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Metabolic Imaging of Glutamine in Cancer.
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Metabolic Imaging of Glutamine in Cancer.

J Nucl Med. 2017 Apr;58(4):533-537

Authors: Zhu L, Ploessl K, Zhou R, Mankoff D, Kung HF

Abstract
Glucose and glutamine are the most abundant nutrients for producing energy and building blocks in normal and tumor cells. Increased glycolysis in tumors, the Warburg Effect, is the basis for (18)F-FDG PET imaging. Cancer cells can also be genetically reprogrammed to use glutamine. 5-(11)C-(2S)-glutamine and (18)F-(2S,4R)4-fluoroglutamine may be useful complementary tools to measure changes in tumor metabolism. In glioma patients, the tracer (18)F-(2S,4R)4-fluoroglutamine showed tumor-to-background contrast different from that of (18)F-FDG and differences in uptake in glioma patients with clinical progression of disease versus stable disease (tumor-to-brain ratio > 3.7 in clinically active glioma tumors, minimal or no specific uptake in clinically stable tumors). These preliminary results suggest that (18)F-(2S,4R)4-fluoroglutamine PET may be a new tool for probing in vivo metabolism of glutamine in cancer patients and for guiding glutamine-targeted therapeutics. Further studies of uptake mechanism, and comparison of kinetics for (18)F-(2S,4R)4-fluoroglutamine versus the (11)C-labeled native glutamine, will be important and enlightening.

PMID: 28232608 [PubMed - indexed for MEDLINE]




Repeatability of SUV in Oncologic (18)F-FDG PET.
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Repeatability of SUV in Oncologic (18)F-FDG PET.

J Nucl Med. 2017 Apr;58(4):523-532

Authors: Lodge MA

Abstract
Quantitative analysis can potentially improve the accuracy and consistency of (18)F-FDG PET, particularly for the assessment of tumor response to treatment. Although not without limitations, SUV has emerged as the predominant metric for tumor quantification with (18)F-FDG PET. Growing literature suggests that the difference between SUVs measured before and after treatment can be used to predict tumor response at an early stage. SUV is, however, associated with multiple sources of variability, and to best use SUV for response assessment, an understanding of the repeatability of the technique is required. Test-retest studies involve repeated scanning of the same patient on the same scanner using the same protocol no more than a few days apart and provide basic information on the repeatability of the technique. Multiple test-retest studies have been performed to assess SUV repeatability, although a comparison of reports is complicated by the use of different methodologies and statistical metrics. This article reviews the available data, addressing issues such as different repeatability metrics, relative units, log transformation, and asymmetric limits of repeatability. When acquired with careful attention to protocol, tumor SUV has a within-subject coefficient of variation of approximately 10%. In a response assessment setting, SUV reductions of more than 25% and increases of more than 33% are unlikely to be due to measurement variability. Broader margins may be required for sites with less rigorous protocol compliance, but in general, SUV is a highly repeatable imaging biomarker that is ideally suited to monitoring tumor response to treatment in individual patients.

PMID: 28232605 [PubMed - indexed for MEDLINE]




Fluorescence-Based Molecular Imaging of Porcine Urinary Bladder Sentinel Lymph Nodes.
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Fluorescence-Based Molecular Imaging of Porcine Urinary Bladder Sentinel Lymph Nodes.

J Nucl Med. 2017 Apr;58(4):547-553

Authors: Lee HJ, Barback CV, Hoh CK, Qin Z, Kader K, Hall DJ, Vera DR, Kane CJ

Abstract
The primary objective was to test the ability of a laparoscopic camera system to detect the fluorescent signal emanating from sentinel lymph nodes (SLNs) approximately 2 d after injection and imaging of a positron-emitting molecular imaging agent into the submucosa of the porcine urinary bladder. Methods: Three female pigs underwent a submucosal injection of the bladder with fluorescent-tagged tilmanocept, radiolabeled with both (68)Ga and (99m)Tc. One hour after injection, a pelvic PET/CT scan was acquired for preoperative SLN mapping. Approximately 36 h later, robotic SLN mapping was performed using a fluorescence-capable camera system. After identification of the fluorescent lymph nodes, a pelvic lymph node dissection was completed with robotic assistance. All excised nodal packets (n = 36) were assayed for (99m)Tc activity, which established a lymph node as an SLN. (99m)Tc activity was also used to calculate the amount of dye within each lymph node. Results: All of the SLNs defined by the ex vivo γ-well assay of (99m)Tc activity were detected by fluorescence mode imaging. The time between injection and robotic SLN mapping ranged from 32 to 38 h. A total of 5 fluorescent lymph nodes were detected; 2 pigs had 2 fluorescent lymph nodes and 1 pig exhibited a single lymph node. Four of the 5 SLNs exhibited increased SUVs of 12.4-139.0 obtained from PET/CT. The dye content of the injection sites ranged from 371 to 1,441 pmol, which represented 16.5%-64.1% of the injected dose; the amount of dye within the SLNs ranged from 8.5 to 88 pmol, which was equivalent to 0.38%-3.91% of the administered dose. Conclusion: Fluorescent-labeled (68)Ga-tilmanocept allows for PET imaging and real-time intraoperative detection of SLNs during robotic surgery.

PMID: 28153955 [PubMed - indexed for MEDLINE]




In Vivo PET Imaging of the Cancer Integrin αvβ6 Using (68)Ga-Labeled Cyclic RGD Nonapeptides.
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In Vivo PET Imaging of the Cancer Integrin αvβ6 Using (68)Ga-Labeled Cyclic RGD Nonapeptides.

J Nucl Med. 2017 Apr;58(4):671-677

Authors: Notni J, Reich D, Maltsev OV, Kapp TG, Steiger K, Hoffmann F, Esposito I, Weichert W, Kessler H, Wester HJ

Abstract
Expression of the cellular transmembrane receptor αvβ6 integrin is essentially restricted to malignant epithelial cells in carcinomas of a broad variety of lineages, whereas it is virtually absent in normal adult tissues. Thus, it is a highly attractive target for tumor imaging and therapy. Furthermore, αvβ6 integrin plays an important role for the epithelial-mesenchymal interaction and the development of fibrosis. Methods: On the basis of the (68)Ga chelators TRAP (triazacyclononane-triphosphinate) and NODAGA, we synthesized mono-, di-, and trimeric conjugates of the αvβ6 integrin-selective peptide cyclo(FRGDLAFp(NMe)K) via click chemistry. These were labeled with (68)Ga and screened regarding their suitability for in vivo imaging of αvβ6 integrin expression by PET and ex vivo biodistribution in severe combined immunodeficiency mice bearing H2009 tumor (human lung adenocarcinoma) xenografts. For these, αvβ6 integrin expression in tumor and other tissues was determined by β6 immunohistochemistry. Results: Despite the multimers showing higher αvβ6 integrin affinities (23-120 pM) than the monomers (260 pM), the best results-that is, low background uptake and excellent tumor delineation-were obtained with the TRAP-based monomer (68)Ga-avebehexin. This compound showed the most favorable pharmacokinetics because of its high polarity (log D = -3.7) and presence of additional negative charges (carboxylates) on the chelator, promoting renal clearance. Although tumor uptake was low (0.65% ± 0.04% injected dose per gram tissue [%ID/g]), it was still higher than in all other organs except the kidneys, ranging from a maximum for the stomach (0.52 ± 0.04 %ID/g) to almost negligible for the pancreas (0.07 ± 0.01 %ID/g). A low but significant target expression in tumor, lung, and stomach was confirmed by immunohistochemistry. Conclusion: Because of highly sensitive PET imaging even of tissues with low αvβ6 integrin expression density, we anticipate clinical applicability of (68)Ga-avebehexin for imaging of αvβ6 tumors and fibrosis by PET.

