo data exist in human brain tumors. This work aimed to study hypoxia and angiogenesis, in vivo and in situ, in patients admitted with GBM using multimodal imaging. Methods: Twenty-three GBM patients were assessed by (18)F-fluoromisonidazole ((18)F-FMISO) PET and conventional and perfusion MRI before surgery. The level and location of hypoxia ((18)F-FMISO uptake, evaluated by tumor-to-blood [T/B] ratio), vascularization (cerebral blood volume [CBV]), and vascular permeability (contrast enhancement after gadolinium injection) were analyzed. The spatial relationship between tumor hypoxia and angiogenesis was assessed by an overlap analysis of the volume of (18)F-FMISO uptake and the volumes of the high CBV regions and the contrast-enhancement regions. Results: A significant correlation was found between hypoxia and hypervascularization, especially for their maximum values (volume of maximal tumor hypoxia vs. relative CBV: r = 0.61, P = 0.002) and their volumes (hypoxia vs. hypervascularization: r = 0.91, P < 0.001). A large proportion of the high CBVs collocated with hypoxia (81.3%) and with contrast enhancement (46.5%). Conclusion: These results support the hypothesis of a tight association between hypoxia and angiogenesis. Our results suggest that there is insufficient tumor oxygenation in human GBM, despite increased tumor vascularization.

PMID: 28596159 [PubMed - indexed for MEDLINE]




Molecular Imaging of Human Embryonic Stem Cells Stably Expressing Human PET Reporter Genes After Zinc Finger Nuclease-Mediated Genome Editing.
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Molecular Imaging of Human Embryonic Stem Cells Stably Expressing Human PET Reporter Genes After Zinc Finger Nuclease-Mediated Genome Editing.

J Nucl Med. 2017 Oct;58(10):1659-1665

Authors: Wolfs E, Holvoet B, Ordovas L, Breuls N, Helsen N, Schönberger M, Raitano S, Struys T, Vanbilloen B, Casteels C, Sampaolesi M, Van Laere K, Lambrichts I, Verfaillie CM, Deroose CM

Abstract
Molecular imaging is indispensable for determining the fate and persistence of engrafted stem cells. Standard strategies for transgene induction involve the use of viral vectors prone to silencing and insertional mutagenesis or the use of nonhuman genes. Methods: We used zinc finger nucleases to induce stable expression of human imaging reporter genes into the safe-harbor locus adeno-associated virus integration site 1 in human embryonic stem cells. Plasmids were generated carrying reporter genes for fluorescence, bioluminescence imaging, and human PET reporter genes. Results: In vitro assays confirmed their functionality, and embryonic stem cells retained differentiation capacity. Teratoma formation assays were performed, and tumors were imaged over time with PET and bioluminescence imaging. Conclusion: This study demonstrates the application of genome editing for targeted integration of human imaging reporter genes in human embryonic stem cells for long-term molecular imaging.

PMID: 28596158 [PubMed - indexed for MEDLINE]




Exploring New Multimodal Quantitative Imaging Indices for the Assessment of Osseous Tumor Burden in Prostate Cancer Using (68)Ga-PSMA PET/CT.
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Exploring New Multimodal Quantitative Imaging Indices for the Assessment of Osseous Tumor Burden in Prostate Cancer Using (68)Ga-PSMA PET/CT.

J Nucl Med. 2017 Oct;58(10):1632-1637

Authors: Bieth M, Krönke M, Tauber R, Dahlbender M, Retz M, Nekolla SG, Menze B, Maurer T, Eiber M, Schwaiger M

Abstract
PET combined with CT and prostate-specific membrane antigen (PSMA) ligands has gained significant interest for staging prostate cancer (PC). In this study, we propose 2 multimodal quantitative indices as imaging biomarkers for the assessment of osseous tumor burden using (68)Ga-PSMA PET/CT and present preliminary clinical data. Methods: We defined 2 bone PET indices (BPIs) that incorporate anatomic information from CT and functional information from (68)Ga-PSMA PET: BPIVOL is the percentage of bone volume affected by tumor and BPISUV additionally considers the level of PSMA expression. We describe a semiautomatic computation method based on segmentation of bones in CT and of lesions in PET. Data from 45 patients with castration-resistant PC and bone metastases during (223)Ra-dichloride were retrospectively analyzed. We evaluated the computational stability and reproducibility of the proposed indices and explored their relation to the prostate-specific antigen blood value, the bone scan index (BSI), and disease classification using PERCIST. Results: On the technical side, BPIVOL and BPISUV showed an interobserver maximum difference of 3.5%, and their computation took only a few minutes. On the clinical side, BPIVOL and BPISUV showed significant correlations with BSI (r = 0.76 and 0.74, respectively, P < 0.001) and prostate-specific antigen values (r = 0.57 and 0.54, respectively, P < 0.01). When the proposed indices were compared against expert rating using PERCIST, BPIVOL and BPISUV showed better agreement than BSI, indicating their potential for objective response evaluation. Conclusion: We propose the evaluation of BPIVOL and BPISUV as imaging biomarkers for (68)Ga-PSMA PET/CT in a prospective study exploring their potential for outcome prediction in patients with bone metastases from PC.

PMID: 28546330 [PubMed - indexed for MEDLINE]




Imaging Macrophage Accumulation in a Murine Model of Chronic Pancreatitis with (125)I-Iodo-DPA-713 SPECT/CT.
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Imaging Macrophage Accumulation in a Murine Model of Chronic Pancreatitis with (125)I-Iodo-DPA-713 SPECT/CT.

