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Purpose: Hypoxia is one of the main causes of the failure to achieve local control using radiotherapy. This is due to the increased radioresistance of hypoxic cells. (18)F-fluoromisonidazole ((18)F-FMISO) positron emission tomography (PET) is a noninvasive imaging technique that can assist in the identification of intratumor regions of hypoxia. The aim of this study was to evaluate the reproducibility of (18)F-FMISO intratumor distribution using two pretreatment PET scans.Methods and Materials: We enrolled 20 head and neck cancer patients in this study. Of these, 6 were excluded from the analysis for technical reasons. All patients underwent an (18)F-fluorodeoxyglucose study, followed by two (18)F-FMISO studies 3 days apart. The hypoxic volumes were delineated according to a tumor/blood ratio >or=1.2. The (18)F-FMISO tracer distributions from the two (18)F-FMISO studies were co-registered on a voxel-by-voxel basis using the computed tomography images from the PET/computed tomography examinations. A correlation between the (18)F-FMISO intensities of the corresponding spatial voxels was derived.Results: A voxel-by-voxel analysis of the (18)F-FMISO distributions in the entire tumor volume showed a strong correlation in 71% of the patients. Restraining the correlation to putatively hypoxic zones reduced the number of patients exhibiting a strong correlation to 46%.Conclusion: Variability in spatial uptake can occur between repeat (18)F-FMISO PET scans in patients with head and neck cancer. Blood data for one patient was not available. Of 13 patients, 6 had well-correlated intratumor distributions of (18)F-FMISO-suggestive of chronic hypoxia. More work is required to identify the underlying causes of changes in intratumor distribution before single-time-point (18)F-FMISO PET images can be used as the basis of hypoxia-targeting intensity-modulated radiotherapy. [ABSTRACT FROM AUTHOR]

Background: The small molecule radiotracer 124 I-PU-H71 is an imaging biomarker of epichaperome formation. The tracer has been established to localize in tissues under chronic stress, specifically in cancer cells and neurodegenerative brain cells. A first-in-human imaging trial using positron emission tomography (PET) in cancer patients revealed unexpected tracer accumulation in the myocardium., Purpose: To describe human 124 I-PU-H71 myocardial biodistribution and pharmacokinetics in a series of cancer patients with no history of cardiovascular disease., Methods: 25 cancer patients (age 22-75 years, M:F - 7:18) with no history of cardiovascular disease received intravenous injections with microdose 124 I-PU-H71 while at rest, followed by dynamic and gated/non-gated PET image data acquisitions. Region-of-interest (ROI) analysis of left ventricular myocardium (LVmyo) and background left atrium quantified tracer concentrations as standardized uptake value (SUV) and uptake ratios. Kinetic rate constants were evaluated by a two-tissue compartment model., Results: Myocardial accumulation of 124 I-PU-H71 was prominent in all patients, with median LVmyo SUVmean (interquartile range, IQR) of 2.8 (IQR, 2.13-3.29), 2.5 (IQR, 1.94-2.98), 2.4 (IQR, 1.73-3.31) and 1.0 (IQR, 0.61-2.45), and median LVmyo/blood-pool ratios of 1.9 (IQR, 1.57-2.38), 2.0 (IQR, 1.53-2.32), 3.6 (IQR, 2.91-4.06) and 3.9 (IQR, 2.62-5.08) at 1-9 min, 14-23 min, 3-4 h and 21-25 h, respectively on non-gated PET images. Myocardium showed peak uptake within 2 min post-injection, with sustained myocardial tracer-concentration at 4 h post-injection. Pharmacokinetic modeling revealed median K 1 = 0.45 ml/min/g (IQR, 0.38-0.62); k 2 = 0.47 min - 1 (IQR, 0.27-0.71); k 3 = 0.16 min - 1 (IQR, 0.09-0.26); and k 4 = 0.0038 min - 1 (IQR, 0.0015-0.0057). Regional assessment demonstrated essentially uniform tracer uptake in LV and myocardial segments; with normal LVEF in all patients (mean 57.7 ± 3.5%); and no patients suffered cardiac events over subsequent 12-month period., Conclusion: Our study finds human myocardial epichaperome expression, as quantified by 124 I-PU-H71 PET. Our data indicates PU-H71 PET merits further study as a myocardial epichaperome biomarker, with potential application in drug development, possibly as a biomarker in subclinical cardiac dysfunction., Competing Interests: Competing interests The authors declare no competing interests.

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.)