PMID: 27980050 [PubMed - indexed for MEDLINE]




Practical Immuno-PET Radiotracer Design Considerations for Human Immune Checkpoint Imaging.
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Practical Immuno-PET Radiotracer Design Considerations for Human Immune Checkpoint Imaging.

J Nucl Med. 2017 Apr;58(4):538-546

Authors: Mayer AT, Natarajan A, Gordon SR, Maute RL, McCracken MN, Ring AM, Weissman IL, Gambhir SS

Abstract
Immune checkpoint blockade has emerged as a promising cancer treatment paradigm. Unfortunately, there are still a large number of patients and malignancies that do not respond to therapy. A major barrier to validating biomarkers for the prediction and monitoring of responders to clinical checkpoint blockade has been the lack of imaging tools to accurately assess dynamic immune checkpoint expression. Here, we sought to optimize noninvasive immuno-PET imaging of human programmed death-ligand 1 (PD-L1) expression, in a preclinical model, using a small high-affinity engineered protein scaffold (HAC-PD1). Six HAC-PD1 radiotracer variants were developed and used in preclinical imaging and biodistribution studies to assess their ability to detect human PD-L1 expression in vivo. Radiotracer design modifications included chelate, glycosylation, and radiometal. HACA-PD1 was adopted as the naming convention for aglycosylated tracer variants. NOD scid γ-(NSG) mice were inoculated with subcutaneous tumors engineered to either be constitutively positive (CT26 hPD-L1) or be negative (ΔmPD-L1 CT26) for human PD-L1 expression. When the tumors had grown to an average size of 1 cm in diameter, mice were injected with 0.75-2.25 MBq (∼10 μg) of an engineered radiotracer variant and imaged. At 1 h after injection, organs were harvested for biodistribution. Of the practical immuno-PET tracer modifications considered, glycosylation was the most prominent design factor affecting tracer uptake, specificity, and clearance. In imaging studies, aglycosylated (64)Cu-NOTA-HACA-PD1 most accurately visualized human PD-L1 expression in vivo. We reasoned that because of the scaffold's small size (14 kDa), its pharmacokinetics may be suitable for labeling with the short-lived and widely clinically available radiometal (68)Ga. At 1 h after injection, (68)Ga-NOTA-HACA-PD1 and (68)Ga-DOTA-HACA-PD1 exhibited promising target-to-background ratios in ex vivo biodistribution studies (12.3 and 15.2 tumor-to-muscle ratios, respectively). Notably, all HAC-PD1 radiotracer variants enabled much earlier detection of human PD-L1 expression (1 h after injection) than previously reported radiolabeled antibodies (>24 h after injection). This work provides a template for assessing immuno-PET tracer design parameters and supports the translation of small engineered protein radiotracers for imaging human immune checkpoints.

PMID: 27980047 [PubMed - indexed for MEDLINE]




(13)N-Ammonia PET/CT Detection of Myocardial Perfusion Abnormalities in Beagle Dogs After Local Heart Irradiation.
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(13)N-Ammonia PET/CT Detection of Myocardial Perfusion Abnormalities in Beagle Dogs After Local Heart Irradiation.

J Nucl Med. 2017 Apr;58(4):605-610

Authors: Song J, Yan R, Wu Z, Li J, Yan M, Hao X, Liu J, Li S

Abstract
Our objective was to determine the potential value of (13)N-ammonia PET/CT myocardial perfusion imaging (MPI) for early detection of myocardial perfusion changes induced by radiation damage. Methods: Thirty-six Beagle dogs were randomly divided into a control group (n = 18) or an irradiation group (n = 18). The latter underwent local irradiation to the left ventricular anterior cardiac wall with a single dose of 20 Gy, whereas the former received sham irradiation. All dogs underwent (13)N-ammonia PET/CT MPI 1 wk before irradiation and at 3, 6, and 12 mo after sham or local irradiation. One week after undergoing (13)N-ammonia PET/CT MPI, the irradiation group underwent coronary angiography. Six randomly selected dogs from each group were sacrificed and used to detect pathologic cardiac injury at 3, 6, and 12 mo after irradiation. Results: Compared with the control group and baseline, the irradiation group showed significantly increased perfusion in the irradiated area of the heart at 3 mo after irradiation, perfusion reduction at 6 mo after irradiation, and a perfusion defect at 12 mo after irradiation. There was no significant difference in the left ventricular ejection fraction between the control and irradiation groups at baseline or at 3 mo after irradiation. The irradiation group showed a reduction of left ventricular ejection fraction compared with the control group at 6 mo (50.0% ± 8.1% vs. 59.3% ± 4.1%, P = 0.016) and 12 mo (47.2% ± 6.7% vs. 57.4% ± 3.3%, P = 0.002) after irradiation. No coronary stenosis was observed in the irradiation group. Regional wall motion abnormalities appeared in the irradiated area at 6 mo after irradiation, and its extent was enlarged at 12 mo after irradiation. Pathologic changes were observed; radiation-induced myocardial tissue damage and microvascular fibrosis in the irradiated area progressively increased over time. Conclusion:(13)N-ammonia PET/CT MPI can dynamically detect myocardial perfusion changes together with global and regional left ventricular dysfunction induced by irradiation and may be a valuable method for monitoring radiation-induced heart disease.

PMID: 27908971 [PubMed - indexed for MEDLINE]




Synthesis and Evaluation of the Estrogen Receptor β-Selective Radioligand 2-(18)F-Fluoro-6-(6-Hydroxynaphthalen-2-yl)Pyridin-3-ol: Comparison with 16α-(18)F-Fluoro-17β-Estradiol.
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Synthesis and Evaluation of the Estrogen Receptor β-Selective Radioligand 2-(18)F-Fluoro-6-(6-Hydroxynaphthalen-2-yl)Pyridin-3-ol: Comparison with 16α-(18)F-Fluoro-17β-Estradiol.