J Nucl Med. 2017 Oct;58(10):1685-1690

Authors: Foss CA, Liu L, Mease RC, Wang H, Pasricha P, Pomper MG

Abstract
Pancreatitis remains a diagnostic challenge in patients with mild to moderate disease, with current imaging modalities being inadequate. Given the prominent macrophage infiltration in chronic pancreatitis, we hypothesized that (125)I-iodo-DPA-713, a small-molecule radiotracer that specifically targets macrophages, could be used with SPECT/CT to image pancreatic inflammation in a relevant experimental model. Methods: Chronic pancreatitis was induced with cerulein in C57BL/6 mice, which were contrasted with saline-injected control mice. The animals were imaged at 7 wk after induction using N,N-diethyl-2-(2-(3-(125)I-iodo-4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ((125)I-iodo-DPA-713) SPECT/CT or (18)F-FDG PET/CT. The biodistribution of (125)I-iodo-DPA-713 was determined under the same conditions, and a pair of mice was imaged using a fluorescent analog of (125)I-iodo-DPA-713, DPA-713-IRDye800CW, for correlative histology. Results: Pancreatic (125)I-iodo-DPA-713 uptake was significantly higher in treated mice than control mice (5.17% ± 1.18% vs. 2.41% ± 0.34% injected dose/g, P = 0.02), as corroborated by imaging. Mice imaged with (18)F-FDG PET/CT showed cerulein-enhanced pancreatic uptake in addition to a moderate signal from healthy pancreas. Near-infrared fluorescence imaging with DPA-713-IRDye800CW showed strong pancreatic uptake, focal liver uptake, and gastrointestinal uptake in the treated mice, whereas the control mice showed only urinary excretion. Ex vivo fluorescence microscopy revealed a large influx of macrophages in the pancreas colocalizing with the retained fluorescent probe in the treated but not the control mice. Conclusion: These data support the application of both (125)I-iodo-DPA-713 SPECT/CT and DPA-713-IRDye800CW near-infrared fluorescence to delineate pancreatic, liver, or intestinal inflammation in living mice.

PMID: 28522739 [PubMed - indexed for MEDLINE]




Imaging of Programmed Cell Death Ligand 1: Impact of Protein Concentration on Distribution of Anti-PD-L1 SPECT Agents in an Immunocompetent Murine Model of Melanoma.
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Imaging of Programmed Cell Death Ligand 1: Impact of Protein Concentration on Distribution of Anti-PD-L1 SPECT Agents in an Immunocompetent Murine Model of Melanoma.

J Nucl Med. 2017 Oct;58(10):1560-1566

Authors: Nedrow JR, Josefsson A, Park S, Ranka S, Roy S, Sgouros G

Abstract
Programmed cell death ligand 1 (PD-L1) is part of an immune checkpoint system that is essential for preventing autoimmunity and cancer. Recent approaches in immunotherapy that target immune checkpoints have shown great promise in a variety of cancers, including metastatic melanoma. The use of targeted molecular imaging would help identify patients who will best respond to anti-PD-L1 treatment while potentially providing key information to limit immune-related adverse effects. Recently, we developed an antibody-based PD-L1-targeted SPECT agent-(111)In-diethylenetriaminepentaacetic acid (DTPA)-anti-PD-L1-to identify PD-L1-positive tumors in vivo. To best use such PD-L1-targeted imaging agents, it is important, as a first step, to understand how the signal is affected by different parameters. Methods: We evaluated the impact of protein concentration on the distribution of (111)In-DTPA-anti-PD-L1 in a murine model of aggressive melanoma. Results:(111)In-DTPA-anti-PD-L1 (dissociation constant, 0.6 ± 0.1 nM) demonstrated increased uptake in B16F10 tumors at protein concentrations equaling or exceeding 1 mg/kg at 24 h and 3 mg/kg at 72 h. At 24 h, the PD-L1-rich spleen and lungs demonstrated decreasing uptake with increasing protein concentration. At 72 h, uptake in the thymus was significantly increased at protein concentrations of 3 mg/kg or greater. Both time points demonstrated increased tracer amounts remaining in circulation as the amount of cold antibody was increased. Conclusion: These studies demonstrate that (111)In-DTPA-anti-PD-L1 is capable of identifying tumors that overexpresses PD-L1 and monitoring the impact of PD-L1-rich organs on the distribution of anti-PD-L1 antibodies.

PMID: 28522738 [PubMed - indexed for MEDLINE]




Specific Imaging of Bacterial Infection Using 6″-(18)F-Fluoromaltotriose: A Second-Generation PET Tracer Targeting the Maltodextrin Transporter in Bacteria.
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Specific Imaging of Bacterial Infection Using 6″-(18)F-Fluoromaltotriose: A Second-Generation PET Tracer Targeting the Maltodextrin Transporter in Bacteria.

J Nucl Med. 2017 Oct;58(10):1679-1684

Authors: Gowrishankar G, Hardy J, Wardak M, Namavari M, Reeves RE, Neofytou E, Srinivasan A, Wu JC, Contag CH, Gambhir SS

Abstract
6″-(18)F-fluoromaltotriose is a PET tracer that can potentially be used to image and localize most bacterial infections, much like (18)F-FDG has been used to image and localize most cancers. However, unlike (18)F-FDG, 6″-(18)F-fluoromaltotriose is not taken up by inflammatory lesions and appears to be specific to bacterial infections by targeting the maltodextrin transporter that is expressed in gram-positive and gram-negative strains of bacteria. Methods: 6″-(18)F-fluoromaltotriose was synthesized with high radiochemical purity and evaluated in several clinically relevant bacterial strains in cultures and in living mice. Results: 6″-(18)F-fluoromaltotriose was taken up in both gram-positive and gram-negative bacterial strains. 6″-(18)F-fluoromaltotriose was also able to detect Pseudomonas aeruginosa in a clinically relevant mouse model of wound infection. The utility of 6″-(18)F-fluoromaltotriose to help monitor antibiotic therapies was also evaluated in rats. Conclusion: 6″-(18)F-fluoromaltotriose is a promising new tracer that has significant diagnostic utility, with the potential to change the clinical management of patients with infectious diseases of bacterial origin.

PMID: 28490473 [PubMed - indexed for MEDLINE]




SSTR-Mediated Imaging in Breast Cancer: Is There a Role for Radiolabeled Somatostatin Receptor Antagonists?
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SSTR-Mediated Imaging in Breast Cancer: Is There a Role for Radiolabeled Somatostatin Receptor Antagonists?