Diffuse intrinsic pontine glioma (DIPG) is a rare childhood malignancy with poor prognosis. There are no effective treatment options other than external beam therapy. We conducted a pilot, first-in-human study using 124 I-omburtamab imaging and theranostics as a therapeutic approach using a localized convection-enhanced delivery (CED) technique for administering radiolabeled antibody. We report the detailed pharmacokinetics and dosimetry results of intratumoral delivery of 124 I-omburtamab. Methods: Forty-five DIPG patients who received 9.0-370.7 MBq of 124 I-omburtamab intratumorally via CED underwent serial brain and whole-body PET/CT imaging at 3-5 time points after injection within 4, 24-48, 72-96, 120-144, and 168-240 h from the end of infusion. Serial blood samples were obtained for kinetic analysis. Whole-body, blood, lesion, and normal-tissue activities were measured, kinetic parameters (uptake and clearance half-life times) estimated, and radiation-absorbed doses calculated using the OLINDA software program. Results: All patients showed prominent activity within the lesion that was retained over several days and was detectable up to the last time point of imaging, with a mean 124 I residence time in the lesion of 24.9 h and dose equivalent of 353 ± 181 mSv/MBq. Whole-body doses were low, with a dose equivalent of 0.69 ± 0.28 mSv/MBq. Systemic distribution and activities in normal organs and blood were low. Radiation dose to blood was very low, with a mean value of 0.27 ± 0.21 mGy/MBq. Whole-body clearance was monoexponential with a mean biologic half-life of 62.7 h and an effective half-life of 37.9 h. Blood clearance was biexponential, with a mean biologic half-life of 22.2 h for the rapid α phase and 155 h for the slower β phase. Conclusion: Intratumoral CED of 124 I-omburtamab is a novel theranostics approach in DIPG. It allows for delivery of high radiation doses to the DIPG lesions, with high lesion activities and low systemic activities and high tumor-to-normal-tissue ratios and achieving a wide safety margin. Imaging of the actual therapeutic administration of 124 I-omburtamab allows for direct estimation of the therapeutic lesion and normal-tissue-absorbed doses., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Preclinical dosimetry is essential for guiding the design of animal radiopharmaceutical biodistribution, imaging, and therapy experiments, evaluating efficacy and/or toxicities in such experiments, ensuring compliance with ethical standards for animal research, and, perhaps most importantly, providing reasonable initial estimates of normal-organ doses in humans, required for clinical translation of new radiopharmaceuticals. This MIB Guide provides a basic protocol for obtaining preclinical dosimetry estimates with organ-level dosimetry software., (© 2023. The Author(s), under exclusive licence to World Molecular Imaging Society.)

Background: Potential risk associated with low-dose radiation exposures is often expressed using the effective dose (E) quantity. Other risk-related quantities have been proposed as alternatives. The recently introduced risk index (RI) shares similarities with E but expands the metric to incorporate medical imaging-appropriate risks factors including patient-specific size, age, and sex., Purpose: The aim of this work is to examine the RI metric for quantifying stochastic radiation risk and demonstrate its applications in nuclear imaging. The advantages in this improved metric may help the field progress toward stratified risk consideration in the course of patient management, improve efforts for procedure optimization, and support an evolution in the science of radiation risk assessment., Methods: In this study we describe, implement, and calculate RI for various diagnostic nuclear imaging scenarios using reference biokinetics published in ICRP Publication 128 for commonly utilized radiopharmaceuticals. All absorbed dose, E and RI calculations were performed using the freely available MIRDcalc nuclear medicine dosimetry software; the organ specific risk parameters used in the software are also benchmarked in this text. The resulting RI and E values are compared and various trends in RI values identified., Results: E and RI coefficients were calculated for 3016 use cases. Notably RI values vary depending on patient characteristics. Overall, across the population, global trends in RI values can be identified. In general, RI values were 2.15 times higher for females than males, due to higher risk coefficients and activities being distributed in smaller reference masses. The pediatric patients showed higher RIs than adults, as younger patients generally receive higher absorbed doses per administered activity, and are more radiosensitive, and have a longer projected lifespan at risk. A compendium of E and RI values is also provided in table format to serve as a reference for the community., Conclusions: RI is a rational quantity that could be used for justification, risk communication and protocol optimization in medical imaging. It has some advantages when compared to the long-utilized E value with respect to personalization, since accounts for patient size, age, sex, and natural incidence of cancer risk., (© 2023 American Association of Physicists in Medicine.)

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.)