J Nucl Med. 2017 Apr;58(4):554-559

Authors: Antunes IF, van Waarde A, Dierckx RA, de Vries EG, Hospers GA, de Vries EF

Abstract
Estrogen receptors (ERs) are targets for endocrine treatment of estrogen-dependent cancers. The ER consists of 2 isoforms, ERα and ERβ, which have distinct biologic functions. Whereas activation of ERα stimulates cell proliferation and cell survival, ERβ promotes apoptosis. PET of ERα and ERβ levels could provide more insight in response to hormonal treatment. 16α-(18)F-fluoro-17β-estradiol ((18)F-FES) is a PET tracer for ER with relative selectivity for ERα. Here we report the synthesis and evaluation of a potential ERβ-selective PET tracer: 2-(18)F-fluoro-6-(6-hydroxynaphthalen-2-yl)pyridin-3-ol ((18)F-FHNP). Methods:(18)F-FHNP was synthesized by fluorination of the corresponding nitro precursor, followed by acidic removal of the 2-methoxyethoxymethyl protecting group. In vitro affinity of (18)F-FHNP and (18)F-FES for ER was evaluated in SKOV3 ovarian carcinoma cells. PET imaging and ex vivo biodistribution studies with (18)F-FHNP and (18)F-FES were conducted in athymic nude mice bearing a SKOV3 xenografts. Results:(18)F-FHNP had nanomolar affinity for ERs, with a 3.5 times higher affinity for ERβ. (18)F-FHNP was obtained in 15%-40% radiochemical yield (decay-corrected), with a specific activity of 279 ± 75 GBq/μmol. (18)F-FHNP had a dissociation constant of 2 nM and maximum binding capacity of 18 fmol/10(6) cells, and (18)F-FES had a dissociation constant of 3 nM and maximum binding capacity 83 fmol/10(6) SKOV3 cells. Both (18)F-FHNP and (18)F-FES PET could clearly visualize the tumor in male mice bearing a SKOV3 xenograft. Biodistribution studies showed similar distribution of (18)F-FHNP and (18)F-FES in most peripheral organs. (18)F-FES showed a 2-fold-higher tumor uptake than (18)F-FHNP. The tumor-to-plasma ratio of (18)F-FES decreased 55% (P = 0.024) and 8% (P = 0.68) when administered in the presence of estradiol (nonselective) and genistein (ERβ-selective), respectively. The tumor-to-plasma ratio of (18)F-FHNP decreased 41% (P = 0.004) and 64% (P = 0.0009) when administered with estradiol and genistein, respectively. Conclusion: The new PET tracer (18)F-FHNP has suitable properties for imaging and shows relative selectivity for ERβ.

PMID: 27908969 [PubMed - indexed for MEDLINE]




Novel "Add-On" Molecule Based on Evans Blue Confers Superior Pharmacokinetics and Transforms Drugs to Theranostic Agents.
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Novel "Add-On" Molecule Based on Evans Blue Confers Superior Pharmacokinetics and Transforms Drugs to Theranostic Agents.

J Nucl Med. 2017 Apr;58(4):590-597

Authors: Chen H, Jacobson O, Niu G, Weiss ID, Kiesewetter DO, Liu Y, Ma Y, Wu H, Chen X

Abstract
One of the major design considerations for a drug is its pharmacokinetics in the blood. A drug with a short half-life in the blood is less available at a target organ. Such a limitation dictates treatment with either high doses or more frequent doses, both of which may increase the likelihood of undesirable side effects. To address the need for additional methods to improve the blood half-life of drugs and molecular imaging agents, we developed an "add-on" molecule that contains 3 groups: a truncated Evans blue dye molecule that binds to albumin with a low micromolar affinity and provides a prolonged half-life in the blood; a metal chelate that allows radiolabeling for imaging and radiotherapy; and maleimide for easy conjugation to drug molecules. Methods: The truncated Evans blue molecule was conjugated with the chelator NOTA or DOTA, and the resulting conjugate was denoted as NMEB or DMEB, respectively. As a proof of concept, we coupled NMEB and DMEB to c(RGDfK), which is a small cyclic arginine-glycine-aspartic acid (RGD) peptide, for targeting integrin αvβ3 NMEB and DMEB were radiolabeled with (64)Cu and (90)Y, respectively, and tested in xenograft models. Results: The resulting radiolabeled conjugates showed a prolonged circulation half-life and enhanced tumor accumulation in integrin αvβ3-expressing tumors. Tumor uptake was markedly improved over that with NOTA- or DOTA-conjugated c(RGDfK). Tumor radiotherapy experiments in mice with (90)Y-DMEB-RGD showed promising results; existing tumors were eliminated. Conclusion: Conjugation of our novel add-on molecule, NMEB or DMEB, to potential tracers or therapeutic agents improved blood half-life and tumor uptake and could transform such agents into theranostic entities.

PMID: 27879373 [PubMed - indexed for MEDLINE]




(99m)Tc-Duramycin SPECT Imaging of Early Tumor Response to Targeted Therapy: A Comparison with (18)F-FDG PET.
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(99m)Tc-Duramycin SPECT Imaging of Early Tumor Response to Targeted Therapy: A Comparison with (18)F-FDG PET.

J Nucl Med. 2017 Apr;58(4):665-670

Authors: Elvas F, Boddaert J, Vangestel C, Pak K, Gray B, Kumar-Singh S, Staelens S, Stroobants S, Wyffels L

Abstract
Molecular imaging of cell death may provide a detailed readout of the cellular response to novel therapies and prognostic information on tumor treatment efficacy, assisting in the design of individualized therapy. We compared the predictive power of cell death imaging using (99m)Tc-duramycin with the current gold standard (18)F-FDG for treatment response evaluation after targeted therapy. Methods: Early therapy response evaluation was assessed by (99m)Tc-duramycin SPECT and (18)F-FDG PET imaging in treatment-sensitive COLO205 and treatment-resistant HT29 human colorectal cancer xenografts 24 h after a single dose of conatumumab or IgG1 control. The specificity of (99m)Tc-duramycin for apoptosis was assessed using (99m)Tc-linear duramycin control radiotracer. Radiotracer uptake was validated ex vivo by γ-counting and autoradiography and compared with cleaved caspase-3 (CC3) activation and DNA fragmentation (TdT-mediated dUTP nick-end labeling [TUNEL]). Data were analyzed with the Student t test and Pearson correlation. All statistical tests were 2-sided. Results: COLO205 tumor uptake of (99m)Tc-duramycin was increased 7-fold from baseline in conatumumab- versus IgG1-treated control mice (P < 0.001), in good correlation with histologic analysis of apoptosis (CC3, r = 0.842, and TUNEL, r = 0.894; P < 0.001). No response was detected in HT29 tumors. No change in (99m)Tc-linear duramycin uptake could be detected in COLO205 tumors after treatment, indicating specificity of the (99m)Tc-duramycin tumor signal. (18)F-FDG uptake was not significantly increased from baseline in conatumumab- versus IgG1-treated COLO205 and HT29 tumor-bearing mice (P = 0.104 and 0.779, respectively) and did not correlate with immunohistochemical evidence of apoptosis. Conclusion: We have demonstrated that (99m)Tc-duramycin specifically accumulates in apoptotic tumors in which (18)F-FDG was not able to differentiate responding from nonresponding tumors early after treatment. (99m)Tc-duramycin holds promise as a noninvasive imaging radiotracer for early treatment evaluation in the clinic.

