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Background: Substantial improvements in spatial resolution in brain positron emission tomography (PET) scanners have greatly reduced partial volume effect, making head movement the main source of image blur. To achieve high-resolution PET neuroimaging, precise real-time estimation of both head position and orientation is essential for accurate motion compensation., Purpose: A high-resolution electromagnetic motion tracking (EMMT) system with an event-by-event motion correction is developed for PET-CT scanners., Methods: EMMT is comprised of a source, an array of sensors, and a readout electronic unit (REU). The source acts as a transmitter and emits an EM dipole field. It is placed in close proximity to the sensor array and detects changes in EM flux density due to sensor movement. The REU digitizes signals from each sensor and captures precise rotational and translational movements in real time. Tracked motion in the EMMT coordinate system is synchronized with the PET list-mode data and transformed into the scanner coordinate system by locating paired positions in both systems. The optimal rigid motion is estimated using singular value decomposition. The rigid motion and depth-of-interaction (DOI) parallax effect are corrected by event-by-event rebinning of mispositioned lines-of-response (LORs). We integrated the EMMT with our recently developed ultra-high resolution Prism-PET prototype brain scanner and a commercial Siemens Biograph mCT PET-CT scanner. We assessed the imaging performance of the Prism-PET/EMMT system using multi-frame motion of point sources and phantoms. The mCT/EMMT system was validated using a set of point sources attached to both a mannequin head and a human volunteer, for simulating multiframe and continuous motions, respectively. Additionally, a human subject for [ 18 F]MK6240 PET imaging was included., Results: The tracking accuracy of the Prism-PET/EMMT system was quantified as a root-mean-square (RMS) error of 0.49 ∘ $^{\circ }$ for 100 ∘ $^{\circ }$ axial rotations, and an RMS error of 0.15 mm for 100 mm translations.The percent difference (%diff) in average full width at half maximum (FWHM) of point source between motion-corrected and static images, within a motion range of ± 20 ∘ $\pm 20^\circ$ and ± $\pm$ 10 mm from the center of the scanner's field-of-view (FOV), was 3.9%. The measured recovery coefficients of the 2.5-mm diameter sphere in the activity-filled partial volume correction phantom were 23.9%, 70.8%, and 74.0% for the phantom with multi-frame motion, with motion and motion compensation, and without motion, respectively. In the mCT/EMMT system, the %diff in average FWHM of point sources between motion-corrected and static images, within a motion range of ± 30 ∘ $\pm 30^\circ$ and ± $\pm$ 10 mm from the center of the FOV, was 14%. Applying motion correction to the [ 18 F]MK6240 PET imaging reduced the motion-induced spill-in artifact in the lateral ventricle region, lowering its standardized uptake value ratio (SUVR) from 0.70 to 0.34., Conclusions: The proposed EMMT system is a cost-effective, high frame-rate, and none-line-of-sight alternative to infrared camera-based tracking systems and is capable of achieving high rotational and translational tracking accuracies for mitigating motion-induced blur in high-resolution brain dedicated PET scanners., (© 2024 American Association of Physicists in Medicine.)

Purpose: Treatment of pediatric cancers with doxorubicin is a common and predictable cause of cardiomyopathy. Early diagnosis of treatment-induced cardiotoxicity and intervention are major determinants for the prevention of advanced disease. The onset of cardiomyopathies is often accompanied by profound changes in lipid metabolism, including an enhanced uptake of short-chain fatty acids (SCFA). Therefore, we explored the utility of 2-[ 18 F]fluoropropionic acid ([ 18 F]FPA), an SCFA analog, as an imaging biomarker of cardiac injury in mice exposed to doxorubicin. Procedures : Cardiotoxicity and cardiac dysfunction were induced in mice by an 8-dose regimen of doxorubicin (cumulative dose 24 mg/kg) administered over 14 days. The effects of doxorubicin exposure were assessed by measurement of heart weights, left ventricular ejection fractions, and blood cardiac troponin levels. Whole body and cardiac [ 18 F]FPA uptakes were determined by PET and tissue gamma counting in the presence or absence of AZD3965, a pharmacological inhibitor of monocarboxylate transporter 1 (MCT1). Radiation absorbed doses were estimated using tissue time-activity concentrations., Results: Significantly higher cardiac [ 18 F]FPA uptake was observed in doxorubicin-treated animals. This uptake remained constant from 30 min to 120 min post-injection. Pharmacological inhibition of MCT1-mediated transport by AZD3965 selectively decreased the uptake of [ 18 F]FPA in tissues other than the heart. Co-administration of [ 18 F]FPA and AZD3965 enhanced the imaging contrast of the diseased heart while reducing overall exposure to radioactivity., Conclusions: [ 18 F]FPA, especially when co-administered with AZD3965, is a new tool for imaging changes in fatty acid metabolism occurring in response to doxorubicin-induced cardiomyopathy by PET., Competing Interests: Conflicts of Interest: The authors declare that they have no conflict of interest with regard to this study.

Here, we report a magnetogenetic system, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. Adeno-associated virus (AAV)-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine-2a receptor-Cre drivers resulted in motor freezing when placed in a magnetic resonance imaging machine or adjacent to a transcranial magnetic stimulation device. Functional imaging and fiber photometry confirmed activation in response to magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing Cre into the globus pallidus led to similar circuit specificity and motor responses. Last, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in the subthalamic nucleus in PitX2-Cre parkinsonian mice resulted in reduced c-fos expression and motor rotational behavior. These data demonstrate that magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits noninvasively in vivo using clinically available devices.

Radiolabeled small-molecule DOTA-haptens can be combined with antitumor/anti-DOTA bispecific antibodies (BsAbs) for pretargeted radioimmunotherapy (PRIT). For optimized delivery of the theranostic γ- and β-emitting isotope 177 Lu with DOTA-based PRIT (DOTA-PRIT), bivalent Gemini (DOTA-Bn-thiourea-PEG4-thiourea-Bn-DOTA, aka (3,6,9,12-tetraoxatetradecane-1,14-diyl)bis(DOTA-benzyl thiourea)) was developed. Methods: Gemini was synthesized by linking 2 S -2-(4-isothiocyanatobenzyl)-DOTA molecules together via a 1,14-diamino-PEG4 linker. [ 177 Lu]Lu-Gemini was prepared with no-carrier-added 177 LuCl 3 to a molar-specific activity of 123 GBq/μmol and radiochemical purity of more than 99%. The specificity of BsAb- 177 Lu-Gemini was verified in vitro. Subsequently, we evaluated biodistribution and whole-body clearance for [ 177 Lu]Lu-Gemini and, for comparison, our gold-standard monovalent [ 177 Lu]Lu- S -2-(4-aminobenzyl)-DOTA ([ 177 Lu]Lu-DOTA-Bn) in naïve (tumor-free) athymic nude mice. For our proof-of-concept system, a 3-step pretargeting approach was performed with an established DOTA-PRIT regimen (anti-GPA33/anti-DOTA IgG-scFv BsAb, a clearing agent, and [ 177 Lu]Lu-Gemini) in mouse models. Results: Initial in vivo studies showed that [ 177 Lu]Lu-Gemini behaved similarly to [ 177 Lu]Lu-DOTA-Bn, with almost identical blood and whole-body clearance kinetics, as well as biodistribution and mouse kidney dosimetry. Pretargeting [ 177 Lu]Lu-Gemini to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [ 177 Lu]Lu-Gemini for blood, tumor, liver, spleen, and kidneys of 3.99, 455, 6.93, 5.36, and 14.0 cGy/MBq, respectively. Tumor-to-normal tissue absorbed-dose ratios (i.e., therapeutic indices [TIs]) for the blood and kidneys were 114 and 33, respectively. In addition, we demonstrate that the use of bivalent [ 177 Lu]Lu-Gemini in DOTA-PRIT leads to improved TIs and augmented [ 177 Lu]Lu-Gemini tumor uptake and retention in comparison to monovalent [ 177 Lu]Lu-DOTA-Bn. Finally, we established efficacy in SW1222 tumor-bearing mice, demonstrating that a single injection of anti-GPA33 DOTA-PRIT with 44 MBq (1.2 mCi) of [ 177 Lu]Lu-Gemini (estimated tumor-absorbed dose, 200 Gy) induced complete responses in 5 of 5 animals and a histologic cure in 2 of 5 (40%) animals. Moreover, a significant increase in survival compared with nontreated controls was noted (maximum tolerated dose not reached). Conclusion: We have developed a bivalent DOTA-radiohapten, [ 177 Lu]Lu-Gemini, that showed improved radiopharmacology for DOTA-PRIT application. The use of bivalent [ 177 Lu]Lu-Gemini in DOTA-PRIT, as opposed to monovalent [ 177 Lu]Lu-DOTA-Bn, allows curative treatments with considerably less administered 177 Lu activity while still achieving high TIs for both the blood (>100) and the kidneys (>30)., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Here we report a novel suite of magnetogenetic tools, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. AAV-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine 2a receptor-cre driver mice resulted in motor freezing when placed in an MRI or adjacent to a transcranial magnetic stimulation (TMS) device. Functional imaging and fiber photometry both confirmed activation of the target region in response to the magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing cre into the globus pallidus led to similar circuit specificity and motor responses. Finally, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in subthalamic nucleus in PitX2-cre parkinsonian mice resulted in reduced local c-fos expression and motor rotational behavior. These data demonstrate that magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits non-invasively in-vivo using clinically available devices., Competing Interests: Competing interest The authors declare no competing interests.