J Nucl Med. 2017 Oct;58(10):1609-1614

Authors: Dalm SU, Haeck J, Doeswijk GN, de Blois E, de Jong M, van Deurzen CHM

Abstract
Recent studies have shown enhanced tumor targeting by novel somatostatin receptor (SSTR) antagonists compared with clinically widely used agonists. However, these results have been obtained mostly in neuroendocrine tumors, and only limited data are available for cancer types with lower SSTR expression, including breast cancer (BC). To date, two studies have reported higher binding of the antagonist than the agonist in BC, but in both studies only a limited number of cases were evaluated. In this preclinical study, we further investigated whether the application of an SSTR antagonist can improve SSTR-mediated BC imaging in a large panel of BC specimens. We also generated an in vivo BC mouse model and performed SPECT/MRI and biodistribution studies. Methods: Binding of (111)In-DOTA-Tyr(3)-octreotate (SSTR agonist) and (111)In-DOTA-JR11 (SSTR antagonist) to 40 human BC specimens was compared using in vitro autoradiography. SSTR2 immunostaining was performed to confirm SSTR2 expression of the tumor cells. Furthermore, binding of the radiolabeled SSTR agonist and antagonist was analyzed in tissue material from 6 patient-derived xenografts. One patient-derived xenograft, the estrogen receptor-positive model T126, was chosen to generate in vivo mouse models containing orthotopic breast tumors for in vivo SPECT/MRI and biodistribution studies after injection with (177)Lu-DOTA-Tyr(3)-octreotate or (177)Lu-DOTA-JR11. Results:(111)In-DOTA-JR11 binding to human BC tissue was significantly higher than (111)In-DOTA-Tyr(3)-octreotate binding (P < 0.001). The median ratio of antagonist binding versus agonist binding was 3.39 (interquartile range, 2-5). SSTR2 immunostaining confirmed SSTR2 expression on the tumor cells. SPECT/MRI of the mouse model found better tumor visualization with the antagonist. This result was in line with the significantly higher tumor uptake of the radiolabeled antagonist than of the agonist as measured in biodistribution studies 285 min after radiotracer injection (percentage injected dose per gram of tissue: 1.92 ± 0.43 vs. 0.90 ± 0.17; P = 0.002). Conclusion: SSTR antagonists are promising candidates for BC imaging.

PMID: 28450563 [PubMed - indexed for MEDLINE]




High-Contrast PET Imaging of Vasopressin V1B Receptors with a Novel Radioligand, (11)C-TASP699.
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High-Contrast PET Imaging of Vasopressin V1B Receptors with a Novel Radioligand, (11)C-TASP699.

J Nucl Med. 2017 Oct;58(10):1652-1658

Authors: Koga K, Nagai Y, Hanyu M, Yoshinaga M, Chaki S, Ohtake N, Ozaki S, Zhang MR, Suhara T, Higuchi M

Abstract
Vasopressin 1B receptors (V1BRs) are abundantly expressed in the pituitary, and in vivo PET of V1BRs was recently enabled by our development of a specific radioligand, (11)C-TASP0434299, derivatized from pyridopyrimidin-4-one. Here, we identified a novel pyridopyrimidin-4-one analog, N-tert-butyl-2-[2-(6-(11)C-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]acetamide ((11)C-TASP0410699, hereafter referred to as (11)C-TASP699), as a potent V1BR radioligand producing a higher image contrast for the target than (11)C-TASP0434299. Methods: In vitro properties of TASP699 were assessed by assaying its affinity for human V1BR and its selectivity for off-target molecules. Radioactive uptake in the pituitary was analyzed using PET in rhesus monkeys after intravenous administration of (11)C-TASP699. Serial doses of a selective V1BR antagonist, 2-[2-(3-chloro-4-fluorophenyl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]-N-isopropylacetamide hydrochloride (TASP0390325), were administered before the radioligand injection. Autoradiographic labeling of monkey pituitary slices with (11)C-TASP699 was conducted with or without nonradioactive V1BR antagonists. Results: The half maximal inhibitory concentration (IC50) of TASP699 for human V1BRs (0.165 nM) was lower than that of TASP0434299 (0.526 nM), whereas its IC50 values for off-target molecules exceeded 1 μM. PET imaging in monkeys demonstrated that the peak pituitary uptake of (11)C-TASP699 was almost equivalent to that of (11)C-TASP0434299 and that pretreatment with TASP0390325 inhibited the retention of (11)C-TASP699 in a dose-dependent manner, inducing nearly full occupancy at 0.3 mg/kg. Specific radioligand binding was determined as a specific-to-nondisplaceable uptake ratio at equilibrium using radioactivity retentions at 60 min in baseline and blocking studies. This ratio for (11)C-TASP699 was approximately 2.5-fold greater than that of (11)C-TASP0434299. A reversed-phase high-performance liquid chromatography study identified the parent and polar radiometabolites. Affinities of 2 predicted metabolite candidates for V1BRs were more than 10 times weaker than that of the parent. Intense autoradiographic labeling of the anterior pituitary with (11)C-TASP699 was inhibited with TASP0390325 in a concentration-dependent manner. Conclusion:(11)C-TASP699 yielded PET images of pituitary V1BRs with a higher contrast than (11)C-TASP0434299, supporting the applicability of (11)C-TASP699 in the assessment of neuropsychiatric diseases and dose findings for test drugs in clinical trials.

PMID: 28450560 [PubMed - indexed for MEDLINE]




Improved Detection of Transosseous Meningiomas Using (68)Ga-DOTATATE PET/CT Compared with Contrast-Enhanced MRI.
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Improved Detection of Transosseous Meningiomas Using (68)Ga-DOTATATE PET/CT Compared with Contrast-Enhanced MRI.