PMID: 27879368 [PubMed - indexed for MEDLINE]




Functional Estrogen Receptor Imaging Before Neoadjuvant Therapy for Primary Breast Cancer.
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Functional Estrogen Receptor Imaging Before Neoadjuvant Therapy for Primary Breast Cancer.

J Nucl Med. 2017 Apr;58(4):560-562

Authors: Fowler AM, Linden HM

Abstract
Estrogen receptor α (ERα) is a critical prognostic and predictive biomarker in breast cancer. ERα expression is used to determine whether patients should be treated with endocrine therapy, which is designed to block ERα signaling. Endocrine therapy given for 5-10 y after surgery improves progression-free and overall survival for patients with ER-positive primary breast cancer. However, disease recurrence and development of metastatic disease can occur despite appropriate treatment with endocrine therapy. Thus, a functional test performed at the time of initial diagnosis that can identify which patients would do well with endocrine therapy alone versus those who require adjuvant chemotherapy would be impactful for improving patient outcomes.

PMID: 27856629 [PubMed - indexed for MEDLINE]




Longitudinal Small-Animal PET Imaging of the zQ175 Mouse Model of Huntington Disease Shows In Vivo Changes of Molecular Targets in the Striatum and Cerebral Cortex.
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Longitudinal Small-Animal PET Imaging of the zQ175 Mouse Model of Huntington Disease Shows In Vivo Changes of Molecular Targets in the Striatum and Cerebral Cortex.

J Nucl Med. 2017 Apr;58(4):617-622

Authors: Häggkvist J, Tóth M, Tari L, Varnäs K, Svedberg M, Forsberg A, Nag S, Dominguez C, Munoz-Sanjuan I, Bard J, Wityak J, Varrone A, Halldin C, Mrzljak L

Abstract
Since the discovery of the HTT gene in 1993, numerous animal models have been developed to study the progression of Huntington disease (HD) and to evaluate potential new therapeutics. In the present study, we used small-animal PET to characterize the expression of molecular targets in the recently reported HD animal model, the zQ175 mouse model. Methods: Male heterozygous zQ175 (Htt(tm1Mfc)/190JChdi, CHDI-81003003) and wild-type (WT, C57BL/6J) animals were imaged with the dopamine D2 receptor radioligand (11)C-raclopride, the PDE10A radioligand (18)F-MNI-659, the dopamine D1 receptor radioligand (11)C-NNC 112, and the 5-HT2A radioligand (11)C-MDL 100907 at 6 and 9 mo of age. The outcome measure was the binding potential (BPND), using the cerebellum as the reference region. Selected regions of interest were the striatum for all radioligands and additionally the striatum, rostral cortex, caudal cortex, and hippocampus for (11)C-NNC 112 and (11)C-MDL 100907. Results: At 6 mo of age, the BPND in the striatum was lower in zQ175 than WT animals by 40% for (11)C-raclopride, by 52% for (18)F-MNI-659, by 28% for (11)C-NNC, and by 11% for (11)C-MDL 100907. In the rostral cortex, D1 receptor binding was 22% lower in zQ175 than WT animals. We found an overall reduction in D1 and 5-HT2A binding in the hippocampus of zQ175 compared with WT animals. The BPND of (11)C-MDL 100907 in the caudal cortex was also lower in zQ175 WT animals. At 9 mo, there was a slight further reduction of D1, D2, and 5-HT2ABPND in the striatum, whereas PDE10A reached a plateau. Cortical markers were also slightly further decreased at 9 mo in zQ175 animals. Conclusion: Our study indicates a marked reduction of ligand binding to D1 and D2 and 5-HT2A receptors as well as loss of PDE10A enzyme in the striatum of zQ175 mice as compared with WT animals, in agreement with data obtained in clinical PET studies of patients with HD. The zQ175 mouse model recapitulates the expression pattern seen in humans with HD and may have value in further elucidating pathophysiologic events and therapeutic strategies.

PMID: 27856625 [PubMed - indexed for MEDLINE]




Spectral Clustering Predicts Tumor Tissue Heterogeneity Using Dynamic (18)F-FDG PET: A Complement to the Standard Compartmental Modeling Approach.
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Spectral Clustering Predicts Tumor Tissue Heterogeneity Using Dynamic (18)F-FDG PET: A Complement to the Standard Compartmental Modeling Approach.

J Nucl Med. 2017 Apr;58(4):651-657

Authors: Katiyar P, Divine MR, Kohlhofer U, Quintanilla-Martinez L, Schölkopf B, Pichler BJ, Disselhorst JA

Abstract
In this study, we described and validated an unsupervised segmentation algorithm for the assessment of tumor heterogeneity using dynamic (18)F-FDG PET. The aim of our study was to objectively evaluate the proposed method and make comparisons with compartmental modeling parametric maps and SUV segmentations using simulations of clinically relevant tumor tissue types. Methods: An irreversible 2-tissue-compartmental model was implemented to simulate clinical and preclinical (18)F-FDG PET time-activity curves using population-based arterial input functions (80 clinical and 12 preclinical) and the kinetic parameter values of 3 tumor tissue types. The simulated time-activity curves were corrupted with different levels of noise and used to calculate the tissue-type misclassification errors of spectral clustering (SC), parametric maps, and SUV segmentation. The utility of the inverse noise variance- and Laplacian score-derived frame weighting schemes before SC was also investigated. Finally, the SC scheme with the best results was tested on a dynamic (18)F-FDG measurement of a mouse bearing subcutaneous colon cancer and validated using histology. Results: In the preclinical setup, the inverse noise variance-weighted SC exhibited the lowest misclassification errors (8.09%-28.53%) at all noise levels in contrast to the Laplacian score-weighted SC (16.12%-31.23%), unweighted SC (25.73%-40.03%), parametric maps (28.02%-61.45%), and SUV (45.49%-45.63%) segmentation. The classification efficacy of both weighted SC schemes in the clinical case was comparable to the unweighted SC. When applied to the dynamic (18)F-FDG measurement of colon cancer, the proposed algorithm accurately identified densely vascularized regions from the rest of the tumor. In addition, the segmented regions and clusterwise average time-activity curves showed excellent correlation with the tumor histology. Conclusion: The promising results of SC mark its position as a robust tool for quantification of tumor heterogeneity using dynamic PET studies. Because SC tumor segmentation is based on the intrinsic structure of the underlying data, it can be easily applied to other cancer types as well.

PMID: 27811120 [PubMed - indexed for MEDLINE]




Performing Repeated Quantitative Small-Animal PET with an Arterial Input Function Is Routinely Feasible in Rats.
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Performing Repeated Quantitative Small-Animal PET with an Arterial Input Function Is Routinely Feasible in Rats.