Brain fluid clearance by pathways including the recently described paravascular glymphatic system is a critical homeostatic mechanism by which metabolic products, toxins, and other wastes are removed from the brain. Brain fluid clearance may be especially important after traumatic brain injury (TBI), when blood, neuronal debris, inflammatory cells, and other substances can be released and/or deposited. Using a non-invasive dynamic positron emission tomography (PET) method that models the rate at which an intravenously injected radiolabeled molecule (in this case 11 C-flumazenil) is cleared from ventricular cerebrospinal fluid (CSF), we estimated the overall efficiency of brain fluid clearance in humans who had experienced complicated-mild or moderate TBI 3-6 months before neuroimaging ( n  = 7) as compared to healthy controls ( n  = 9). While there was no significant difference in ventricular clearance between TBI subjects and controls, there was a significant group difference in dependence of ventricular clearance upon tracer delivery/blood flow to the ventricles. Specifically, in controls, ventricular clearance was highly, linearly dependent upon blood flow to the ventricle, but this relation was disrupted in TBI subjects. When accounting for blood flow and group-specific alterations in blood flow, ventricular clearance was slightly (non-significantly) increased in TBI subjects as compared to controls. Current results contrast with past studies showing reduced glymphatic function after TBI and are consistent with possible differential effects of TBI on glymphatic versus non-glymphatic clearance mechanisms. Further study using multi-modal methods capable of assessing and disentangling blood flow and different aspects of fluid clearance is needed to clarify clearance alterations after TBI., Competing Interests: No competing financial interests exist., (© Tracy Butler et al., 2024; Published by Mary Ann Liebert, Inc.)

Based on studies in experimental animals demonstrating that administration of adeno-associated virus (AAV) vectors to the cerebrospinal fluid (CSF) is an effective route to transfer genes to the nervous system, there are increasing number of clinical trials using the CSF route to treat nervous system disorders. With the knowledge that the CSF turns over four to five times daily, and evidence in experimental animals that at least some of CSF administered AAV vectors are distributed to systemic organs, we asked: with AAV administration to the CSF, what fraction of the total dose remains in the nervous system and what fraction goes off target and is delivered systemically? To quantify the biodistribution of AAV capsids immediately after administration, we covalently labeled AAV capsids with iodine 124 (I-124), a cyclotron generated positron emitter, enabling quantitative positron emission tomography scanning of capsid distribution for up to 96 h after AAV vector administration. We assessed the biodistribution to nonhuman primates of I-124-labeled capsids from different AAV clades, including 9 (clade F), rh.10 (E), PHP.eB (F), hu68 (F), and rh91(A). The analysis demonstrated that 60-90% of AAV vectors administered to the CSF through either the intracisternal or intrathecal (lumbar) routes distributed systemically to major organs. These observations have potentially significant clinical implications regarding accuracy of AAV vector dosing to the nervous system, evoking systemic immunity at levels similar to that with systemic administration, and potential toxicity of genes designed to treat nervous system disorders being expressed in non-nervous system organs. Based on these data, individuals in clinical trials using AAV vectors administered to the CSF should be monitored for systemic as well as nervous system adverse events and CNS dosing considerations should account for a significant AAV systemic distribution.

Epithelial ovarian cancer (EOC) is often asymptomatic and presents clinically in an advanced stage as widespread peritoneal microscopic disease that is generally considered to be surgically incurable. Targeted α-therapy with the α-particle-emitting radionuclide 225 Ac (half-life, 9.92 d) is a high-linear-energy-transfer treatment approach effective for small-volume disease and even single cells. Here, we report the use of human epidermal growth factor receptor 2 (HER2) 225 Ac-pretargeted radioimmunotherapy (PRIT) to treat a mouse model of human EOC SKOV3 xenografts growing as peritoneal carcinomatosis (PC). Methods: On day 0, 10 5 SKOV3 cells transduced with a luciferase reporter gene were implanted intraperitoneally in nude mice, and tumor engraftment was verified by bioluminescent imaging (BLI). On day 15, treatment was started using 1 or 2 cycles of 3-step anti-HER2 225 Ac-PRIT (37 kBq/cycle as 225 Ac- Proteus DOTA), separated by a 1-wk interval. Efficacy and toxicity were monitored for up to 154 d. Results: Untreated PC-tumor-bearing nude mice showed a median survival of 112 d. We used 2 independent measures of response to evaluate the efficacy of 225 Ac-PRIT. First, a greater proportion of the treated mice (9/10 1-cycle and 8/10 2-cycle; total, 17/20; 85%) survived long-term compared with controls (9/27, 33%), and significantly prolonged survival was documented (log-rank [Mantel-Cox] P = 0.0042). Second, using BLI, a significant difference in the integrated BLI signal area to 98 d was noted between controls and treated groups ( P = 0.0354). Of a total of 8 mice from the 2-cycle treatment group (74 kBq total) that were evaluated by necropsy, kidney radiotoxicity was mild and did not manifest itself clinically (normal serum blood urea nitrogen and creatinine). Dosimetry estimates (relative biological effectiveness-weighted dose, where relative biological effectiveness = 5) per 37 kBq administered for tumors and kidneys were 56.9 and 16.1 Gy, respectively. One-cycle and 2-cycle treatments were equally effective. With immunohistology, mild tubular changes attributable to α-toxicity were observed in both therapeutic groups. Conclusion: Treatment of EOC PC-tumor-bearing mice with anti-HER2 225 Ac-PRIT resulted in histologic cures and prolonged survival with minimal toxicity. Targeted α-therapy using the anti-HER2 225 Ac-PRIT system is a potential treatment for otherwise incurable EOC., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background and Purpose: The choroid plexus (CP) within the brain ventricles is well-known to produce cerebrospinal fluid (CSF). Recently, the CP has been recognized as critical in modulating inflammation. MRI-measured CP enlargement has been reported in neuroinflammatory disorders like MS as well as with aging and neurodegeneration. The basis of MRI-measured CP enlargement is unknown. On the basis of tissue studies demonstrating CP calcification as a common pathology associated with aging and disease, we hypothesized that previously unmeasured CP calcification contributes to MRI-measured CP volume and may be more specifically associated with neuroinflammation., Materials and Methods: We analyzed 60 subjects (43 healthy controls and 17 subjects with Parkinson's disease) who underwent PET/CT using 11 C-PK11195, a radiotracer sensitive to the translocator protein expressed by activated microglia. Cortical inflammation was quantified as nondisplaceable binding potential. Choroid plexus calcium was measured via manual tracing on low-dose CT acquired with PET and automatically using a new CT/MRI method. Linear regression assessed the contribution of choroid plexus calcium, age, diagnosis, sex, overall volume of the choroid plexus, and ventricle volume to cortical inflammation., Results: Fully automated choroid plexus calcium quantification was accurate (intraclass correlation coefficient with manual tracing = .98). Subject age and choroid plexus calcium were the only significant predictors of neuroinflammation., Conclusions: Choroid plexus calcification can be accurately and automatically quantified using low-dose CT and MRI. Choroid plexus calcification-but not choroid plexus volume-predicted cortical inflammation. Previously unmeasured choroid plexus calcium may explain recent reports of choroid plexus enlargement in human inflammatory and other diseases. Choroid plexus calcification may be a specific and relatively easily acquired biomarker for neuroinflammation and choroid plexus pathology in humans., (© 2023 by American Journal of Neuroradiology.)