Preclinical dosimetry is essential for guiding the design of animal radiopharmaceutical biodistribution, imaging, and therapy experiments, evaluating efficacy and/or toxicities in such experiments, ensuring compliance with ethical standards for animal research, and providing reasonable initial estimates of normal-organ doses in humans, required for clinical translation of new radiopharmaceuticals. This MIB guide provides a basic protocol for obtaining preclinical dosimetry estimates with organ-level dosimetry software., Competing Interests: CONFLICT OF INTEREST No competing interests declared.

Radiolabeled antibody treatment with 131 I-omburtamab, administered intraventricularly into the cerebrospinal fluid (CSF) space, can deliver therapeutic absorbed doses to sites of leptomeningeal disease. Assessment of distribution and radiation dosimetry is a key element in optimizing such treatments. Using a theranostic approach, we performed pretreatment 131 I-omburtamab imaging and dosimetric analysis in patients before therapy. Methods: Whole-body planar images were acquired 3 ± 1, 23 ± 2, and 47 ± 2 h after intracranioventricular administration of 75 ± 5 MBq of 131 I-omburtamab via an Ommaya reservoir. Multiple blood samples were also obtained for kinetic analysis. Separate regions of interest (ROIs) were manually drawn to include the lateral ventricles, entire spinal canal CSF space, and over the whole body. Count data in the ROIs were corrected for background and physical decay, converted to activity, and subsequently fitted to an exponential clearance function. The radiation absorbed dose was estimated to the CSF, separately to the spinal column and ventricles, and to the whole body and blood. Biodistribution of the injected radiolabeled antibody was assessed for all patients. Results: Ninety-five patients were included in the analysis. Biodistribution showed prompt localization in the ventricles and spinal CSF space with low systemic distribution, noted primarily as hepatic, renal, and bladder activity after the first day. Using ROI analysis, the effective half-lives were 13 ± 11 h (range, 5-75 h) for CSF in the spinal column, 8 ± 3 h (range, 3-17 h) for ventricles, and 41 ± 11 (range, 23-81 h) for the whole body. Mean absorbed doses were 0.63 ± 0.38 cGy/MBq (range, 0.24-2.25 cGy/MBq) for CSF in the spinal column, 1.03 ± 0.69 cGy/MBq (range, 0.27-5.15 cGy/MBq) for the ventricular CSF, and 0.45 ± 0.32 mGy/MBq (range, 0.05-1.43 mGy/MBq) for the whole body. Conclusion: Pretherapeutic imaging with 131 I-omburtamab allows assessment of biodistribution and dosimetry before the administration of therapeutic activity. Absorbed doses to the CSF compartments and whole body derived from the widely applicable serial 131 I-omburtamab planar images had acceptable agreement with previously reported data determined from serial 124 I-omburtamab PET scans., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Intraventricular compartmental radioimmunotherapy (cRIT) with 131-I-omburtamab is a potential therapy for recurrent primary brain tumors that can seed the thecal space. These patients often previously received external beam radiotherapy (EBRT) to a portion or full craniospinal axis (CSI) as part of upfront therapy. Little is known regarding outcomes after re-irradiation as part of multimodality therapy including cRIT. This study evaluates predictors of response, patterns of failure, and radiologic events after cRIT., Methods: Patients with recurrent medulloblastoma or ependymoma who received 131-I-omburtamab on a prospective clinical trial were included. Extent of disease at cRIT initiation (no evidence of disease [NED] vs measurable disease [MD]) was assessed as associated with progression-free (PFS) and overall survival (OS) by Kaplan-Meier analysis., Results: All 27 patients (20 medulloblastoma, 7 ependymoma) had EBRT preceding cRIT: most (22, 81%) included CSI (median dose 2340 cGy, boost to 5400 cGy). Twelve (44%) also received EBRT at relapse as bridging to cRIT. There were no cases of radionecrosis. At cRIT initiation, 11 (55%) medulloblastoma and 3 (43%) ependymoma patients were NED, associated with improved PFS (p = 0.002) and OS (p = 0.048) in medulloblastoma. Most relapses were multifocal. With medium follow-up of 3.0 years (95% confidence interval, 1.8-7.4), 6 patients remain alive with NED., Conclusion: For patients with medulloblastoma, remission at time of cRIT was associated with significantly improved survival outcomes. Relapses are often multifocal, particularly in the setting of measurable disease at cRIT initiation. EBRT is a promising tool to achieve NED status at cRIT initiation, with no cases of radiation necrosis., (© 2023. The Author(s).)