J Nucl Med. 2017 Oct;58(10):1580-1587

Authors: Kunz WG, Jungblut LM, Kazmierczak PM, Vettermann FJ, Bollenbacher A, Tonn JC, Schichor C, Rominger A, Albert NL, Bartenstein P, Reiser MF, Cyran CC

Abstract
(68)Ga-DOTATATE PET/CT enables detection of meningioma tissue based on somatostatin receptor 2 expression. Transosseous extension of intracranial meningiomas is known to be an important risk factor for tumor recurrence and patient mortality. We analyzed the diagnostic performance of (68)Ga-DOTATATE PET/CT and contrast-enhanced MRI (CE-MRI) for the detection of osseous infiltration using qualitative and quantitative imaging parameters. Methods: In this institutional review board-approved retrospective study, subjects were selected from 327 consecutive (68)Ga-DOTATATE PET/CT examinations for evaluation of confirmed or suspected meningioma. Inclusion criteria were CE-MRI within 30 d and pathology-confirmed meningioma diagnosis with inclusion or exclusion of transosseous extension as the standard of reference. Imaging was analyzed by two readers. Tracer uptake values and meningioma volumes were determined. χ(2), Mann-Whitney U, Wilcoxon signed rank, and McNemar tests, as well as receiver-operating-characteristic analyses, were performed to compare variables and diagnostic performance. Results: Eighty-two patients fulfilled the inclusion criteria. Patients with transosseous extension of meningioma (n = 67) showed significantly larger lesions (median, 12.8 vs. 3.3 mL; P < 0.001) and significantly higher tracer uptake values (median SUVmax, 14.2 vs. 7.6; P = 0.011) than patients with extraosseous meningiomas (n = 15). (68)Ga-DOTATATE PET/CT in comparison to CE-MRI performed at a higher sensitivity (98.5% vs. 53.7%) while maintaining high specificity (86.7% vs. 93.3%) in the detection of osseous involvement (P < 0.001). In receiver-operating-characteristic analysis, PET/CT assessment performed better than CE-MRI (area under the curve, 0.932 vs. 0.773). PET/CT- and CE-MRI-based volume estimation yielded comparable results for extraosseous meningiomas (P = 0.132) and the extraosseous part of transosseous meningiomas (P = 0.636), whereas the volume of the intraosseous part was assessed as significantly larger by PET/CT (P < 0.001). Conclusion:(68)Ga-DOTATATE PET/CT enables improved detection of the transosseous extension of intracranial meningiomas compared with CE-MRI.

PMID: 28450556 [PubMed - indexed for MEDLINE]




(68)Ga-PSMA-11 PET/CT Interobserver Agreement for Prostate Cancer Assessments: An International Multicenter Prospective Study.
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(68)Ga-PSMA-11 PET/CT Interobserver Agreement for Prostate Cancer Assessments: An International Multicenter Prospective Study.

J Nucl Med. 2017 Oct;58(10):1617-1623

Authors: Fendler WP, Calais J, Allen-Auerbach M, Bluemel C, Eberhardt N, Emmett L, Gupta P, Hartenbach M, Hope TA, Okamoto S, Pfob CH, Pöppel TD, Rischpler C, Schwarzenböck S, Stebner V, Unterrainer M, Zacho HD, Maurer T, Gratzke C, Crispin A, Czernin J, Herrmann K, Eiber M

Abstract
The interobserver agreement for (68)Ga-PSMA-11 PET/CT study interpretations in patients with prostate cancer is unknown. Methods:(68)Ga-PSMA-11 PET/CT was performed in 50 patients with prostate cancer for biochemical recurrence (n = 25), primary diagnosis (n = 10), biochemical persistence after primary therapy (n = 5), or staging of known metastatic disease (n = 10). Images were reviewed by 16 observers who used a standardized approach for interpretation of local (T), nodal (N), bone (Mb), or visceral (Mc) involvement. Observers were classified as having a low (<30 prior (68)Ga-PSMA-11 PET/CT studies; n = 5), intermediate (30-300 studies; n = 5), or high level of experience (>300 studies; n = 6). Histopathology (n = 25, 50%), post-external-beam radiation therapy prostate-specific antigen response (n = 15, 30%), or follow-up PET/CT (n = 10, 20%) served as a standard of reference. Observer groups were compared by overall agreement (% patients matching the standard of reference) and Fleiss' κ with mean and corresponding 95% confidence interval (CI). Results: Agreement among all observers was substantial for T (κ = 0.62; 95% CI, 0.59-0.64) and N (κ = 0.74; 95% CI, 0.71-0.76) staging and almost perfect for Mb (κ = 0.88; 95% CI, 0.86-0.91) staging. Level of experience positively correlated with agreement for T (κ = 0.73/0.66/0.50 for high/intermediate/low experience, respectively), N (κ = 0.80/0.76/0.64, respectively), and Mc staging (κ = 0.61/0.46/0.36, respectively). Interobserver agreement for Mb was almost perfect irrespective of prior experience (κ = 0.87/0.91/0.88, respectively). Observers with low experience, when compared with intermediate and high experience, demonstrated significantly lower median overall agreement (54% vs. 66% and 76%, P = 0.041) and specificity for T staging (73% vs. 88% and 93%, P = 0.032). Conclusion: The interpretation of (68)Ga-PSMA-11 PET/CT for prostate cancer staging is highly consistent among observers with high levels of experience, especially for nodal and bone assessments. Initial training on at least 30 patient cases is recommended to ensure acceptable performance.

PMID: 28408531 [PubMed - indexed for MEDLINE]




Alternative Means of Estimating (131)I Maximum Permissible Activity to Treat Thyroid Cancer.
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Alternative Means of Estimating (131)I Maximum Permissible Activity to Treat Thyroid Cancer.

J Nucl Med. 2017 Oct;58(10):1588-1595

Authors: Nichols KJ, Robeson W, Yoshida-Hay M, Zanzonico PB, Leveque F, Bhargava KK, Tronco GG, Palestro CJ