Background: Anthracycline cardiotoxicity is a concern in survivors of childhood cancers. Recent evidence suggests that remote ischemic conditioning (RIC) may offer myocardial protection., Objectives: This randomized sham-controlled single-blind study tested the hypothesis that RIC may reduce myocardial injury in pediatric cancer patients receiving anthracycline chemotherapy., Methods: We performed a phase 2 sham-controlled single-blind randomized controlled trial to determine the impact of RIC on myocardial injury in pediatric cancer patients receiving anthracycline-based chemotherapy. Patients were randomized to receive RIC (3 cycles of 5-minute inflation of a blood pressure cuff placed over 1 limb to 15 mm Hg above systolic pressure) or sham intervention. The intervention was applied within 60 minutes before initiation of the first dose and before up to 4 cycles of anthracycline therapy. The primary outcome was the plasma high-sensitivity cardiac troponin T (hs-cTnT) level. The secondary outcome measures included echocardiographic indexes of left ventricular systolic and diastolic function and the occurrence of cardiovascular events., Results: A total of 68 children 10.9 ± 3.9 years of age were randomized to receive RIC (n = 34) or sham (n = 34) intervention. Plasma levels of hs-cTnT showed a progressive increase across time points in the RIC ( P < 0.001) and sham ( P < 0.001) groups. At each of the time points, there were no significant differences in hs-cTnT levels or LV tissue Doppler and strain parameters between the 2 groups (all P > 0.05). None of the patients developed heart failure or cardiac arrhythmias., Conclusions: RIC did not exhibit cardioprotective effects in childhood cancer patients receiving anthracycline-based chemotherapy. (Remote Ischaemic Preconditioning in Childhood Cancer [RIPC]; NCT03166813)., Competing Interests: This study was supported by the Health and Health Services Research Fund, Food and Health Bureau, Hong Kong SAR Government (grant 05161506). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Radiopharmaceutical therapy is a rapidly growing field for the treatment of cancer due to its high specificity and ability to target individual affected cells. A key component of the pre-clinical development of a new therapeutic radiopharmaceutical is the determination of its time-dependent distribution in tumors, normal tissues, and the whole body in mouse tumor models. Here, we provide an overview of the available instrumentation for the novice in radiation measurement. We also detail the methodology for assessing distribution and kinetics of a radiopharmaceutical and calculating radiation absorbed dose in mice using a gamma counter or a PET or SPECT camera., Competing Interests: Disclosures EKF provides remunerated consulting to Invicro (Boston, MA, USA) and Y-mabs (New York, NY, USA). PBZ provides remunerated consulting to Novartis (Basel, Switzerland) and Radionetics (San Diego, CA) and has intellectual property licensed to Y-mabs (New York, NY, USA)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Children with cancer and childhood cancer survivors (CCS) are at risk for developing chemotherapy-induced cardiomyopathy. Myocardial deformation imaging has shown potential in the early detection of subclinical myocardial damage with implications on therapeutic interventions and improvement of outcomes. The aim of this study was to perform a systemic review and meta-analysis of literature on the assessment of left ventricular and right ventricular myocardial deformation by speckle-tracking echocardiography at rest and during stress in children with cancer during and in survivors after chemotherapy., Methods: A systematic review was performed through searching MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature, the Cochrane Central Register of Controlled Trials, and Scopus. Search hedges were created to cover the concepts of childhood cancer, chemotherapy, radiotherapy, anthracycline, cardiotoxicity, speckle-tracking, myocardial strain, and myocardial deformation. Two independent investigators reviewed the eligibility of articles for inclusion. The weighted mean difference in ventricular strain between pre- and postchemotherapy treatment and that between long-term CCS and healthy subjects were estimated using random-effect models with 95% CIs. Heterogeneity and publication bias were assessed using I 2 statistics and the Egger test, respectively., Results: Of the total of 8,703 records initially identified, 42 studies with a total of 5,430 children with cancer were included. Of these 42 studies that showed heterogeneities, nine assessed early myocardial injury during chemotherapy, 30 assessed late myocardial injury after chemotherapy with no publication bias, and three studied myocardial mechanics during stress. The main findings were as follows: (1) left ventricular systolic deformation is impaired in children with cancer during the initial treatment phase and among long-term CCS, while data on changes in right ventricular deformation are limited and inconclusive; (2) the predictive value of early reduction of myocardial strain imaging in forecasting subsequent development of cardiotoxicity is unknown, as it has not been studied; (3) limited data suggest the possibility of impaired left ventricular contractile mechanics during stress in CCS; and (4) cumulative anthracycline dose and chest-directed radiotherapy are consistently identified as factors associated with impaired myocardial deformation., Conclusions: Myocardial strain imaging by speckle-tracking echocardiography unveils early evidence of myocardial injury in children with cancer and long-term CCS. To support its adoption for clinical use, more data are required for the better understating of myocardial deformation parameters in the risk stratification of children with cancer and prediction of development of cardiomyopathy among CCS., (Copyright © 2022 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Radionuclide therapy is a rapidly expanding oncological treatment method. Overwhelmingly, the application of radionuclide therapy in clinical practice relies on fixed or empirical dosing strategies. In principle, the application of dosimetry promises to improve patient outcomes by tailoring administered radionuclide therapy activities to each patient's unique tumour burden and tumour uptake. However, robust prospective data are scarce due to few prospective randomised clinical trials investigating the use of dosimetry in radionuclide therapy. In this Review, we describe the role of dosimetry as it has been applied historically and in modern clinical practice and its potential future applications. We further emphasise areas of future growth and a potential pathway to optimised personalised activity modulation of radionuclide therapy., Competing Interests: Declaration of interests TAH declares research grants from Clovis Oncology and AAA/Novartis; consulting fees from Curium, Ipsen, and Blue Earth Diagnostics; a leadership role in the North American Neuroendocrine Tumor Society; and stock or stock options in RayzeBio, a radiopharmaceuticals company. EKF declares consulting fees for dosimetry from Invicro and Ymabs. RRF declares a research grant from the US Department of Defense Prostate Cancer Research Program on radionuclide therapy development. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Peritoneal carcinomatosis (PC) is considered incurable, and more effective therapies are needed. Herein we test the hypothesis that GPA33-directed intracompartmental pretargeted radioimmunotherapy (PRIT) can cure colorectal peritoneal carcinomatosis. Nude mice were implanted intraperitoneally with luciferase-transduced GPA33-expressing SW1222 cells for aggressive peritoneal carcinomatosis (e.g., resected tumor mass 0.369 ± 0.246 g; n = 17 on day 29). For GPA33-PRIT, we administered intraperitoneally a high-affinity anti-GPA33/anti-DOTA bispecific antibody (BsAb), followed by clearing agent (intravenous), and lutetium-177 (Lu-177) or yttrium-86 (Y-86) radiolabeled DOTA-radiohapten (intraperitoneal) for beta/gamma-emitter therapy and PET imaging, respectively. The DOTA-radiohaptens were prepared from S -2-(4-aminobenzyl)-1,4,7, 10-tetraazacyclododecane tetraacetic acid chelate (DOTA-Bn). Efficacy and toxicity of single- versus three-cycle therapy were evaluated in mice 26-27 days post-tumor implantation. Single-cycle treatment ([ 177 Lu]LuDOTA-Bn 111 MBq; tumor dose: 4,992 cGy) significantly prolonged median survival (MS) approximately 2-fold to 84.5 days in comparison with controls ( P = 0.007). With three-cycle therapy (once weekly, total 333 MBq; tumor dose: 14,975 cGy), 6/8 (75%) survived long-term (MS > 183 days). Furthermore, for these treated long-term survivors, 1 mouse was completely disease free (microscopic "cure") at necropsy; the others showed stabilized disease, which was detectable during PET-CT using [ 86 Y]DOTA-Bn. Treatment controls had MS ranging from 42-52.5 days ( P < 0.001) and 19/20 mice succumbed to progressive intraperitoneal disease by 69 days. Multi-cycle GPA33 DOTA-PRIT significantly prolongs survival with reversible myelosuppression and no chronic marrow (929 cGy to blood) or kidney (982 cGy) radiotoxicity, with therapeutic indices of 12 for blood and 12 for kidneys. MTD was not reached., (©2021 American Association for Cancer Research.)

We assessed right ventricular (RV)-pulmonary arterial (PA) coupling in patients with repaired tetralogy of Fallot (TOF). Sixty patients (34 males) aged 18.6 ± 8.3 years at 14.8 ± 7.4 years after repair and 60 controls were studied. Two-dimensional, tissue Doppler and speckle tracking echocardiography and colour flow mapping were performed to assess RV end-systolic (ESA) and -diastolic areas, tricuspid valve Doppler and myocardial velocities, left ventricular (LV) and RV deformation and pulmonary (PR), tricuspid regurgitation (TR), respectively. The ratios of RV area change to ESA and peak tricuspid annular systolic (s) velocity to RV ESA indexed to body surface area reflected RV-PA coupling. Patients had greater RV areas and reduced tricuspid annular and myocardial velocities, LV and RV myocardial mechanics compared to controls (all p < 0.05). Both RV area change/ESA ratio and peak tricuspid annular s velocity/indexed RV ESA ratio were reduced in patients (all p < 0.001). Sixty-one and 100% of patients had, respectively, RV area change/ESA ratio and peak tricuspid annular s velocity/indexed RV ESA ratio < -2SD of controls. Indices of RV-PA coupling correlated positively with tricuspid myocardial velocities, LV and RV deformation and inversely with PR and TR (all p < 0.05). Multivariate analysis showed RV systolic strain rate, PR and TR as independent predictors of both RV-PA coupling indices, whilst age, gender and LV systolic strain were also predictors of peak tricuspid annular s velocity/indexed RV ESA ratio (all p < 0.05). In conclusion, RV-PA coupling is impaired and is associated with RV and LV mechanics and severity of PR and TR in patients with repaired TOF., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Repeated mild Traumatic Brain Injury (TBI) is a risk factor for Chronic Traumatic Encephalopathy (CTE), characterized pathologically by neurofibrillary tau deposition in the depths of brain sulci and surrounding blood vessels. The mechanism by which TBI leads to CTE remains unknown but has been posited to relate to axonal shear injury leading to release and possibly deposition of tau at the time of injury. As part of an IRB-approved study designed to learn how processes occurring acutely after TBI may predict later proteinopathy and neurodegeneration, we performed tau PET using 18F-MK6240 and MRI within 14 days of complicated mild TBI in three subjects. PET radiotracer accumulation was apparent in regions of traumatic hemorrhage in all subjects, with prominent intraparenchymal PET signal in one young subject with a history of repeated sports-related concussions. These results are consistent with off-target tracer binding to blood products as well as possible on-target binding to chronically and/or acutely-deposited neurofibrillary tau. Both explanations are highly relevant to applying tau PET to understanding TBI and CTE. Additional study is needed to assess the potential utility of tau PET in understanding how processes occurring acutely after TBI, such as release and deposition of tau and blood from damaged axons and blood vessels, may relate to development CTE years later., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: We hypothesize that cardiac magnetic resonance (CMR) native T1 is associated with myocardial deformation in thalassaemia patients. The present study aimed to compare CMR native T1 values to conventional T2* values in patients with beta-thalassaemia and to explore relationships between these CMR parameters of myocardial iron overload and left ventricular (LV) and left atrial (LA) myocardial deformation., Methods: Thirty-four (16 males) patients aged 35.5 ± 9.2 years were studied. Myocardial T2* and T1 mapping were performed to assess the cardiac iron overload, while two-dimensional speckle-tracking echocardiography was performed in determine LV and LA myocardial deformation., Results: T2* was 36.4 ± 8.7 ms with 3 patients having myocardial iron load (T2*<20 ms). The native T1 was 947.1 ± 84.8 ms, which was significantly lower than the reported normal values in the literature. There was a significant correlation between T1 and T2* values (r = 0.68, p < 0.001). There were no significant correlations between T1 and T2* values and conventional and tissue Doppler parameters of left ventricular systolic and diastolic function. On the other hand, T1, but not T2*, values were found to correlate negatively with maximum LA area indexed by body surface area (r = -0.34, p = 0.047) and positively with LA strain rate at atrial contraction (r = 0.36, p = 0.04). There were no associations between either of these CMR parameters with indices of ventricular deformation., Conclusions: In patients with beta-thalassaemia major, native T1 values are decreased, associated with T2* values, and correlated with maximum LA area and LA strain rate at atrial contraction., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Aims: This study determined the associations between right atrial (RA) and right ventricular (RV) mechanics and liver stiffness in adults with repaired tetralogy of Fallot (TOF), pulmonary atresia with intact ventricular septum (PAVIS), and pulmonary stenosis (PS)., Methods and Results: Ninety subjects including 26 repaired TOF, 24 PAIVS, and 20 PS patients and 20 controls were studied. Hepatic shear wave velocity and tissue elasticity (E), measures of liver stiffness, were assessed by two-dimensional shear wave elastography, while RA and RV mechanics were assessed by speckle tracking echocardiography. Deformation analyses revealed worse RV systolic strain and strain rate, and RA peak positive and total strain, and strain rates at ventricular systole and at early diastole in all of the patient groups compared with controls (all P < 0.05). Compared with controls, all of the patient groups had significantly greater shear wave velocity and hepatic E-value (all P < 0.05). Shear wave velocity and hepatic E-value correlated negatively with RV systolic strain rate, and RA positive strain, total strain, and strain rate at ventricular systole and at early diastole (all P < 0.05). Multivariate analyses revealed RA strain rate at early diastole (P = 0.015, P < 0.001), maximum RA size (P < 0.001, P < 0.001), and severity of pulmonary regurgitation (P = 0.05, Pp = 0.014) as significant correlates of shear wave velocity and hepatic E-value., Conclusion: In adults with repaired TOF, PAIVS, and PS, RA dysfunction and pulmonary regurgitation are associated with liver stiffness., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Purpose: To evaluate safety and efficacy of radiation segmentectomy (RS) with 90 Y glass microspheres in patients with limited metastatic liver disease not amenable to resection or percutaneous ablation., Methods: Patients with ≤ 3 tumors treated with RS from 6/2015 to 12/2017 were included. Target tumor radiation dose was > 190 Gy based on medical internal radiation dose (MIRD) dosimetry. Tumor response, local tumor progression (LTP), LTP-free survival (LTPFS) and disease progression rate in the treated segment were defined using Choi and RECIST 1.1 criteria. Toxicities were evaluated using modified SIR criteria., Results: Ten patients with 14 tumors underwent 12 RS. Median tumor size was 3 cm (range 1.4-5.6). Median follow-up was 17.8 months (range 1.6-37.3). Response rates per Choi and RECIST 1.1 criteria were 8/8 (100%) and 4/9 (44%), respectively. Overall LTP rate was 3/14 (21%) during the study period. One-, two- and three-year LTPFS was 83%, 83% and 69%, respectively. Median LTPFS was not reached. Disease progression rate in the treated segment was 6/18 (33%). Median overall survival was 41.5 months (IQR 16.7-41.5). Median delivered tumor radiation dose was 293 Gy (range 163-1303). One major complication was recorded in a patient post-Whipple procedure who suffered anaphylactic reaction to prophylactic cefotetan and liver abscess in RS region 6.5 months post-RS. All patients were alive on last follow-up., Conclusion: RS of ≤ 3 hepatic segments can safely provide a 2-year local tumor control rate of 83% in selected patients with limited metastatic liver disease and limited treatment options. Optimal dosimetry methodology requires further investigation.