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: I-123 meta-iodobenzylguanidine (MIBG) imaging has long been employed to noninvasively assess the integrity of human norepinephrine transporter-1 and, hence, myocardial sympathetic innervation. Positron-emitting F-18 meta-fluorobenzylguanidine (MFBG) has recently been developed for potentially superior quantitative characterization. We assessed the feasibility of MFBG imaging of myocardial sympathetic innervation., Methods: 16 patients were imaged with MFBG PET (30-minute dynamic imaging of chest, followed by 3 whole-body acquisitions between 30 minutes and 4-hour post-injection). Blood kinetics were assessed from multiple samples. Pharmacokinetic modeling with reversible 1- and 2-compartment models was performed. Kinetic rate constants were re-calculated from truncated datasets. All patients underwent concurrent MIBG SPECT., Results: MFBG myocardial uptake was rapid and sustained; the mean standardized uptake value (SUV (mean ± standard deviation)) was 5.1 ± 2.2 and 3.4 ± 1.9 at 1 hour and 3-4-hour post-injection, respectively. The mean K 1 and distribution volume (V T ) were 1.1 ± 0.6 mL/min/g and 34 ± 22 mL/cm 3 , respectively. Both were reproducible when re-calculated from truncated 1-hour datasets (Intraclass Correlation Coefficient of 0.99 and 0.91, respectively). Spearman's ϱ = 0.86 between MFBG SUV and V T and 0.80 between MFBG PET-derived V T and MIBG SPECT-derived heart-to-mediastinum activity concentration ratio., Conclusion: MFBG is a promising PET radiotracer for the assessment of myocardial sympathetic innervation., (© 2022. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

The aim of this study was to assess the pharmacokinetics, biodistribution, and radiation dosimetry of 124 I-omburtamab administered intraperitoneally in patients with desmoplastic small round cell tumor. Methods: Eligible patients diagnosed with desmoplastic small round cell tumor with peritoneal involvement were enrolled in a phase I trial of intraperitoneal radioimmunotherapy with 131 I-omburtamab. After thyroid blockade and before radioimmunotherapy, patients received approximately 74 MBq of 124 I-omburtamab intraperitoneally. Five serial PET/CT scans were obtained up to 144 h after injection. Multiple blood samples were obtained up to 120 h after injection. Organ-absorbed doses were calculated with OLINDA/EXM. Results: Thirty-one patients were studied. Blood pharmacokinetics exhibited a biphasic pattern consisting of an initial rising phase with a median half-time (±SD) of 23 ± 15 h and a subsequent falling phase with a median half-time of 56 ± 34 h. Peritoneal distribution was heterogeneous and diffuse in most patients. Self-dose to the peritoneal cavity was 0.58 ± 0.19 mGy/MBq. Systemic distribution and activity in major organs were low. The median absorbed doses were 0.72 ± 0.23 mGy/MBq for liver, 0.48 ± 0.17 mGy/MBq for spleen, and 0.57 ± 0.12 mGy/MBq for kidneys. The mean effective dose was 0.31 ± 0.10 mSv/MBq. Whole-body and peritoneal cavity biologic half-times were 45 ± 9 and 24 ± 5 h, respectively. Conclusion: PET/CT imaging with intraperitoneally administered 124 I-omburtamab enables assessment of intraperitoneal distribution and estimation of absorbed dose to peritoneal space and normal organs before therapy., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

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.)

Radiopharmaceutical therapy (RPT) is defined as the delivery of radioactive atoms to tumor-associated targets. In RPT, imaging is built into the mode of treatment since the radionuclides used in RPT often emit photons or can be imaged using a surrogate. Such imaging may be used to estimate tumor-absorbed dose. We examine and try to elucidate those factors that impact the absorbed dose-versus-response relationship for RPT agents. These include the role of inflammation- or immune-mediated effects, the significance of theranostic imaging, radiobiology, differences in dosimetry methods, pharmacokinetic differences across patients, and the impact of tumor hypoxia on response to RPT., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

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.)

Purpose: 124 I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose 124 I-PU-H71 for PET to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging., Experimental Design: Adult patients with cancer ( n = 30) received 124 I-PU-H71 tracer (201±12 MBq, <25 μg) intravenous bolus followed by PET/CT scans and blood radioassays., Results: 124 I-PU-H71 PET detected tumors of different cancer types (breast, lymphoma, neuroblastoma, genitourinary, gynecologic, sarcoma, and pancreas). 124 I-PU-H71 was retained by tumors for several days while it cleared rapidly from bones, healthy soft tissues, and blood. Radiation dosimetry is favorable and patients suffered no adverse effects., Conclusions: Our first-in-human results demonstrate the safety and feasibility of noninvasive in vivo detection of tumor epichaperomes using 124 I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics., (©2020 American Association for Cancer Research.)