Abstract
To protect bone marrow from overirradiation, the maximum permissible activity (MPA) of (131)I to treat thyroid cancer is that which limits the absorbed dose to blood (as a surrogate of marrow) to less than 200 cGy. The conventional approach (method 1) requires repeated γ-camera whole-body measurements along with blood samples. We sought to determine whether reliable MPA values can be obtained by simplified procedures. Methods: Data acquired over multiple time points were examined retrospectively for 65 thyroid cancer patients, referred to determine (131)I uptake and MPA for initial treatment after thyroidectomy (n = 39), including 17 patients with compromised renal function and 22 patients with known (n = 16) or suspected (n = 6) metastases. The total absorbed dose to blood (DTotal) was the sum of mean whole-body γ-ray dose component (Dγ) from uncollimated γ-camera measurements and dose due to β emissions (Dβ) from blood samples. Method 2 estimated DTotal from Dβ alone, method 3 estimated DTotal from Dγ alone, and method 4 estimated DTotal from a single 48-h γ-camera measurement. MPA was computed as 200 cGy/DTotal for each DTotal estimate. Results: Method 2 had the strongest correlation with conventional method 1 (r = 0.98) and values similar to method 1 (21.0 ± 13.7 cGy/GBq vs. 21.0 ± 14.1 cGy/GBq, P = 0.11), whereas method 3 had a weaker (P = 0.001) correlation (r = 0.94) and method 4 had the weakest (P < 0.0001) correlation (r = 0.69) and lower dose (16.3 ± 14.8 cGy/GBq, P < 0.0001). Consequently, correlation with method 1 MPA was strongest for method 2 MPA (r = 0.99) and weakest for method 4 (r = 0. 75). Method 2 and method 1 values agreed equally well regardless of whether patients had been treated with (131)I previously or had abnormal renal function. Conclusion: Because MPA based on blood measurements alone is comparable to MPA obtained with combined body counting and blood sampling, blood measurements alone are sufficient for determining MPA.

PMID: 28408530 [PubMed - indexed for MEDLINE]




Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with (225)Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding.
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Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with (225)Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding.

J Nucl Med. 2017 Oct;58(10):1624-1631

Authors: Kratochwil C, Bruchertseifer F, Rathke H, Bronzel M, Apostolidis C, Weichert W, Haberkorn U, Giesel FL, Morgenstern A

Abstract
The aim of this study was to develop a treatment protocol for (225)Ac-PSMA-617 α-radiation therapy in advanced-stage, metastatic castration-resistant prostate cancer patients with prostate-specific membrane antigen (PSMA)-positive tumor phenotype. Methods: A dosimetry estimate was calculated on the basis of time-activity curves derived from serially obtained (177)Lu-PSMA-617 scans extrapolated to the physical half-life of (225)Ac, assuming instant decay of unstable daughter nuclides. Salvage therapies empirically conducted with 50 (n = 4), 100 (n = 4), 150 (n = 2), and 200 kBq/kg (n = 4) of (225)Ac-PSMA-617 were evaluated retrospectively regarding toxicity and treatment response. Eight of 14 patients received further cycles in either 2- or 4-mo intervals with identical or deescalated activities. Results: Dosimetry estimates for 1 MBq of (225)Ac-PSMA-617 assuming a relative biologic effectiveness of 5 revealed mean doses of 2.3 Sv for salivary glands, 0.7 Sv for kidneys, and 0.05 Sv for red marrow that are composed of 99.4% α, 0.5% β, and 0.1% photon radiation, respectively. In clinical application, severe xerostomia became the dose-limiting toxicity if treatment activity exceeded 100 kBq/kg per cycle. At 100 kBq/kg, the duration of prostate-specific antigen decline was less than 4 mo, but if therapy was repeated every 2 mo patients experienced additive antitumor effects. Treatment activities of 50 kBq/kg were without toxicity but induced insufficient antitumor response in these high-tumor-burden patients. Remarkable antitumor activity by means of objective radiologic response or tumor marker decline was observed in 9 of 11 evaluable patients. Conclusion: For advanced-stage patients, a treatment activity of 100 kBq/kg of (225)Ac-PSMA-617 per cycle repeated every 8 wk presents a reasonable trade-off between toxicity and biochemical response.

PMID: 28408529 [PubMed - indexed for MEDLINE]




(18)F-Tetrafluoroborate, a PET Probe for Imaging Sodium/Iodide Symporter Expression: Whole-Body Biodistribution, Safety, and Radiation Dosimetry in Thyroid Cancer Patients.
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(18)F-Tetrafluoroborate, a PET Probe for Imaging Sodium/Iodide Symporter Expression: Whole-Body Biodistribution, Safety, and Radiation Dosimetry in Thyroid Cancer Patients.

J Nucl Med. 2017 Oct;58(10):1666-1671

Authors: O'Doherty J, Jauregui-Osoro M, Brothwood T, Szyszko T, Marsden PK, O'Doherty MJ, Cook GJR, Blower PJ, Lewington V

Abstract
We report the safety, biodistribution, and internal radiation dosimetry, in humans with thyroid cancer, of (18)F-tetrafluoroborate ((18)F-TFB), a novel PET radioligand for imaging the human sodium/iodide symporter (hNIS). Methods: Serial whole-body PET scans of 5 subjects with recently diagnosed thyroid cancer were acquired before surgery for up to 4 h after injection of 184 ± 15 MBq of (18)F-TFB. Activity was determined in whole blood, plasma, and urine. Mean organ-absorbed doses and effective doses were calculated via quantitative image analysis and using OLINDA/EXM software. Results: Images showed a high uptake of (18)F-TFB in known areas of high hNIS expression (thyroid, salivary glands, and stomach). Excretion was predominantly renal. No adverse effects in relation to safety of the radiopharmaceutical were observed. The effective dose was 0.0326 ± 0.0018 mSv/MBq. The critical tissues/organs receiving the highest mean sex-averaged absorbed doses were the thyroid (0.135 ± 0.079 mSv/MBq), stomach (0.069 ± 0.022 mSv/MBq), and salivary glands (parotids, 0.031 ± 0.011 mSv/MBq; submandibular, 0.061 ± 0.031 mSv/MBq). Other organs of interest were the bladder (0.102 ± 0.046 mSv/MBq) and kidneys (0.029 ± 0.009 mSv/MBq). Conclusion: Imaging using (18)F-TFB imparts a radiation exposure similar in magnitude to many other (18)F-labeled radiotracers. (18)F-TFB shows a biodistribution similar to (99m)Tc-pertechnetate, a known nonorganified hNIS tracer, and is pharmacologically and radiobiologically safe in humans. Phase 2 trials for (18)F-TFB as an hNIS imaging agent are warranted.