We determined the occurrence of aortic regurgitation (AR), AR progression and risk factors in patients followed up for up to three decades after closure of subarterial VSD. We reviewed the outcomes of 86 patients categorized into three groups: group I comprised 37 patients without AR and had VSD closure alone, group II comprised 40 patients with AR and had VSD closure without aortic valvoplasty, and group III comprised 9 patients with AR and required both VSD closure and aortic valvoplasty. Patients were followed up for 18.9 ± 7.3 years (median 19.5 years, range 3.5-36.6). At latest follow up, 54.7% (47/86) of patients had AR. The prevalence of progression of AR from any one grade to the next one higher was 37.2% (32/86). Freedom from AR progression was 75.6%, 52.1%, and 22.2% at 20 years of follow-up for groups I, II and III, respectively (p < 0.05). On the other hand, progression to moderate to severe AR occurred only in 4.7% (4/86). Group I and II patients were free from progression to significant AR, while only 33.3% of group III patients were free from progression on follow-up (p < 0.001). Multivariate Cox regression analysis showed that severity of preoperative AR was the significant risk factor for persistence and progression of postoperative AR after VSD closure. In conclusion, aortic regurgitation is common and may progress even after surgical repair of subarterial VSD. Severity of preoperative AR is the most significant predictor of persistence and progression of AR after surgical closure of subarterial VSD.

Purpose: Radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF) has been shown to be a safe and promising treatment for leptomeningeal metastases. Pharmacokinetic models for intraOmmaya antiGD2 monoclonal antibody 131 I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply pharmacokinetic modeling to intraOmmaya 131 I-omburtamab (8H9), an antiB7-H3 antibody which has shown promise in RIT of leptomeningeal metastases., Methods: Serial CSF samples were collected and radioassayed from 61 patients undergoing a total of 177 intraOmmaya administrations of 131 I-omburtamab for leptomeningeal malignancy. A two-compartment pharmacokinetic model with 12 differential equations was constructed and fitted to the radioactivity measurements of CSF samples collected from patients. The model was used to improve anti-tumor dose while reducing off-target toxicity. Mathematical endpoints were (a) the area under the concentration curve (AUC) of the tumor-bound antibody, AUC [C IAR (t)], (b) the AUC of the unbound "harmful" antibody, AUC [C IA (t)], and (c) the therapeutic index, AUC [C IAR (t)] ÷ AUC [C IA (t)]., Results: The model fit CSF radioactivity data well (mean R = 96.4%). The median immunoreactivity of 131 I-omburtamab matched literature values at 69.1%. Off-target toxicity (AUC [C IA (t)]) was predicted to increase more quickly than AUC [C IAR (t)] as a function of 131 I-omburtamab dose, but the balance of therapeutic index and AUC [C IAR (t)] remained favorable over a broad range of administered doses (0.48-1.40 mg or 881-2592 MBq). While antitumor dose and therapeutic index increased with antigen density, the optimal administered dose did not. Dose fractionization into two separate injections increased therapeutic index by 38%, and splitting into 5 injections by 82%. Increasing antibody immunoreactivity to 100% only increased therapeutic index by 17.5%., Conclusion: The 2-compartmental pharmacokinetic model when applied to intraOmmaya 131 I-omburtamab yielded both intuitive and nonintuitive therapeutic predictions. The potential advantage of further dose fractionization warrants clinical validation., Clinical Trial Registration: ClinicalTrials.gov , NCT00089245.

Purpose: Many cancer treatments suffer from dose-limiting toxicities to vital organs due to poor therapeutic indices. To overcome these challenges we developed a novel multimerization platform that rapidly removes tumor-targeting proteins from the blood to substantially improve therapeutic index., Experimental Design: The platform was designed as a fusion of a self-assembling and disassembling (SADA) domain to a tandem single-chain bispecific antibody (BsAb, anti-ganglioside GD2 × anti-DOTA). SADA-BsAbs were assessed with multiple in vivo tumor models using two-step pretargeted radioimmunotherapy (PRIT) to evaluate tumor uptake, dosimetry, and antitumor responses., Results: SADA-BsAbs self-assembled into stable tetramers (220 kDa), but could also disassemble into dimers or monomers (55 kDa) that rapidly cleared via renal filtration and substantially reduced immunogenicity in mice. When used with rapidly clearing DOTA-caged PET isotopes, SADA-BsAbs demonstrated accurate tumor localization, dosimetry, and improved imaging contrast by PET/CT. When combined with therapeutic isotopes, two-step SADA-PRIT safely delivered massive doses of alpha-emitting ( 225 Ac, 1.48 MBq/kg) or beta-emitting ( 177 Lu, 6,660 MBq/kg) S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA) payloads to tumors, ablating them without any short-term or long-term toxicities to the bone marrow, kidneys, or liver., Conclusions: The SADA-BsAb platform safely delivered large doses of radioisotopes to tumors and demonstrated no toxicities to the bone marrow, kidneys, or liver. Because of its modularity, SADA-BsAbs can be easily adapted to most tumor antigens, tumor types, or drug delivery approaches to improve therapeutic index and maximize the delivered dose. See related commentary by Capala and Kunos, p. 377 ., (©2020 American Association for Cancer Research.)

Photons, electrons and protons have therapeutic use however positrons have only been used for diagnostic imaging purposes. The energies of positrons (β + ) from F-18 (0.633 MeV) and electrons (β - ) from I-131 (0.606 MeV) are very close and have similar equilibrium dose constants. Since [ 18 F]-fluorodeoxyglucose ( 18 F-FDG) clears rapidly from circulation, administration of 37-74 GBq (1-2 Ci) of 18 F-FDG is relatively safe from an internal radiation dosimetry point of view. We initiated a phase I dose escalation study to assess the safety, toxicity, and potential therapeutic utility of administering 100-200 mCi/m 2 18 F-FDG delivered over a 1 to 5 day period in patients with advanced lymphomas and solid tumors refractory to standard of care treatment (SCT). Here we report the results of the first four patients treated. Four patients with advanced cancers received a single dose of 3.7-7.4 GBq/m 2 (100-200 mCi/m 2 ) 18 F-FDG. We monitored the patients for adverse effects and for response. No treatment-related toxicities were observed. There was no increased radiation exposure to personnel. Two patients showed decrease in the index lesions' SUVs by 17-33% (Day 1) and 25-31% (Day 30) post treatment. The two other patients showed stable disease on 18 F-PET-CT. Interestingly, responses were seen at low radiotherapy doses (below 1 Gy). This exploratory study demonstrated the safety of therapeutic administration of up to 14.2 GBq (385 mCi) 18 F-FDG. In patients with 18 F-FDG-avid cancers, targeted radionuclide 18 F-FDG therapy appears safe and may offer clinical benefit., Competing Interests: None., (AJNMMI Copyright © 2020.)