J Nucl Med. 2017 Apr;58(4):611-616

Authors: Huang CC, Wu CH, Huang YY, Tzen KY, Chen SF, Tsai ML, Wu HM

Abstract
Performing quantitative small-animal PET with an arterial input function has been considered technically challenging. Here, we introduce a catheterization procedure that keeps a rat physiologically stable for 1.5 mo. We demonstrated the feasibility of quantitative small-animal (18)F-FDG PET in rats by performing it repeatedly to monitor the time course of variations in the cerebral metabolic rate of glucose (CMRglc). Methods: Aseptic surgery was performed on 2 rats. Each rat underwent catheterization of the right femoral artery and left femoral vein. The catheters were sealed with microinjection ports and then implanted subcutaneously. Over the next 3 wk, each rat underwent (18)F-FDG quantitative small-animal PET 6 times. The CMRglc of each brain region was calculated using a 3-compartment model and an operational equation that included a k*4Results: On 6 mornings, we completed 12 (18)F-FDG quantitative small-animal PET studies on 2 rats. The rats grew steadily before and after the 6 quantitative small-animal PET studies. The CMRglc of the conscious brain (e.g., right parietal region, 99.6 ± 10.2 μmol/100 g/min; n = 6) was comparable to that for (14)C-deoxyglucose autoradiographic methods. Conclusion: Maintaining good blood patency in catheterized rats is not difficult. Longitudinal quantitative small-animal PET imaging with an arterial input function can be performed routinely.

PMID: 27789717 [PubMed - indexed for MEDLINE]




Modeling Strategies for Quantification of In Vivo (18)F-AV-1451 Binding in Patients with Tau Pathology.
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Modeling Strategies for Quantification of In Vivo (18)F-AV-1451 Binding in Patients with Tau Pathology.

J Nucl Med. 2017 Apr;58(4):623-631

Authors: Hahn A, Schain M, Erlandsson M, Sjölin P, James GM, Strandberg OT, Hägerström D, Lanzenberger R, Jögi J, Olsson TG, Smith R, Hansson O

Abstract
Aggregation of hyperphosphorylated tau is a major hallmark of many neurodegenerative diseases, including Alzheimer disease (AD). In vivo imaging with PET may offer important insights into pathophysiologic mechanisms, diagnosis, and disease progression. We describe different strategies for quantification of (18)F-AV-1451 (T807) tau binding, including models with blood sampling and noninvasive alternatives. Methods: Fifteen subjects (4 controls, 6 AD, 3 progressive supranuclear palsy, 2 cortico basal syndrome) underwent 180-min PET with (18)F-AV-1451 and arterial blood sampling. Modeling with arterial input functions included 1-, 2-, and 3-tissue-compartment models and the Logan plot. Using the cerebellum as reference region, we applied the simplified reference tissue model 2 and Logan reference plot. Finally, simplified outcome measures were calculated as ratio, with reference to cerebellar concentrations (SUV ratio [SUVR]) and SUVs. Results: Tissue compartment models were not able to describe the kinetics of (18)F-AV-1451, with poor fits in 33%-53% of cortical regions and 80% in subcortical areas. In contrast, the Logan plot showed excellent fits and parameter variance (total volume of distribution SE < 5%). Compared with the 180-min arterial-based Logan model, strong agreement was obtained for the Logan reference plot also for a reduced scan time of 100 min (R(2) = 0.91) and SUVR 100-120 min (R(2) = 0.94), with 80-100 min already representing a reasonable compromise between duration and accuracy (R(2) = 0.93). Time-activity curves and kinetic parameters were equal for cortical regions and the cerebellum in control subjects but different in the putamen. Cerebellar total volumes of distribution were higher in controls than patients. For these methods, increased cortical binding was observed for AD patients and to some extent for cortico basal syndrome, but not progressive supranuclear palsy. Conclusion: The Logan plot provided the best estimate of tau binding using arterial input functions. Assuming that the cerebellum is a valid reference region, simplified methods seem to provide robust alternatives for quantification, such as the Logan reference plot with 100-min scan time. Furthermore, SUVRs between target and cerebellar activities obtained from an 80- to 100-min static scan offer promising potential for clinical routine application.

PMID: 27765859 [PubMed - indexed for MEDLINE]




(18)F-FET PET Uptake Characteristics in Patients with Newly Diagnosed and Untreated Brain Metastasis.
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(18)F-FET PET Uptake Characteristics in Patients with Newly Diagnosed and Untreated Brain Metastasis.

J Nucl Med. 2017 Apr;58(4):584-589

Authors: Unterrainer M, Galldiks N, Suchorska B, Kowalew LC, Wenter V, Schmid-Tannwald C, Niyazi M, Bartenstein P, Langen KJ, Albert NL

Abstract
In patients with brain metastasis, PET using labeled amino acids has gained clinical importance, mainly regarding the differentiation of viable tumor tissue from treatment-related effects. However, there is still limited knowledge concerning the uptake characteristics in patients with newly diagnosed and untreated brain metastases. Hence, we evaluated the uptake characteristics in these patients using dynamic O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET) PET. Methods: Patients with newly diagnosed brain metastases without prior local therapy and (18)F-FET PET scanning were retrospectively identified in 2 centers. Static and dynamic PET parameters (maximal/mean tumor-to-brain-ratio [TBRmax/TBRmean], biologic tumor volume [BTV], and time-activity curves with minimal time to peak [TTPmin]) were evaluated and correlated with MRI parameters (maximal lesion diameter, volume of contrast enhancement) and originating primary tumor. Results: Forty-five brain metastases in 30 patients were included. Forty of 45 metastases (89%) had a TBRmax ≥ 1.6 and were classified as (18)F-FET-positive (median TBRmax, 2.53 [range, 1.64-9.47]; TBRmean, 1.86 [range, 1.63-5.48]; and BTV, 3.59 mL [range, 0.04-23.98 mL], respectively). In 39 of 45 brain metastases eligible for dynamic analysis, a wide range of TTPmin was observed (median, 22.5 min; range, 4.5-47.5 min). All (18)F-FET-negative metastases had a diameter of ≤ 1.0 cm, whereas metastases with a > 1.0 cm diameter all showed pathologic (18)F-FET uptake, which did not correlate with lesion size. The highest variability of uptake intensity was observed within the group of melanoma metastases. Conclusion: Untreated metastases predominantly show increased (18)F-FET uptake, and only a third of metastases < 1.0 cm were (18)F-FET-negative, most likely because of scanner resolution and partial-volume effects. In metastases > 1.0 cm, (18)F-FET uptake intensity was highly variable and independent of tumor size (even intraindividually). (18)F-FET PET might provide additional information beyond the tumor extent by reflecting molecular features of a metastasis and might be a useful tool for future clinical applications, for example, response assessment.

PMID: 27754904 [PubMed - indexed for MEDLINE]




Posttreatment PET/CT Rather Than Interim PET/CT Using Deauville Criteria Predicts Outcome in Pediatric Hodgkin Lymphoma: A Prospective Study Comparing PET/CT with Conventional Imaging.
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Posttreatment PET/CT Rather Than Interim PET/CT Using Deauville Criteria Predicts Outcome in Pediatric Hodgkin Lymphoma: A Prospective Study Comparing PET/CT with Conventional Imaging.