PMID: 28385795 [PubMed - indexed for MEDLINE]




Reader Training for the Restaging of Biochemically Recurrent Prostate Cancer Using (18)F-Fluciclovine PET/CT.
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Reader Training for the Restaging of Biochemically Recurrent Prostate Cancer Using (18)F-Fluciclovine PET/CT.

J Nucl Med. 2017 Oct;58(10):1596-1602

Authors: Miller MP, Kostakoglu L, Pryma D, Yu JQ, Chau A, Perlman E, Clarke B, Rosen D, Ward P

Abstract
(18)F-Fluciclovine is a novel PET/CT tracer. This blinded image evaluation (BIE) sought to demonstrate that, after limited training, readers naïve to (18)F-fluciclovine could interpret (18)F-fluciclovine images from subjects with biochemically recurrent prostate cancer with acceptable diagnostic performance and reproducibility. The primary objectives were to establish individual readers' diagnostic performance and the overall interpretation (2/3 reader concordance) compared with standard-of-truth data (histopathology or clinical follow-up) and to evaluate interreader reproducibility. Secondary objectives included comparison to the expert reader and assessment of intrareader reproducibility. Methods:(18)F-Fluciclovine PET/CT images (n = 121) and corresponding standard-of-truth data were collected from 110 subjects at Emory University using a single-time-point static acquisition starting 5 min after injection of approximately 370 MBq of (18)F-fluciclovine. Three readers were trained using standardized interpretation methodology and subsequently evaluated the images in a blinded manner. Analyses were conducted at the lesion, region (prostate, including bed and seminal vesicle, or extraprostatic, including all lymph nodes, bone, or soft-tissue metastasis), and subject level. Results: Lesion-level overall positive predictive value was 70.5%. The readers' positive predictive value and negative predictive value were broadly consistent with each other and with the onsite read. Sensitivity was highest for readers 1 and 2 (68.5% and 63.9%, respectively) whereas specificity was highest for reader 3 (83.6%). Overall, prostate-level sensitivity was high (91.4%), but specificity was moderate (48.7%). Interreader agreement was 94.7%, 74.4%, and 70.3% for the lesion, prostate, and extraprostatic levels, respectively, with associated Fleiss' κ-values of 0.54, 0.50, and 0.57. Intrareader agreement was 97.8%, 96.9%, and 99.1% at the lesion level; 100%, 100%, and 91.7% in the prostate region; and 83.3%, 75.0%, and 83.3% in the extraprostatic region for readers 1, 2, and 3, respectively. Concordance between the BIE and the onsite reader exceeded 75% for each reader at the lesion, region, and subject levels. Conclusion: Specific training in the use of standardized interpretation methodology for assessment of (18)F-fluciclovine PET/CT images enables naïve readers to achieve acceptable diagnostic performance and reproducibility when staging recurrent prostate cancer.

PMID: 28385791 [PubMed - indexed for MEDLINE]




(18)F-Fluoromisonidazole Kinetic Modeling for Characterization of Tumor Perfusion and Hypoxia in Response to Antiangiogenic Therapy.
Related Articles (18)F-Fluoromisonidazole Kinetic Modeling for Characterization of Tumor Perfusion and Hypoxia in Response to Antiangiogenic Therapy. J Nucl Med. 2017 Oct;58(10):1567-1573 Authors: Grkovski M, Emmas SA, Carlin SD Abstract Multiparametric imaging of tumor perfusion and hypoxia with dynamic (18)F-fluoromisonidazole ((18)F-FMISO) PET may allow for an improved response assessment to antiangiogenic therapies. Cediranib (AZD2171) is a potent inhibitor of tyrosine kinase activity associated with vascular endothelial growth factor receptors 1, 2, and 3, currently in phase II/III clinical trials. Serial dynamic (18)F-FMISO PET was performed to investigate changes in tumor biomarkers of perfusion and hypoxia after cediranib treatment. Methods: Twenty-one rats bearing HT29 colorectal xenograft tumors were randomized into a vehicle-treated control group (0.5% methylcellulose daily for 2 d [5 rats] or 7 d [4 rats]) and a cediranib-treated test group (3 mg/kg daily for 2 or 7 d; 6 rats in both groups). All rats were imaged before and after treatment, using a 90-min dynamic PET acquisition after administration of 42.1 ± 3.9 MBq of (18)F-FMISO by tail vein injection. Tumor volumes were delineated manually, and the input function was image-derived (abdominal aorta). Kinetic modeling was performed using an irreversible 1-plasma 2-tissue compartmental model to estimate the kinetic rate constants K1, K1/k2, and k3-surrogates for perfusion, (18)F-FMISO distribution volume, and hypoxia-mediated entrapment, respectively. Tumor-to-blood ratios (TBRs) were calculated on the last dynamic frame (80-90 min). Tumors were assessed ex vivo by digital autoradiography and immunofluorescence for microscopic visualization of perfusion (pimonidazole) and hypoxia (Hoechst 33342). Results: Cediranib treatment resulted in significant reduction of mean voxelwise (18)F-FMISO TBR, K1, and K1/k2 in both the 2-d and the 7-d groups (P < 0.05). The k3 parameter was increased in both groups but reached significance only in the 2-d group. In the vehicle-treated groups, no significant change in TBR, K1, K1/k2, or k3 was observed (P > 0.2). Ex vivo tumor analysis confirmed the presence of hypoxic tumor regions that nevertheless exhibited relatively lower (18)F-FMISO uptake. Conclusion:(18)F-FMISO kinetic modeling reveals a more detailed response to antiangiogenic treatment than a single static image is able to reveal. The reduced mean K1 reflects a reduction in tumor vascular perfusion, whereas the increased k3 reflects a rise in hypoxia-mediated entrapment of the radiotracer. However, if only late static images are analyzed, the observed reduction in (18)F-FMISO uptake after treatment with cediranib may be mistakenly interpreted as a global decrease, rather than an increase, in tumor hypoxia. These findings support the use of (18)F-FMISO kinetic modeling to more accurately characterize the response to treatments that have a direct effect on tumor vascularization and perfusion. PMID: 28360207 [PubMed - indexed for MEDLINE] [...]