A method is presented for quantitative analysis of the biodistribution of adeno-associated virus (AAV) gene transfer vectors following in vivo administration. We used iodine-124 (I-124) radiolabeling of the AAV capsid and positron emission tomography combined with compartmental modeling to quantify whole-body and organ-specific biodistribution of AAV capsids from 1 to 72 h following administration. Using intravenous (IV) and intracisternal (IC) routes of administration of AAVrh.10 and AAV9 vectors to nonhuman primates in the absence or presence of anticapsid immunity, we have identified novel insights into initial capsid biodistribution and organ-specific capsid half-life. Neither I-124-labeled AAVrh.10 nor AAV9 administered intravenously was detected at significant levels in the brain relative to the administered vector dose. Approximately 50% of the intravenously administered labeled capsids were dispersed throughout the body, independent of the liver, heart, and spleen. When administered by the IC route, the labeled capsid had a half-life of ∼10 h in the cerebral spinal fluid (CSF), suggesting that by this route, the CSF serves as a source with slow diffusion into the brain. For both IV and IC administration, there was significant influence of pre-existing anticapsid immunity on I-124-capsid biodistribution. The methodology facilitates quantitative in vivo viral vector dosimetry, which can serve as a technique for evaluation of both on- and off-target organ biodistribution, and potentially accelerate gene therapy development through rapid prototyping of novel vector designs.

This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using 225 Ac and its theranostic pair, 111 In. We call our novel tumor-targeting DOTA-hapten PRIT system "proteus-DOTA" or "Pr." Herein we report the first results of radiochemistry development, radiopharmacology, and stoichiometry of tumor antigen binding, including the role of specific activity, anti-tumor efficacy, and normal tissue toxicity with the Pr-PRIT approach (as α-DOTA-PRIT). A series of α-DOTA-PRIT therapy studies were performed in three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2), including evaluation of chronic toxicity at ~20 weeks of select survivors. Methods: Preliminary biodistribution experiments in SW1222 tumor-bearing mice revealed that 225 Ac could not be efficiently pretargeted with current DOTA-Bn hapten utilized for 177 Lu or 90 Y, leading to poor tumor uptake in vivo . Therefore, we synthesized Pr consisting of an empty DOTA-chelate for 225 Ac, tethered via a short polyethylene glycol linker to a lutetium-complexed DOTA for picomolar anti-DOTA chelate single-chain variable fragment (scFv) binding. Pr was radiolabeled with 225 Ac and its imaging surrogate, 111 In. In vitro studies verified anti-DOTA scFv recognition of [ 225 Ac]Pr, and in vivo biodistribution and clearance studies were performed to evaluate hapten suitability and in vivo targeting efficiency. Results: Intravenously (i.v.) administered 225 Ac- or 111 In-radiolabeled Pr in mice showed rapid renal clearance and minimal normal tissue retention. In vivo pretargeting studies show high tumor accumulation of Pr (16.71 ± 5.11 %IA/g or 13.19 ± 3.88 %IA/g at 24 h p.i. for [ 225 Ac]Pr and [ 111 In]Pr, respectively) and relatively low uptake in normal tissues (all average ≤ 1.4 %IA/g at 24 h p.i.). Maximum tolerated dose (MTD) was not reached for either [ 225 Ac]Pr alone or pretargeted [ 225 Ac]Pr at administered activities up to 296 kBq/mouse. Single-cycle treatment consisting of α-DOTA-PRIT with either huA33-C825 bispecific anti-tumor/anti-DOTA-hapten antibody (BsAb), anti-HER2-C825 BsAb, or hu3F8-C825 BsAb for targeting GPA33, HER2, or GD2, respectively, was highly effective. In the GPA33 model, no complete responses (CRs) were observed but prolonged overall survival of treated animals was 42 d for α-DOTA-PRIT vs. 25 d for [ 225 Ac]Pr only ( P < 0.0001); for GD2, CRs (7/7, 100%) and histologic cures (4/7, 57%); and for HER2, CRs (7/19, 37%) and histologic cures (10/19, 56%) with no acute or chronic toxicity. Conclusions: [ 225 Ac]Pr and its imaging biomarker [ 111 In]Pr demonstrate optimal radiopharmacologic behavior for theranostic applications of α-DOTA-PRIT. For this initial evaluation of efficacy and toxicity, single-cycle treatment regimens were performed in all three systems. Histologic toxicity was not observed, so MTD was not observed. Prolonged overall survival, CRs, and histologic cures were observed in treated animals. In comparison to RIT with anti-tumor IgG antibodies, [ 225 Ac]Pr has a much improved safety profile. Ultimately, these data will be used to guide clinical development of toxicity and efficacy studies of [ 225 Ac]Pr, with the goal of delivering massive lethal doses of radiation to achieve a high probability of cure without toxicity., Competing Interests: Competing Interests: N.K.C reports receiving commercial research grants from Y-mAbs Therapeutics, Inc. in 2015 and Abpro-Labs, Inc. in 2017, holding ownership interest/equity in Y-mAbs Therapeutics and in Abpro-Labs, and owning stock options in Eureka Therapeutics, Inc. N.K.C is the inventor and owner of issued patents licensed by MSK to Y-mAbs Therapeutics, Biotec Pharmacon, and Abpro Labs. These include US patents 6451995, 7507724, 7704973, 7740845, 7666424, 9315585, and multiple pending patents. N.K.C is a scientific advisory board member of Abpro Labs and Eureka Therapeutics. N.K.C, S.M.L, and S.M.C were named as one of the inventors in the following patent applications relating to GPA33: SK2014-074, SK2015-091, SK2017-079, SK2018-045, SK2014-116, SK2016-052, and SK2018-068 filed by MSK. S.M.L reports receiving commercial research grants from Genentech, Inc., WILEX AG, Telix Pharmaceuticals Limited, and Regeneron Pharmaceuticals, Inc.; holding ownership interest/equity in Elucida Oncology, Inc. and Y-mAbs Therapeutics, and holding stock in ImaginAb, Inc. S.M.L is the inventor and owner of issued patents both currently unlicensed and licensed by MSK to Samus Therapeutics, Inc., Elucida Oncology, Inc., and Y-mAbs Therapeutics, Inc. S.M.L serves or has served as a consultant to Cynvec LLC, Eli Lilly & Co., Prescient Therapeutics Limited, Advanced Innovative Partners, LLC, Gerson Lehrman Group, Progenics Pharmaceuticals, Inc., and Janssen Pharmaceuticals, Inc. G.Y and O.O are listed as inventors and receive royalties from patents that were filed by MSK. O.O is an unpaid member of the scientific advisory board of Angiogenex and owns shares in Angiogenex. B.H.S and N.K.C are inventors on US Patent No. 62/502,151. D.A.S is a consultant to, on the board of, and/or has equity in: PGNX, SLS, KLUS, IOVA, PFE, ATNM, Oncopep and Eureka Therapeutics. MSK has filed for patent protection on behalf of D.A.S for technology discussed in this paper. All other authors have no competing interests., (© The author(s).)

Background: The QRS-T angle has been associated with adverse cardiovascular events and sudden cardiac deaths. We determined frontal QRS-T angle in patients with complete transposition of the great arteries (TGA) after atrial switch operation and repaired tetralogy of Fallot (TOF) and explored its relationships with ventricular mechanics., Methods: Thirty TGA patients aged 32.3 ± 4.4 years after atrial switch operation and 47 repaired TOF patients aged 28.7 ± 6.0 years were studied. The frontal planar QRS-T angle and QRS duration were measured from 12-lead electrocardiograms. Right (RV) and left ventricular (LV) strain parameters were determined using speckle tracking echocardiography., Results: Compared with TOF patients, TGA patients after atrial switch operation had significantly greater frontal QRS-T angle (136.3° ± 43.5° vs 74.5° ± 59.6°, p < 0.001), greater prevalence of QRS-T angle ≥ 100° (83.3% vs 29.8%, p < 0.001), and showed progressive increase in QRS-T angle over a duration of 3.3 ± 1.0 years (p = 0.035). The QRS-T angle correlated positively with QRS duration in both the TGA (r = 0.61, p < 0.001) and TOF (r = 0.30, p < 0.043) groups. Among TGA patients, QRS-T angle was found to correlate negatively with systemic RV global longitudinal strain (r = - 0.49, p = 0.007), early diastolic strain rate (r = - 0.41, p = 0.026), and fractional area change (r = - 0.38, p = 0.045), but not subpulmonary LV strain indices. By contrast, among repaired TOF patients, there were no significant correlations between QRS-T angle and systemic and subpulmonary ventricular strain indices (all p > 0.05)., Conclusion: Increased frontal QRS-T angle is prevalent in TGA patients after atrial switch operation and is related to worse systemic RV mechanics.