J Nucl Med. 2017 Apr;58(4):577-583

Authors: Bakhshi S, Bhethanabhotla S, Kumar R, Agarwal K, Sharma P, Thulkar S, Malhotra A, Dhawan D, Vishnubhatla S

Abstract
Data about the significance of (18)F-FDG PET at interim assessment and end of treatment in pediatric Hodgkin lymphoma (HL) are limited. Methods: Patients (≤18 y) with HL were prospectively evaluated with contrast-enhanced CT (CECT) and PET combined with low-dose CT (PET/CT) at baseline, after 2 cycles of chemotherapy, and after completion of treatment. Revised International Working Group (RIW) criteria and Deauville 5 point-scale for response assessment by PET/CT were used. All patients received doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine chemotherapy along with involved-field radiotherapy (25 Gy) for early stage (IA, IB, and IIA) and advanced stage (IIB-IV) with bulky disease. Results: Of the 57 enrolled patients, median follow-up was 81.6 mo (range, 11-97.5 mo). Treatment decisions were based on CECT. At baseline, PET/CT versus CECT identified 67 more disease sites; 23 patients (40.3%) were upstaged and of them in 9 patients (39%) upstaging would have affected treatment decision; notably none of these patients relapsed. The specificity of interim PET/CT based on RIW criteria (61.5%) and Deauville criteria (91.4%) for predicting relapse was higher than CECT (40.3%) (P = 0.03 and P < 0.0001, respectively). Event-free survival based on interim PET/CT (RIW) response was 93.3 ± 4.1 versus 89.6 ± 3.8 (positive vs. negative scan, respectively; P = 0.44). The specificity of posttreatment PET/CT (Deauville) was 95.7% versus 76.4% by CECT (P = 0.006). Posttreatment PET/CT (Deauville) showed significantly inferior overall survival in patients with positive scan versus negative scan results (66.4 ± 22.5 vs. 94.5 ± 2.0, P = 0.029). Conclusion: Interim PET/CT has better specificity, and use of Deauville criteria further improves it. Escalation of therapy based on interim PET in pediatric HL needs further conclusive evidence to justify its use. Posttreatment PET/CT (Deauville) predicts overall survival and has better specificity in comparison to conventional imaging.

PMID: 27754902 [PubMed - indexed for MEDLINE]




Predicting Regional Pattern of Longitudinal β-Amyloid Accumulation by Baseline PET.
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Predicting Regional Pattern of Longitudinal β-Amyloid Accumulation by Baseline PET.

J Nucl Med. 2017 Apr;58(4):639-645

Authors: Guo T, Brendel M, Grimmer T, Rominger A, Yakushev I, Alzheimer’s Disease Neuroimaging Initiative

Abstract
Knowledge about spatial and temporal patterns of β-amyloid (Aβ) accumulation is essential for understanding Alzheimer disease (AD) and for design of antiamyloid drug trials. Here, we tested whether the regional pattern of longitudinal Aβ accumulation can be predicted by baseline amyloid PET. Methods: Baseline and 2-y follow-up (18)F-florbetapir PET data from 58 patients with incipient and manifest dementia due to AD were analyzed. With the determination of how fast amyloid deposits in a given region relative to the whole-brain gray matter, a pseudotemporal accumulation rate for each region was calculated. The actual accumulation rate of (18)F-florbetapir was calculated from follow-up data. Results: Pseudotemporal measurements from baseline PET data explained 87% (P < 0.001) of the variance in longitudinal accumulation rate across 62 regions. The method accurately predicted the top 10 fast and slow accumulating regions. Conclusion: Pseudotemporal analysis of baseline PET images is capable of predicting the regional pattern of longitudinal Aβ accumulation in AD at a group level. This approach may be useful in exploring spatial patterns of Aβ accumulation in other amyloid-associated disorders such as Lewy body disease and atypical forms of AD. In addition, the method allows identification of brain regions with a high accumulation rate of Aβ, which are of particular interest for antiamyloid clinical trials.

PMID: 27754901 [PubMed - indexed for MEDLINE]




Assessment of P-Glycoprotein Transport Activity at the Human Blood-Retina Barrier with (R)-(11)C-Verapamil PET.
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Assessment of P-Glycoprotein Transport Activity at the Human Blood-Retina Barrier with (R)-(11)C-Verapamil PET.

J Nucl Med. 2017 Apr;58(4):678-681

Authors: Bauer M, Karch R, Tournier N, Cisternino S, Wadsak W, Hacker M, Marhofer P, Zeitlinger M, Langer O

Abstract
P-glycoprotein (ABCB1) is expressed at the blood-retina barrier (BRB), where it may control distribution of drugs from blood to the retina and thereby influence drug efficacy and toxicity. Methods: We performed PET scans with the ABCB1 substrate (R)-(11)C-verapamil on 5 healthy male volunteers without and with concurrent infusion of the ABCB1 inhibitor tariquidar. We estimated the rate constants for radiotracer transfer across the BRB (K1, k2) and total retinal distribution volume VTResults: During ABCB1 inhibition, retinal VT and influx rate constant K1 were significantly, by 1.4 ± 0.5-fold and 1.5 ± 0.3-fold, increased compared with baseline. Retinal efflux rate constant k2 was significantly decreased by 2.8 ± 1.0-fold. Conclusion: We found a significant increase in (R)-(11)C-verapamil distribution to the retina during ABCB1 inhibition, which provides first in vivo evidence for ABCB1 transport activity at the human BRB. The increase in retinal distribution was approximately 2.5-fold less pronounced than previously reported for the blood-brain barrier.

PMID: 27738009 [PubMed - indexed for MEDLINE]




Associations Between Somatic Mutations and Metabolic Imaging Phenotypes in Non-Small Cell Lung Cancer.
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Associations Between Somatic Mutations and Metabolic Imaging Phenotypes in Non-Small Cell Lung Cancer.

J Nucl Med. 2017 Apr;58(4):569-576

Authors: Yip SS, Kim J, Coroller TP, Parmar C, Velazquez ER, Huynh E, Mak RH, Aerts HJ