Simulation of Tracer Dose Reduction in (18)F-FDG PET/MRI: Effects on Oncologic Reading, Image Quality, and Artifacts.
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Simulation of Tracer Dose Reduction in (18)F-FDG PET/MRI: Effects on Oncologic Reading, Image Quality, and Artifacts.

J Nucl Med. 2017 Oct;58(10):1699-1705

Authors: Seith F, Schmidt H, Kunz J, Küstner T, Gatidis S, Nikolaou K, la Fougère C, Schwenzer N

Abstract
The aim of our study was to evaluate the effect of stepwise-reduced doses on objective and subjective image parameters and on oncologic readings in whole-body (18)F-FDG PET/MRI. Methods: We retrospectively simulated the stepwise reduction of (18)F-FDG doses of 19 patients (mean age ± SD, 50.9 ± 11.7 y; mean body mass index ± SD, 22.8 ± 3.2 kg/m(2)) who received a whole-body PET/MRI examination from 3 to 0.5 MBq/kg of body weight (kgBW) in intervals of 0.25. Objective imaging parameters were assessed by measuring the SUV and coefficient of variation in different regions (aorta, liver, spleen, kidney, small bowel, lumbar vertebra, psoas muscle, urinary bladder) as well as the noise-equivalent counting rates in each bed position. Subjective image quality was evaluated with a masked reading of each simulated PET compared with the dose of 2 MBq/kgBW. Oncologic reading was performed first according to PERCIST in each dose and second by defining malignant lesions in doses of 2 MBq/kgBW and the maximum dose image (gold standard). The diagnostic confidence of each lesion was measured using a Likert scale. Results: With decreasing doses, regions in the mid abdomen showed a stronger decrease of SUVmean and noise-equivalent counting rates than regions in the upper abdomen (SUVmean, -45% and -15% on average in the small bowel and the liver, respectively). The coefficient of variation showed a nonlinear increase, pronounced below 1.5 MBq/kgBW. Subjective image quality was stable over a range between 1.25 and 2.75 MBq/kgBW compared with 2 MBq/kgBW. However, large photopenic areas in the mid abdomen were observed in 2 patients. In the PERCIST reading, target lesions were above the liver threshold with a stable SUVpeak in all cases down to 2 MBq/kgBW. Eighty-six of 90 lesions were identified correctly with a dose of 2 MBq/kgBW; Likert scores did not differ significantly. Conclusion: A reduction of doses in (18)F-FDG PET/MRI might be possible down to 2 MBq/kgBW in oncologic whole-body examinations. The image quality in the mid abdomen seems to be more affected by lower doses than in the upper abdomen, and in single cases large photopenic areas can occur. Therefore, we do not recommend reducing doses below 3 MBq/kgBW in adults at this time.

PMID: 28360205 [PubMed - indexed for MEDLINE]




Assessing Bone Marrow Activity in Patients with Myelofibrosis: Results of a Pilot Study of (18)F-FLT PET.
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Assessing Bone Marrow Activity in Patients with Myelofibrosis: Results of a Pilot Study of (18)F-FLT PET.

J Nucl Med. 2017 Oct;58(10):1603-1608

Authors: Vercellino L, Ouvrier MJ, Barré E, Cassinat B, de Beco V, Dosquet C, Chevret S, Meignin V, Chomienne C, Toubert ME, Merlet P, Kiladjian JJ

Abstract
An emerging noninvasive approach to assess tissue proliferation uses the PET tracer 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT). To evaluate the diagnostic value of this technique in myelofibrosis, (18)F-FLT PET imaging results were compared with bone marrow histology and bone marrow scintigraphy (BMS), the gold standard techniques in this clinical situation. Methods: Fifteen patients with histology-proven myelofibrosis were included consecutively in the study. Tracers' distributions were assessed using a visual grading assessment score of the uptake in the axial skeleton, proximal and distal limbs, liver, and spleen. This visual score was used to define patterns of tracer distribution and to compare the information provided either by PET or by BMS. A semiquantitative analysis with determination of SUVmax in the same localizations was performed for (18)F-FLT PET. Results: The histology grade of fibrosis correlated with the SUVmax in the axial skeleton (spine and iliac crests) and proximal limbs. (18)F-FLT uptake in these areas was much lower in patients with grade 3 fibrosis than in patients with grade 1 or 2 fibrosis. (18)F-FLT PET showed the same distribution of uptake as BMS in 13 of 14 patients (1 patient did not undergo BMS). In 1 patient, (18)F-FLT PET clearly showed an intense abnormal splenic uptake, whereas spleen uptake was inconclusive with BMS. Conclusion:(18)F-FLT PET appears to be a reliable and convenient technique to assess hematopoietic activity in bone marrow. It yields results close to those observed with BMS. In our study population, (18)F-FLT uptake in the axial skeleton and proximal limbs assessed by SUVmax correlated with the grade of fibrosis. Thus, (18)F-FLT PET may be a useful tool to measure the severity of myelofibrosis, and to monitor noninvasively the patients' status during follow-up. Finally, (18)F-FLT PET may be foreseen as an alternative to BMS.

PMID: 28360204 [PubMed - indexed for MEDLINE]




Evaluation of the Effect of Fingolimod Treatment on Microglial Activation Using Serial PET Imaging in Multiple Sclerosis.
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Evaluation of the Effect of Fingolimod Treatment on Microglial Activation Using Serial PET Imaging in Multiple Sclerosis.