In patients with repaired tetralogy of Fallot (TOF), dysfunction of the right and left ventricles remains an important issue. Adverse right ventricular (RV) remodeling has been related to RV dilation secondary to pulmonary regurgitation, electromechanical dyssynchrony, and myocardial fibrosis. Left ventricular (LV) dysfunction is attributed among other factors to altered ventricular-ventricular interaction. Advancements in echocardiography and cardiac magnetic resonance imaging have enabled direct interrogation of myocardial deformation of both ventricles in terms of myocardial strain and strain rate. Emerging evidence suggests that myocardial deformation imaging may provide incremental information for clinical use. In children and adults with repaired TOF, there is a growing body of literature on the use of myocardial deformation imaging in the assessment of ventricular mechanics and its clinical and prognostic values. The present review aims to provide an overview of impairment in RV and LV mechanics, associations between RV and LV deformation, changes in ventricular deformation after pulmonary valve replacement, and associations between measures of RV and LV deformation and outcomes and to highlight the clinical translational potential of myocardial deformation imaging in patients with repaired TOF., (Copyright © 2020 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

We tested the hypothesis that left ventricular (LV) myocardial stiffness is altered in patients with transposition of great arteries (TGA) after arterial switch operation (ASO) and explored its associations with myocardial calibrated integrated backscatter (cIB) and LV myocardial deformation. Thirty-one patients and twenty-two age-matched controls were studied. LV myocardial stiffness was assessed by diastolic wall strain (DWS) and stiffness indices including (E/e)/LV end-diastolic dimension, (E/LV global longitudinal early diastolic strain rate)/LV end-diastolic volume, and (E/LV global circumferential early diastolic strain rate)/LV end-diastolic volume, where E and e are early diastolic transmitral and mitral annular velocities, respectively. LV myocardial cIB and longitudinal and circumferential myocardial deformation were determined by conventional and speckle tracking echocardiography. Patients had significantly lower DWS, higher stiffness indices, and greater myocardial cIB than controls (all p < 0.05). The LV longitudinal and circumferential systolic strain and systolic and diastolic strain rates were significantly lower in patients than controls (all p < 0.05). Greater average myocardial cIB was associated with lower DWS (r = - 0.44, p = 0.002). Worse DWS and LV stiffness indices were found to correlate with lower mitral annular systolic velocity, mitral annular late diastolic velocity, and LV longitudinal late diastolic strain rate (all p < 0.05). LV longitudinal and circumferential systolic strain and strain rate were also found to correlate with DWS (all p < 0.05). In conclusion, LV myocardial stiffening occurs in adolescents and young adults with TGA after ASO and is associated with impairment of ventricular systolic and diastolic myocardial deformation and myocardial fibrosis.

Radiation dose estimations are key for optimizing therapies. We studied the role of 124 I-omburtamab (8H9) given intraventricularly in assessing the distribution and radiation doses before 131 I-omburtamab therapy in patients with metastatic leptomeningeal disease and compared it with the estimates from cerebrospinal fluid (CSF) sampling. Methods: Patients with histologically proven malignancy and metastatic disease to the central nervous system or leptomeninges who met eligibility criteria for 131 I-omburtamab therapy underwent immuno-PET imaging with 124 I-8H9 followed by 131 I-8H9 antibody therapy. Patients were imaged with approximately 74 MBq of intraventricular 124 I-omburtamab via an Ommaya reservoir. Whole-body PET images were acquired at approximately 4, 24, and 48 h after administration and analyzed for dosimetry calculations. Peripheral blood and CSF samples were obtained at multiple time points for dosimetry estimation. Results: Forty-two patients with complete dosimetry and therapy data were analyzed. 124 I-omburtamab PET-based radiation dosimetry estimations revealed mean (±SD) absorbed dose to the CSF for 131 I-8H9 of 0.62 ± 0.40 cGy/MBq, compared with 2.22 ± 2.19 cGy/MBq based on 124 I-omburtamab CSF samples and 1.53 ± 1.37 cGy/MBq based on 131 I-omburtamab CSF samples. The mean absorbed dose to the blood was 0.051 ± 0.11 cGy/MBq for 124 I-omburtamab samples and 0.07 ± 0.04 cGy/MBq for 131 I-omburtamab samples. The effective whole-body radiation dose for 124 I-omburtamab was 0.49 ± 0.27 mSv/MBq. The mean whole-body clearance half-time was 44.98 ± 16.29 h. Conclusion: PET imaging with 124 I-omburtamab antibody administered intraventricularly allows for noninvasive estimation of dose to CSF and normal organs. High CSF-to-blood absorbed-dose ratios are noted, allowing for an improved therapeutic index to leptomeningeal disease and reduced systemic doses. PET imaging-based estimates were less variable and more reliable than CSF sample-based dosimetry., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

We aimed to interrogate sex differences in cardiac mechanics using two-(2D) and three-(3D) dimensional speckle tracking echocardiography (STE) in survivors of childhood cancers. 83 survivors (43 males) aged 25.6 ± 6.1 years at 16.0 ± 6.1 years after anthracycline therapy and 42 healthy controls (21 males) were studied. 2D STE was performed to assess LV linear deformation in three principal directions, while 3D STE was performed to assess LV ejection fraction, global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and global area strain (GAS). Receiver operating characteristic (ROC) curves were generated to to determine the usefulness of 2D and 3D echocardiographic indices to discriminate between survivors and controls. Survivors of both sex had significantly lower 2D and 3D strain indices compared with sex-specific controls (all p < 0.05). Among survivors, 2D GLS and GRS and all of the 3D indices were similar between males and females (all p > 0.05). Among cancer survivors, multivariate analysis revealed age at study (β = - 0.26, p = 0.022) as a significant determinant of 3D GLS. The area under the ROC curve for 3D GLS was the largest at 0.89 amongst all 3D and 2D strain parameters, while that of 2D GLS was 0.83. For 3D GLS, a cut-off of 16.4% had a sensitivity of 85.7% and a specificity of 80.7% of differentiating survivors from controls. Notwithstanding the finding of impaired LV myocardial mechanics, the present study did not reveal evidence of sexual dimorphism in cardiac mechanics in long term survivors of childhood cancers.

This study aimed to assess left (LA) and right atrial (RA) function in patients with beta-thalassaemia major. Thirty-eight patients (19 males) aged 34.5 ± 10.7 years and 43 (18 males) controls aged 30.3 ± 12.6 years (p = 0.12) were studied. The maximum RA and LA areas were measured using two-dimensional planimetry, while atrial and ventricular strain and strain rates were quantified using speckle-tracking echocardiography. Compared with controls, patients had significantly reduced LA and RA peak positive strain and total strain, and LA strain rate during ventricular systole and at atrial contraction (all p < 0.05). The LA and RA strain parameters were significantly associated (all p < 0.05). The maximum LA (10.2 ± 1.6 cm 2 /m 2 vs. 8.6 ± 1.3 cm 2 /m 2 , p < 0.001) and RA (9.2 ± 1.2 cm 2 /m 2 vs. 7.5 ± 1.3 cm 2 /m 2 , p < 0.001) areas were significantly greater in patients than controls. The LV and RV strain and early strain rates were similar between patients and controls (all p > 0.05). Four patients with significant myocardial iron overload had larger LA area (p < 0.001) than those without. Functional and structural remodeling of both the right and left atria occurs in patients with beta-thalassaemia major, even in the absence of ventricular diastolic dysfunction.

This study determined the circulating levels of TGF-β1 and its association with aortic dilation and elastic properties in congenital heart patients. Forty-six patients after tetralogy of Fallot (TOF) repair, 21 patients post arterial switch and 15 patients post atrial switch for transposition of the great arteries (TGA), 27 patients post Fontan procedure, and 36 controls were studied. Aortic dimensions and elastic properties and ventricular function were assessed by echocardiography. Serum TGF-β1, metalloproteinase (MMP)-2 and MMP-9 levels were quantified. Compared with controls, all groups of patients had significantly larger ascending aortic dimensions and worse elastic properties (all p < 0.05). Aortic stiffness correlated positively with sinus dimension (r = 0.48, p < 0.001) and negatively with indices of ventricular deformation (all p < 0.001). Patients with repaired TOF had significantly higher levels of TGF-β1 (p = 0.005), MMP-2 (p = 0.001) and MMP-9 (p < 0.001) than controls, while patients after atrial switch operation (p = 0.034) and Fontan procedures (p < 0.001) had higher MMP-2 levels. In patients as a group, circulating TGF-β1 levels correlated with MMP-9 (r = 0.44, p < 0.001) and aortic sinus dimension (r = 0.22, p = 0.035). In conclusion, increased circulating TGF-β1, MMP-2, and MMP-9 levels were found in patients with repaired TOF, and increased circulating MMP-2 levels were also evident in patients after atrial switch operation and Fontan procedure.