Abstract
PET-based radiomics have been used to noninvasively quantify the metabolic tumor phenotypes; however, little is known about the relationship between these phenotypes and underlying somatic mutations. This study assessed the association and predictive power of (18)F-FDG PET-based radiomic features for somatic mutations in non-small cell lung cancer patients. Methods: Three hundred forty-eight non-small cell lung cancer patients underwent diagnostic (18)F-FDG PET scans and were tested for genetic mutations. Thirteen percent (44/348) and 28% (96/348) of patients were found to harbor epidermal growth factor receptor (EGFR) or Kristen rat sarcoma viral (KRAS) mutations, respectively. We evaluated 21 imaging features: 19 independent radiomic features quantifying phenotypic traits and 2 conventional features (metabolic tumor volume and maximum SUV). The association between imaging features and mutation status (e.g., EGFR-positive [EGFR+] vs. EGFR-negative) was assessed using the Wilcoxon rank-sum test. The ability of each imaging feature to predict mutation status was evaluated by the area under the receiver operating curve (AUC) and its significance was compared with a random guess (AUC = 0.5) using the Noether test. All P values were corrected for multiple hypothesis testing by controlling the false-discovery rate (FDRWilcoxon, FDRNoether) with a significance threshold of 10%. Results: Eight radiomic features and both conventional features were significantly associated with EGFR mutation status (FDRWilcoxon = 0.01-0.10). One radiomic feature (normalized inverse difference moment) outperformed all other features in predicting EGFR mutation status (EGFR+ vs. EGFR-negative, AUC = 0.67, FDRNoether = 0.0032), as well as differentiating between KRAS-positive and EGFR+ (AUC = 0.65, FDRNoether = 0.05). None of the features was associated with or predictive of KRAS mutation status (KRAS-positive vs. KRAS-negative, AUC = 0.50-0.54). Conclusion: Our results indicate that EGFR mutations may drive different metabolic tumor phenotypes that are captured in PET images, whereas KRAS-mutated tumors do not. This proof-of-concept study sheds light on genotype-phenotype interactions, using radiomics to capture and describe the phenotype, and may have potential for developing noninvasive imaging biomarkers for somatic mutations.

PMID: 27688480 [PubMed - indexed for MEDLINE]




(18)F-FDG PET in Posterior Cortical Atrophy and Dementia with Lewy Bodies.
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(18)F-FDG PET in Posterior Cortical Atrophy and Dementia with Lewy Bodies.

J Nucl Med. 2017 Apr;58(4):632-638

Authors: Whitwell JL, Graff-Radford J, Singh TD, Drubach DA, Senjem ML, Spychalla AJ, Tosakulwong N, Lowe VJ, Josephs KA

Abstract
Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) have both been associated with occipital lobe hypometabolism on (18)F-FDG PET, whereas relative sparing of posterior cingulate metabolism compared with precuneus/cuneus (i.e., cingulate island sign) is a feature of DLB. We aimed to determine whether patterns of hypometabolism or the cingulate island sign differed between PCA and DLB. Methods: Sixteen clinically diagnosed PCA and 13 probable DLB subjects underwent (18)F-FDG PET. All PCA subjects showed β-amyloid deposition on PET scanning. Regional hypometabolism was assessed compared with a control cohort (n = 29) using voxel- and region-level analyses in statistical parametric mapping. A ratio of metabolism in the posterior cingulate to precuneus plus cuneus was calculated to assess the cingulate island sign. In addition, the (18)F-FDG PET scans were visually assessed to determine whether the cingulate island sign was present in each subject. Results: PCA and DLB showed overlapping patterns of hypometabolism involving the lateral occipital lobe, lingual gyrus, cuneus, precuneus, posterior cingulate, inferior parietal lobe, supramarginal gyrus, striatum, and thalamus. However, DLB showed greater hypometabolism in the medial occipital lobe, orbitofrontal cortex, anterior temporal lobe, and caudate nucleus than PCA, and PCA showed more asymmetric patterns of hypometabolism than DLB. The cingulate island sign was present in both DLB and PCA, although it was more asymmetric in PCA. Conclusion: Regional hypometabolism overlaps to a large degree between PCA and DLB, although the degree of involvement of the frontal and anterior temporal lobes and the presence of asymmetry could be useful in differential diagnosis.

PMID: 27688479 [PubMed - indexed for MEDLINE]




Hybrid Surgical Guidance: Does Hardware Integration of γ- and Fluorescence Imaging Modalities Make Sense?
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Hybrid Surgical Guidance: Does Hardware Integration of γ- and Fluorescence Imaging Modalities Make Sense?

J Nucl Med. 2017 Apr;58(4):646-650

Authors: KleinJan GH, Hellingman D, van den Berg NS, van Oosterom MN, Hendricksen K, Horenblas S, Valdes Olmos RA, van Leeuwen FW

Abstract
The clinically applied hybrid tracer indocyanine green-(99m)Tc-nanocolloid enables combined radio- and fluorescence image guidance during sentinel node (SN) biopsy procedures. To provide optimal surgical guidance, this tracer requires the presence of both γ- and fluorescence modalities in the operating room. We reasoned that the combination or integration of these modalities could further evolve the hybrid surgical guidance concept. To study this potential, we clinically applied 2 setups that included the combination of γ-detection modalities and an open surgery fluorescence camera. Methods: To attach the fluorescence camera (VITOM) to either a γ-ray detection probe (GP; VITOM-GP) or a portable γ-camera (GC; Vitom GC), clip-on brackets were designed and printed in 3-dimensional sterilizable RC31. Both combined modalities were evaluated in, respectively, 5 and 6 patients with penile cancer during an SN biopsy procedure using indocyanine green-(99m)Tc-nanocolloid. Intraoperatively, radio- and fluorescence-guided SN detection rates were scored at working distances of 0, 10, 20, and 30 cm for both combinations. Results: Using the VITOM-GP combination, we evaluated 9 SNs. γ-tracing rates were shown to be 100%, 88.9%, 55.6%, and 55.6% at a respective working distance of 0, 10, 20, and 30 cm. Detection rates for the fluorescence imaging-based detection were found to be 100%, 77.8%, and 77.8%, at respective working distances of 10, 20, and 30 cm. When the VITOM-GC setup was used, all 10 intraoperatively evaluated SNs could be visualized with the γ-camera independent of the working distance. Fluorescence detection rates were 90%, 80%, and 80% at 10-, 20-, and 30-cm working distances. The integrated detection modalities were shown to work synergistically; overall the, GC was most valuable for rough localization (10- to 30-cm range) of the SNs, the GP for providing convenient real-time acoustic feedback, whereas fluorescence guidance allowed detailed real-time SN visualization. Conclusion: Our findings suggest that full integration of a fluorescence camera with γ-detector (GP or GC) can be of value when a hybrid, radioactive and fluorescent tracer is used.

PMID: 27688478 [PubMed - indexed for MEDLINE]




Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated α-Radioimmunotherapy with (211)At-MX35-F(ab')2: Influence of Absorbed Tumor Dose and Effect on Long-Term Survival.
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Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated α-Radioimmunotherapy with (211)At-MX35-F(ab')2: Influence of Absorbed Tumor Dose and Effect on Long-Term Survival.