J Nucl Med. 2017 Oct;58(10):1646-1651

Authors: Sucksdorff M, Rissanen E, Tuisku J, Nuutinen S, Paavilainen T, Rokka J, Rinne J, Airas L

Abstract
Traditionally, multiple sclerosis (MS) has been considered a white matter disease with focal inflammatory lesions. It is, however, becoming clear that significant pathology, such as microglial activation, also takes place outside the plaque areas, that is, in areas of normal-appearing white matter (NAWM) and gray matter (GM). Microglial activation can be detected in vivo using 18-kDa translocator protein (TSPO)-binding radioligands and PET. It is unknown whether fingolimod affects microglial activation in MS. The aim of this study was to investigate whether serial PET can be used to evaluate the effect of fingolimod treatment on microglial activation. Methods: Ten relapsing-remitting MS patients were studied using the TSPO radioligand (11)C-(R)-PK11195. Imaging was performed at baseline and after 8 and 24 wk of fingolimod treatment. Eight healthy individuals were imaged for comparison. Microglial activation was evaluated as distribution volume ratio of (11)C-(R)-PK11195. Results: The patients had MS for an average of 7.9 ± 4.3 y (mean ± SD), their total relapses averaged 4 ± 2.4, and their Expanded Disability Status Scale was 2.7 ± 0.5. The patients were switched to fingolimod because of safety reasons or therapy escalation. The mean washout period before the initiation of fingolimod was 2.3 ± 1.1 mo. The patients were clinically stable on fingolimod. At baseline, microglial activation was significantly higher in the combined NAWM and GM areas of MS patients than in healthy controls (P = 0.021). (11)C-(R)-PK11195 binding was reduced (-12.31%) within the combined T2 lesion area after 6 mo of fingolimod treatment (P = 0.040) but not in the areas of NAWM or GM. Conclusion: Fingolimod treatment reduced microglial/macrophage activation at the site of focal inflammatory lesions, presumably by preventing leukocyte trafficking from the periphery. It did not affect the widespread, diffuse microglial activation in the NAWM and GM. The study opens new vistas for designing future therapeutic studies in MS that use the evaluation of microglial activation as an imaging outcome measure.

PMID: 28336784 [PubMed - indexed for MEDLINE]




Three-Dimensional Dosimetry for Radiation Safety Estimates from Intrathecal Administration.
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Three-Dimensional Dosimetry for Radiation Safety Estimates from Intrathecal Administration.

J Nucl Med. 2017 Oct;58(10):1672-1678

Authors: Hesterman JY, Kost SD, Holt RW, Dobson H, Verma A, Mozley PD

Abstract
Intrathecal administration is of growing interest for drug delivery, and its utility is being increasingly investigated through imaging. In this work, the 3-dimensional Voxel-Based Internal Dosimetry Application (VIDA) and 4D Extended Cardiac Torso Phantom (XCAT) were extended to provide radiation safety estimates specific to intrathecal administration. Methods: The 3-dimensional VIDA dosimetry application Monte Carlo simulation was run using a modified XCAT phantom with additional and edited cerebrospinal fluid (CSF) regions to produce voxel-level absorbed dose per unit cumulated activity maps for 9 selected source regions. Simulation validation was performed to compare absorbed dose estimates for common organs in a preexisting dosimetry tool (OLINDA/EXM). Dynamic planar imaging data were acquired in 6 healthy subjects using administered volumes of 5 or 15 mL (n = 3 each) of 185 MBq of (99m)Tc-diethylenetriaminepentaacetic acid. Absorbed dose was estimated for each subject using the intrathecal-specific dosimetry application. Results: Simulation results were within 6% of OLINDA estimates for common organs. Absorbed dose estimates were highest (0.3-0.8 mGy/MBq) in the lumbar CSF space. A whole-body effective dose estimate of 0.003 mSv/MBq was observed. An administered volume dependency was observed with a 15-mL volume, resulting in lower absorbed dose estimates for several intrathecal and nonintrathecal regions. Conclusion: The intrathecal-specific VIDA implementation enables tailored dosimetry estimation for regions most relevant in intrathecal administration. Absorbed doses are highly localized to CSF and spinal regions and should be taken into consideration when designing intrathecal imaging studies. A potentially interesting relationship was observed between absorbed dose and administered volume, which merits further investigation.

PMID: 28336783 [PubMed - indexed for MEDLINE]




Quantitative Evaluation of 2 Scatter-Correction Techniques for (18)F-FDG Brain PET/MRI in Regard to MR-Based Attenuation Correction.
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Quantitative Evaluation of 2 Scatter-Correction Techniques for (18)F-FDG Brain PET/MRI in Regard to MR-Based Attenuation Correction.

J Nucl Med. 2017 Oct;58(10):1691-1698

Authors: Teuho J, Saunavaara V, Tolvanen T, Tuokkola T, Karlsson A, Tuisku J, Teräs M

Abstract
In PET, corrections for photon scatter and attenuation are essential for visual and quantitative consistency. MR attenuation correction (MRAC) is generally conducted by image segmentation and assignment of discrete attenuation coefficients, which offer limited accuracy compared with CT attenuation correction. Potential inaccuracies in MRAC may affect scatter correction, because the attenuation image (μ-map) is used in single scatter simulation (SSS) to calculate the scatter estimate. We assessed the impact of MRAC to scatter correction using 2 scatter-correction techniques and 3 μ-maps for MRAC. Methods: The tail-fitted SSS (TF-SSS) and a Monte Carlo-based single scatter simulation (MC-SSS) algorithm implementations on the Philips Ingenuity TF PET/MR were used with 1 CT-based and 2 MR-based μ-maps. Data from 7 subjects were used in the clinical evaluation, and a phantom study using an anatomic brain phantom was conducted. Scatter-correction sinograms were evaluated for each scatter correction method and μ-map. Absolute image quantification was investigated with the phantom data. Quantitative assessment of PET images was performed by volume-of-interest and ratio image analysis. Results: MRAC did not result in large differences in scatter algorithm performance, especially with TF-SSS. Scatter sinograms and scatter fractions did not reveal large differences regardless of the μ-map used. TF-SSS showed slightly higher absolute quantification. The differences in volume-of-interest analysis between TF-SSS and MC-SSS were 3% at maximum in the phantom and 4% in the patient study. Both algorithms showed excellent correlation with each other with no visual differences between PET images. MC-SSS showed a slight dependency on the μ-map used, with a difference of 2% on average and 4% at maximum when a μ-map without bone was used. Conclusion: The effect of different MR-based μ-maps on the performance of scatter correction was minimal in non-time-of-flight (18)F-FDG PET/MR brain imaging. The SSS algorithm was not affected significantly by MRAC. The performance of the MC-SSS algorithm is comparable but not superior to TF-SSS, warranting further investigations of algorithm optimization and performance with different radiotracers and time-of-flight imaging.

PMID: 28336781 [PubMed - indexed for MEDLINE]