In recent reports, we have shown that optimized pretargeted radioimmunotherapy (PRIT) based on molecularly engineered antibody conjugates and 177 Lu-DOTA chelate (DOTA-PRIT) can be used to cure mice bearing human solid tumor xenografts using antitumor antibodies to minimally internalizing membrane antigens, GPA33 (colon) and GD2 (neuroblastoma). However, many solid tumor membrane antigens are internalized after antibody binding and it is generally believed that internalizing tumor membrane antigens are not suitable targets for PRIT. In this study, we tested the hypothesis that DOTA-PRIT can be performed successfully to target HER2, an internalizing membrane antigen widely expressed in breast, ovarian, and gastroesophageal junction cancers. Methods: DOTA-PRIT was carried out in athymic nude mice bearing BT-474 xenografts, a HER2-expressing human breast cancer, using a three-step dosing regimen consisting of sequential intravenous administrations of: 1) a bispecific IgG-scFv (210 kD) format (BsAb) carrying the IgG sequence of the anti-HER2 antibody trastuzumab and the scFv "C825" with high-affinity, hapten-binding antibody for Bn-DOTA (metal) (BsAb: anti-HER2-C825), 2) a 500 kD dextran-based clearing agent, followed by 3) 177 Lu-DOTA-Bn. At the time of treatment, athymic nude mice bearing established subcutaneous BT-474 tumors (medium- and smaller-sized tumors with tumor volumes of 209 ± 101 mm 3 and ranging from palpable to 30 mm 3 , respectively), were studied along with controls. We studied single- and multi-dose regimens. For groups receiving fractionated treatment, we verified quantitative tumor targeting during each treatment cycle using non-invasive imaging with single-photon emission computed tomography/computed tomography (SPECT/CT). Results: We achieved high therapeutic indices (TI, the ratio of radiation-absorbed dose in tumor to radiation-absorbed dose to critical organs, such as bone marrow) for targeting in blood (TI = 28) and kidney (TI = 7), while delivering average radiation-absorbed doses of 39.9 cGy/MBq to tumor. Based on dosimetry estimates, we implemented a curative fractionated therapeutic regimen for medium-sized tumors that would deliver approximately 70 Gy to tumors, which required treatment with a total of 167 MBq 177 Lu-DOTA-Bn/mouse (estimated absorbed tumor dose: 66 Gy). This regimen was well tolerated and achieved 100% complete responses (CRs; defined herein as tumor volume equal to or smaller than 4.2 mm 3 ), including 62.5% histologic cure (5/8) and 37.5% microscopic residual disease (3/8) at 85 days (d). Treatment controls showed tumor progression to 207 ± 201% of pre-treatment volume at 85 d and no CRs. Finally, we show that treatment with this curative 177 Lu regimen leads to a very low incidence of histopathologic abnormalities in critical organs such as bone marrow and kidney among survivors compared with non-treated controls. Conclusion: Contrary to popular belief, we demonstrate that DOTA-PRIT can be successfully adapted to an internalizing antigen-antibody system such as HER2, with sufficient TIs and absorbed tumor doses to achieve a high probability of cures of established human breast cancer xenografts while sparing critical organs of significant radiotoxicity., Competing Interests: Competing Interests: N.K. Cheung reports receiving commercial research grants from Y-mabs Therapeutics and Abpro-Labs Inc.; holding ownership interest/equity in Y-Mabs Therapeutics Inc., holding ownership interest/equity in Abpro-Labs, and owning stock options in Eureka Therapeutics. NKC is the inventor and owner of issued patents both currently unlicensed and licensed by MSK to Ymabs Therapeutics, Biotec Pharmacon, and Abpro-labs. NKC is an advisory board member for Abpro-Labs and Eureka Therapeutics. SM Larson reports receiving commercial research grants from Genentech, Wilex, Telix and Regeneron; holding ownership interest/equity in Voreyda Theranostics Inc. and Elucida Oncology Inc, and holding stock in ImaginAb. SML is the inventor and owner of issued patents both currently unlicensed and licensed by MSK to Samus Therapeutics and Elucida Oncology Inc. SML is or has been consultant to Cynvec, Eli Lilly, Prescient, Advanced Innovative Partners, Gerson Lehrman, Progenics and Janssen Pharmaceuticals. All other authors have no competing interests.

Antibodies labeled with positron-emitting isotopes have been used for tumor detection, predicting which patients may respond to tumor antigen-directed therapy, and assessing pharmacodynamic effects of drug interventions. Prolactin receptor (PRLR) is overexpressed in breast and prostate cancers and is a new target for cancer therapy. We evaluated REGN2878, an anti-PRLR monoclonal antibody, as an immunoPET reagent. REGN2878 was labeled with Zr-89 after conjugation with desferrioxamine B or labeled with I-131/I-124. In vitro determination of the half-maximal inhibitory concentration (IC50) of parental REGN2878, DFO-REGN2878, and iodinated REGN2878 was performed by examining the effect of the increasing amounts of these on uptake of trace-labeled I-131 REGN2878. REGN1932, a non-PRLR binding antibody, was used as a control. Imaging and biodistribution studies were performed in mice bearing tumor xenografts with various expression levels of PRLR, including MCF-7, transfected MCF-7/PRLR, PC3, and transfected PC3/PRLR and T4D7v11 cell lines. The specificity of uptake in tumors was evaluated by comparing Zr-89 REGN2878 and REGN1932, and in vivo competition compared Zr-89 REGN2878 uptake in tumor xenografts with and without prior injection of 2 mg of nonradioactive REGN2878. The competition binding assay of DFO-REGN2878 at ratios of 3.53-5.77 DFO per antibody showed IC50 values of 0.4917 and 0.7136 nM, respectively, compared to 0.3455 nM for parental REGN2878 and 0.3343 nM for I-124 REGN2878. Imaging and biodistribution studies showed excellent targeting of Zr-89 REGN2878 in PRLR-positive xenografts at delayed times of 189 h (presented as mean ± 1 SD, percent injected activity per mL (%IA/mL) 74.6 ± 33.8%IA/mL). In contrast, MCF-7/PRLR tumor xenografts showed a low uptake (7.0 ± 2.3%IA/mL) of control Zr-89 REGN1932 and a very low uptake and rapid clearance of I-124 REGN2878 (1.4 ± 0.6%IA/mL). Zr-89 REGN2878 has excellent antigen-specific targeting in various PRLR tumor xenograft models. We estimated, using image-based kinetic modeling, that PRLR antigen has a very rapid in vivo turnover half-life of ∼14 min from the cell membrane. Despite relatively modest estimated tumor PRLR expression numbers, PRLR-expressing cells have shown final retention of the Zr-89 REGN2878 antibody, with an uptake that appeared to be related to PRLR expression. This reagent has the potential to be used in clinical trials targeting PRLR.

Radioimmunotherapy of solid tumors using antibody-targeted radionuclides has been limited by low therapeutic indices (TIs). We recently reported a novel 3-step pretargeted radioimmunotherapy (PRIT) strategy based on a glycoprotein A33 (GPA33)-targeting bispecific antibody and a small-molecule radioactive hapten, a complex of 177 Lu and S -2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid ( 177 Lu-DOTA-Bn), that leads to high TIs for radiosensitive tissues such as blood (TI = 73) and kidney (TI = 12). We tested our hypothesis that a fractionated anti-GPA33 DOTA-PRIT regimen calibrated to deliver a radiation absorbed dose to tumor of more than 100 Gy would lead to a high probability of tumor cure while being well tolerated by nude mice bearing subcutaneous GPA33-positive SW1222 xenografts. Methods: We treated groups of nude mice bearing 7-d-old SW1222 xenografts with a fractionated 3-cycle anti-GPA33 DOTA-PRIT regimen (total administered 177 Lu-DOTA-Bn activity, 167 MBq/mouse; estimated radiation absorbed dose to tumor, 110 Gy). In randomly selected mice undergoing treatment, serial SPECT/CT imaging was used to monitor treatment response and calculate radiation absorbed doses to tumor. Necropsy was done on surviving animals 100-200 d after treatment to determine frequency of cure and assess select normal tissues for treatment-related histopathologies. Results: Rapid exponential tumor progression was observed in control treatment groups (i.e., no treatment or 177 Lu-DOTA-Bn only), leading to euthanasia due to excessive tumor burden, whereas 10 of 10 complete responses were observed for the DOTA-PRIT-treated animals within 30 d. Treatment was well tolerated, and 100% histologic cure was achieved in 9 of 9 assessable animals without detectable radiation damage to critical organs, including bone marrow and kidney. Radiation absorbed doses to tumor derived from SPECT/CT (102 Gy) and from biodistribution (110 Gy) agreed to within 6.9%. Of the total dose of approximately 100 Gy, the first dose contributes 30%, the second dose 60%, and the third dose 10%. Conclusion: In a GPA33-positive human colorectal cancer xenograft mouse model, we validated a SPECT/CT-based theranostic PRIT regimen that led to 100% complete responses and 100% cures without any treatment-related toxicities, based on high TIs for radiosensitive tissues. These studies support the view that anti-GPA33 DOTA-PRIT will be a potent radioimmunotherapy regimen for GPA33-positive colorectal cancer tumors in humans., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: We applied a non-linear immunokinetic model to quantitatively compare absolute antibody uptake and turnover in subcutaneous LNCaP human prostate cancer (PCa) xenografts of two radiolabeled forms of the humanized anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 ((124)I-J591 and (89)Zr-J591). Using the model, we examined the impact of dose on the tumor and plasma positron emission tomography (PET)-derived time-activity curves. We also sought to predict the optimal targeting index (ratio of integrated-tumor-to-integrated-plasma activity concentrations) for radioimmunotherapy., Methods: The equilibrium rates of antibody internalization and turnover in the tumors were derived from PET images up to 96 h post-injection using compartmental modeling with a non-linear transfer rate. In addition, we serially imaged groups of LNCaP tumor-bearing mice injected with (89)Zr-J591 antibody doses ranging from antigen subsaturating to saturating to examine the suitability of using a non-linear approach and derived the time-integrated concentration (in μM∙hours) of administered tracer in tumor as a function of the administered dose of antibody., Results: The comparison of (124)I-J591 and (89)Zr-J591 yielded similar model-derived values of the total antigen concentration and internalization rate. The association equilibrium constant (k a) was twofold higher for (124)I, but there was a ~tenfold greater tumoral efflux rate of (124)I from tumor compared to that of (89)Zr. Plots of surface-bound and internalized radiotracers indicate similar behavior up to 24 h p.i. for both (124)I-J591 and (89)Zr-J591, with the effect of differential clearance rates becoming apparent after about 35 h p.i. Estimates of J591/PSMA complex turnover were 3.9-90.5 × 10(12) (for doses from 60 to 240 μg) molecules per hour per gram of tumor (20 % of receptors internalized per hour)., Conclusions: Using quantitative compartmental model methods, surface binding and internalization rates were shown to be similar for both (124)I-J591 and (89)Zr-J591 forms, as expected. The large difference in clearance rates of the radioactivity from the tumor is likely due to differential trapping of residualizing zirconium versus non-residualizing iodine. Our non-linear model was found to be superior to a conventional linear model. This finding and the calculated activity persistence time in tumor have important implications for radioimmunotherapy and other antibody-based therapies in patients.

Purpose: GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn-(radiolanthanide metal) complex., Methods: PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens (177)Lu-or (86)Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model., Results: Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq (177)Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm(3)) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 - 3.0 based on time to 500-mm(3) tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten (86)Y-DOTA-Bn., Conclusion: We have developed anti-GPA33 PRIT as a triple-step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts.