J Nucl Med. 2017 Apr;58(4):598-604

Authors: Bäck T, Chouin N, Lindegren S, Kahu H, Jensen H, Albertsson P, Palm S

Abstract
The goal of this study was to investigate whether targeted α-therapy can be used to successfully treat macrotumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous fractionated regimen of α-radioimmunotherapy in a subcutaneous tumor model in mice. We aimed to evaluate the absorbed dose levels required for tumor eradication and growth monitoring, as well as to evaluate long-term survival after treatment. Methods: Mice bearing subcutaneous tumors (50 mm(3), NIH:OVCAR-3) were injected repeatedly (1-3 intravenous injections 7-10 d apart, allowing bone marrow recovery) with (211)At-MX35-F(ab')2 at different activities (close to acute myelotoxicity). Mean absorbed doses to tumors and organs were estimated from biodistribution data and summed for the fractions. Tumor growth was monitored for 100 d and survival for 1 y after treatment. Toxicity analysis included body weight, white blood cell count, and hematocrit. Results: Effects on tumor growth after fractionated α-radioimmunotherapy with (211)At-MX35-F(ab')2 was strong and dose-dependent. Complete remission (tumor-free fraction, 100%) was found for tumor doses of 12.4 and 16.4 Gy. The administered activities were high, and long-term toxicity effects (≤60 wk) were clear. Above 1 MBq, the median survival decreased linearly with injected activity, from 44 to 11 wk. Toxicity was also seen by reduced body weight. White blood cell count analysis after α-radioimmunotherapy indicated bone marrow recovery for the low-activity groups, whereas for high-activity groups the reduction was close to acute myelotoxicity. A decrease in hematocrit was seen at a late interval (34-59 wk after therapy). The main external indication of poor health was dehydration. Conclusion: Having observed complete eradication of solid tumor xenografts, we conclude that targeted α-therapy regimens may stretch beyond the realm of micrometastatic disease and be eradicative also for macrotumors. Our observations indicate that at least 10 Gy are required. This agrees well with the calculated tumor control probability. Considering a relative biological effectiveness of 5, this dose level seems reasonable. However, complete remission was achieved first at activity levels close to lethal and was accompanied by biologic effects that reduced long-term survival.

PMID: 27688477 [PubMed - indexed for MEDLINE]




Optimization of Image Reconstruction for (90)Y Selective Internal Radiotherapy on a Lutetium Yttrium Orthosilicate PET/CT System Using a Bayesian Penalized Likelihood Reconstruction Algorithm.
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Optimization of Image Reconstruction for (90)Y Selective Internal Radiotherapy on a Lutetium Yttrium Orthosilicate PET/CT System Using a Bayesian Penalized Likelihood Reconstruction Algorithm.

J Nucl Med. 2017 Apr;58(4):658-664

Authors: Rowley LM, Bradley KM, Boardman P, Hallam A, McGowan DR

Abstract
Imaging on a γ-camera with (90)Y after selective internal radiotherapy (SIRT) may allow for verification of treatment delivery but suffers relatively poor spatial resolution and imprecise dosimetry calculation. (90)Y PET/CT imaging is possible on 3-dimensional, time-of-flight machines; however, images are usually poor because of low count statistics and noise. A new PET reconstruction software using a Bayesian penalized likelihood (BPL) reconstruction algorithm (termed Q.Clear) was investigated using phantom and patient scans to optimize the reconstruction for post-SIRT imaging and clarify whether BPL leads to an improvement in clinical image quality using (90)Y. Methods: Phantom studies over an activity range of 0.5-4.2 GBq were performed to assess the contrast recovery, background variability, and contrast-to-noise ratio for a range of BPL and ordered-subset expectation maximization (OSEM) reconstructions on a PET/CT scanner. Patient images after SIRT were reconstructed using the same parameters and were scored and ranked on the basis of image quality, as assessed by visual evaluation, with the corresponding SPECT/CT Bremsstrahlung images by 2 experienced radiologists. Results: Contrast-to-noise ratio was significantly better in BPL reconstructions when compared with OSEM in phantom studies. The patient-derived BPL and matching Bremsstrahlung images scored higher than OSEM reconstructions when scored by radiologists. BPL with a β value of 4,000 was ranked the highest of all images. Deadtime was apparent in the system above a total phantom activity of 3.3 GBq. Conclusion: BPL with a β value of 4,000 is the optimal image reconstruction in PET/CT for confident radiologic reading when compared with other reconstruction parameters for (90)Y imaging after SIRT imaging. Activity in the field of view should be below 3.3 GBq at the time of PET imaging to avoid deadtime losses for this scanner.

PMID: 27688476 [PubMed - indexed for MEDLINE]




A Randomized Feasibility Study of (18)F-Fluoroestradiol PET to Predict Pathologic Response to Neoadjuvant Therapy in Estrogen Receptor-Rich Postmenopausal Breast Cancer.
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A Randomized Feasibility Study of (18)F-Fluoroestradiol PET to Predict Pathologic Response to Neoadjuvant Therapy in Estrogen Receptor-Rich Postmenopausal Breast Cancer.

J Nucl Med. 2017 Apr;58(4):563-568

Authors: Chae SY, Kim SB, Ahn SH, Kim HO, Yoon DH, Ahn JH, Jung KH, Han S, Oh SJ, Lee SJ, Kim HJ, Son BH, Gong G, Lee HS, Moon DH

Abstract
The aim of this study was to explore the ability of (18)F-fluoroestradiol ((18)F-FES) PET/CT imaging to predict pathologic response to neoadjuvant therapy in postmenopausal women with estrogen receptor (ER)-rich breast cancer. Methods: This was a prospective, single-center study conducted as a substudy of the neoadjuvant study of chemotherapy versus endocrine therapy in postmenopausal patients with primary breast cancer (NEOCENT) trial. Patients with ER-rich breast cancer were randomized to neoadjuvant chemotherapy (NC) or neoadjuvant endocrine therapy (NET). The baseline SUVmax of (18)F-FES PET/CT was measured. The pathologic response was assessed by the Miller-Payne system as nonresponse (grades 1 and 2) and response (grades 3-5). Results: Twenty-six patients were enrolled, with pathologic response achieved in 25 (NC, 12; NET, 13). Two patients achieved pathologic complete response after NC, but the remaining 23 patients had residual disease after NC or NET. Eight of 12 patients responded to NC, and 4 of 13 to NET; the difference was marginally significant (P = 0.07). In the NC group, the 2 patients with (18)F-FES-negative tumors and none of the 10 patients with (18)F-FES-avid tumors achieved pathologic complete response (P = 0.02). No difference in the SUVmax between responders and nonresponders was observed in either group. However, 5 of 7 NC patients with a baseline SUVmax of less than 7.3 achieved pathologic response, whereas none of the 5 NET patients with an SUVmax of less than 7.3 were responders (P = 0.03). The SUVmax values of the NC group were negatively correlated with percentage reduction of tumor cellularity (r = -0.63, P = 0.03), whereas those of the NET group showed positive correlation (r = 0.62, P = 0.02). During the median follow-up of 74 mo (range, 44-85 mo), recurrence occurred in only 4 NET patients. In patients with an SUVmax of less than 7.3, recurrence occurred in none of the 8 NC patients and 2 of the 5 NET patients (P = 0.13). Conclusion: Postmenopausal women who are ER-positive, but (18)F-FES-negative, may benefit from NC rather than NET. (18)F-FES PET/CT has the potential to predict response to neoadjuvant therapy in postmenopausal women with ER-rich breast cancer.

PMID: 27688475 [PubMed - indexed for MEDLINE]