While RNA structures have been extensively characterized in vitro, very few techniques exist to probe RNA structures inside cells. Here, we have exploited mechanisms of post-transcriptional regulation to synthesize fluorescence-based probes that assay RNA structures in vivo. Our probing system involves the co-expression of two constructs: (i) a target RNA and (ii) a reporter containing a probe complementary to a region in the target RNA attached to an RBS-sequestering hairpin and fused to a sequence encoding the green fluorescent protein (GFP). When a region of the target RNA is accessible, the area can interact with its complementary probe, resulting in fluorescence. By using this system, we observed varied patterns of structural accessibility along the length of the Tetrahymena group I intron. We performed in vivo DMS footprinting which, along with previous footprinting studies, helped to explain our probing results. Additionally, this novel approach represents a valuable tool to differentiate between RNA variants and to detect structural changes caused by subtle mutations. Our results capture some differences from traditional footprinting assays that could suggest that probing in vivo via oligonucleotide hybridization facilitates the detection of folding intermediates. Importantly, our data indicate that intracellular oligonucleotide probing can be a powerful complement to existing RNA structural probing methods., (© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Purpose: Respiratory motion during PET∕CT imaging can cause substantial image blurring and underestimation of tracer concentration for both static and dynamic studies. In this study, the authors developed an event-by-event respiratory motion correction method that used three-dimensional internal-one-dimensional external motion correlation (INTEX3D) in listmode reconstruction. The authors aim to fully correct for organ/tumor-specific rigid motion caused by respiration using all detected events to eliminate both intraframe and interframe motion, and investigate the quantitative improvement in static and dynamic imaging., Methods: The positional translation of an internal organ or tumor during respiration was first determined from the reconstructions of multiple phase-gated images. A level set (active contour) method was used to segment the targeted internal organs/tumors whose centroids were determined. The mean displacement of the external respiratory signal acquired by the Anzai system that corresponded to each phase-gated frame was determined. Three linear correlations between the 1D Anzai mean displacements and the 3D centroids of the internal organ/tumor were established. The 3D internal motion signal with high temporal resolution was then generated by applying each of the three correlation functions to the entire Anzai trace (40 Hz) to guide event-by-event motion correction in listmode reconstruction. The reference location was determined as the location where CT images were acquired to facilitate phase-matched attenuation correction and anatomical-based postfiltering. The proposed method was evaluated with a NEMA phantom driven by a QUASAR respiratory motion platform, and human studies with two tracers: pancreatic beta cell tracer [(18)F]FP(+)DTBZ and tumor hypoxia tracer [(18)F]fluoromisonidazole (FMISO). An anatomical-based postreconstruction filter was applied to the motion-corrected images to reduce noise while preserving quantitative accuracy and organ boundaries in the patient studies., Results: The INTEX3D method yielded an increase of 5%-9% and 32%-40% in contrast recovery coefficient on the hot spheres in the NEMA phantom, compared to the reconstructions with only 1D motion correction (INTEX1D) and no motion correction, respectively. The proposed method also increased the mean activities of the pancreas and kidney by 9.3% and 11.2%, respectively, across three subjects in the FPDTBZ studies, and the average lesion-to-blood ratio by 20% across three lesions in the FMISO study, compared to the reconstructions without motion correction. In addition, the proposed method reduced intragate motion as compared to phase-gated images. The application of the anatomical-based postreconstruction filter further reduced noise in the background by >50% compared to reconstructions without postfiltering, while preserving quantitative accuracy and organ boundaries. Finally, the measurements of the time-activity curves from a subject with FPDTBZ showed that INTEX3D yielded 18% and 11% maximum increases in tracer concentration in the pancreas and kidney cortex, respectively., Conclusions: These results suggest that the proposed method can effectively compensate for both intragate and intergate respiratory motion while preserving all the counts, and is applicable to dynamic studies.

Full quantitative analysis of brain PET data requires knowledge of the arterial input function into the brain. Such data are normally acquired by arterial sampling with corrections for delay and dispersion to account for the distant sampling site. Several attempts have been made to extract an image-derived input function (IDIF) directly from the internal carotid arteries that supply the brain and are often visible in brain PET images. We have devised a method of delineating the internal carotids in co-registered magnetic resonance (MR) images using the level-set method and applying the segmentations to PET images using a novel centerline approach. Centerlines of the segmented carotids were modeled as cubic splines and re-registered in PET images summed over the early portion of the scan. Using information from the anatomical center of the vessel should minimize partial volume and spillover effects. Centerline time-activity curves were taken as the mean of the values for points along the centerline interpolated from neighboring voxels. A scale factor correction was derived from calculation of cerebral blood flow (CBF) using gold standard arterial blood measurements. We have applied the method to human subject data from multiple injections of [(15)O]water on the HRRT. The method was assessed by calculating the area under the curve (AUC) of the IDIF and the CBF, and comparing these to values computed using the gold standard arterial input curve. The average ratio of IDIF to arterial AUC (apparent recovery coefficient: aRC) across 9 subjects with multiple (n = 69) injections was 0.49 ± 0.09 at 0-30 s post tracer arrival, 0.45 ± 0.09 at 30-60 s, and 0.46 ± 0.09 at 60-90 s. Gray and white matter CBF values were 61.4 ± 11.0 and 15.6 ± 3.0 mL/min/100 g tissue using sampled blood data. Using IDIF centerlines scaled by the average aRC over each subjects' injections, gray and white matter CBF values were 61.3 ± 13.5 and 15.5 ± 3.4 mL/min/100 g tissue. Using global average aRC values, the means were unchanged, and intersubject variability was noticeably reduced. This MR-based centerline method with local re-registration to [(15)O]water PET yields a consistent IDIF over multiple injections in the same subject, thus permitting the absolute quantification of CBF without arterial input function measurements.

Many methods have been proposed for generating an image-derived input function (IDIF) exclusively from PET images. The purpose of this study was to assess the viability of a multimodality approach utilizing registered MR images. 3T-MR and HRRT-PET data were acquired from human subjects. Segmentation of both the left and right carotid arteries was performed in MR images using a 3D level sets method. Vessel centerlines were extracted by parameterization of the segmented voxel coordinates with either a single polynomial curve or a B-spline curve fitted to the segmented data. These centerlines were subsequently re-registered to static PET data to maximize the accurate classification of PET voxels in the ROI. The accuracy of this approach was assessed by comparison of the area under the curve (AUC) of the IDIF to that measured from conventional automated arterial blood sampling.Our method produces curves similar in shape to that of blood sampling. The mean AUC ratio of the centerline region was 0.40±0.19 before re-registration and 0.69±0.26 after re-registration. Increasing the diameter of the carotid ROI produced a smooth reduction in AUC. Thus, even with the high resolution of the HRRT, partial volume correction is still necessary. This study suggests that the combination of PET information with MR segmented regions will demonstrate an improvement over regions based solely on MR or PET alone.

Although liposarcomas are the most common type of sarcoma in adults, they are rare in the head and neck region. Pleomorphic liposarcoma is the least common histologic subtype in all locations. To our knowledge, there have been only 11 reported cases of primary liposarcomas of the major salivary glands, and the pleomorphic variant arising in the parotid gland has been reported only once before. Only 2 of the 11 reported cases of liposarcoma of the major salivary glands in the literature have died of disease, and both cases were of the pleomorphic subtype. We report a case of pleomorphic liposarcoma arising in the left parotid gland of an 80-year-old woman. This case report highlights that, despite conservative surgery followed by 2 local recurrences, our patient is doing well with minimal local morbidity and no demonstrable metastases 30 months after the initial diagnosis. We also present a review of the literature on the subject.

Objective: To discuss some of the obstacles inherent in the design of the randomized controlled trial (RCT) that the surgeon must confront and options to minimize these obstacles., Data Sources: The literature was searched for articles discussing RCTs using MEDLINE from 1966 to 1998., Study Selection: Studies relevant to the general use of RCTs for evaluating surgical questions were selected., Synthesis: Several problems inherent in RCTs were noted: (1) ethical considerations, (2) difficulties in patient accrual, (3) patient preferences, and (4) variability in surgical proficiency/technique. Some means of minimizing these problems are (1) the concept of clinical equipoise, (2) multicenter trials, and (3) stratified sampling of patients. Alternatives to the classic RCT are discussed, namely, the randomized consent design and the patient preference design., Conclusions: The nature of the RCTs is that they are difficult to use to evaluate surgical techniques. Some options are available to minimize these difficulties. Designing and conducting RCTs to evaluate surgical interventions require careful planning and some compromises. Unless the previously mentioned criteria are applied, the validity of the RCT can be considered no greater than that of other trials.

Primary larynx lymphomas, specifically of the mucosa-associated lymphoid tissue, are a rare but documented phenomenon. Transformation of any type of lymphoma that has the presence of Reed-Sternberg cells is unusual in lymph nodes and exceptional in extranodal sites. Herein, we report the first case (to the best of our knowledge in a review of the English literature [MEDLINE 1966-2001]) in which both of these unusual findings are present; that is, an extranodal marginal zone B-cell lymphoma of laryngeal mucosa-associated lymphoid tissue with Hodgkin-like transformation. The patient is a 78-year-old man who presented with intermittent shortness of breath, progressive dysphagia, and intermittent hoarseness. On examination, a large mass of the left supraglottic larynx was identified with a "ball-valve" effect into the laryngeal inlet with inspiration. Examination of the neck showed no palpable masses. Histologic examination of the incisional biopsy showed replacement of the submucosa by sheets of atypical monocytoid B cells (CD20+, CD79a+, lambda+, CD3-) characterized by nuclear atypia, mitotic activity, plasmacytoid differentiation, and restricted for lambda light chains. Dutcher bodies were easily identified. Interspersed throughout the neoplastic lymphoid population were numerous Reed-Sternberg cells and variants immunoreactive for CD30 and CD15 and nonreactive for CD45RB. The patient was treated with 44 cGy to the neck and larynx and was alive and free of disease at last contact, 2.6 years after the original presentation., (Copyright 2002 by W.B. Saunders Company)