An α particle-emitting nanodrug that is a potent and specific antitumor agent and also prompts significant remodeling of local immunity in the tumor microenvironment (TME) has been developed and may impact the treatment of melanoma. Biocompatible ultrasmall fluorescent core-shell silica nanoparticles (C' dots, diameter ∼6.0 nm) have been engineered to target the melanocortin-1 receptor expressed on melanoma through α melanocyte-stimulating hormone peptides attached to the C' dot surface. Actinium-225 is also bound to the nanoparticle to deliver a densely ionizing dose of high-energy α particles to cancer. Nanodrug pharmacokinetic properties are optimal for targeted radionuclide therapy as they exhibit rapid blood clearance, tumor-specific accumulation, minimal off-target localization, and renal elimination. Potent and specific tumor control, arising from the α particles, was observed in a syngeneic animal model of melanoma. Surprisingly, the C' dot component of this drug initiates a favorable pseudopathogenic response in the TME generating distinct changes in the fractions of naive and activated CD8 T cells, Th1 and regulatory T cells, immature dendritic cells, monocytes, MΦ and M1 macrophages, and activated natural killer cells. Concomitant upregulation of the inflammatory cytokine genome and adaptive immune pathways each describes a macrophage-initiated pseudoresponse to a viral-shaped pathogen. This study suggests that therapeutic α-particle irradiation of melanoma using ultrasmall functionalized core-shell silica nanoparticles potently kills tumor cells, and at the same time initiates a distinct immune response in the TME.

Purpose: Radiographic changes of brain metastases after stereotactic radiosurgery (SRS) can signify tumor recurrence and/or radiation necrosis (RN); however, standard imaging modalities cannot easily distinguish between these two entities. We investigated whether 18 F-Fluorocholine uptake in surgical samples of the resected lesions correlates with pathologic evidence of recurrent tumor and PET imaging., Methods: About 14 patients previously treated with SRS that developed radiographic changes were included. All patients underwent a preoperative 40-min dynamic PET/CT concurrent with 392 ± 11 MBq bolus injection of 18 F-Fluorocholine. 18 F-Fluorocholine pharmacokinetics were evaluated by standardized uptake value (SUV), graphical analysis (Patlak plot; K i P ) and an irreversible two-compartment model (K 1 , k 2 , k 3 , and K i ). 12 out of 14 patients were administered an additional 72 ± 14 MBq injection of 18 F-Fluorocholine 95 ± 26 minutes prior to surgical resection. About 113 resected samples from 12 patients were blindly reviewed by a neuropathologist to assess the viable tumor and necrotic content, microvascular proliferation, reactive gliosis, and mono- and polymorphonuclear inflammatory infiltrates. Correlation between these metrics 18 F-Fluorocholine SUV was investigated with a linear mixed model. Comparison of survival distributions of two groups of patients (population median split of PET SUV max ) was performed with the log-rank test., Results: Exactly 10 out of 12 patients for which surgical samples were acquired exhibited pathologic recurrence. Strong correlation was observed between SUV max as measured from a surgically removed sample with highest uptake and by PET (Pearson's r = 0.66). Patients with 18 F-Fluorocholine PET SUV max > 6 experienced poor survival. Surgical samples with viable tumor had higher 18 F-fluorocholine uptake (SUV) than those without tumor (4.5 ± 3.7 and 2.6 ± 3.0; p = 0.01). 18 F-fluorocholine count data from surgical samples is driven not only by the percentage viable tumor but also by the degree of inflammation and reactive gliosis (p ≤ 0.02; multivariate regression)., Conclusions: 18 F-Fluorocholine accumulation is increased in viable tumor; however, inflammation and gliosis may also lead to elevated uptake. Higher 18 F-Fluorocholine PET uptake portends worse prognosis. Kinetic analysis of dynamic 18 F-Fluorocholine PET imaging supports the adequacy of the simpler static SUV metric.

Clearing agents (CAs) can rapidly remove nonlocalized targeting biomolecules from circulation for hepatic catabolism, thereby enhancing the therapeutic index (TI), especially for blood (marrow), of the subsequently administered radioisotope in any multistep pretargeting strategy. Herein we describe the synthesis and in vivo evaluation of a fully synthetic glycodendrimer-based CA for DOTA-based pretargeted radioimmunotherapy (DOTA-PRIT). The novel dendron-CA consists of a nonradioactive yttrium-DOTA-Bn molecule attached via a linker to a glycodendron displaying 16 terminal α-thio- N -acetylgalactosamine (α-SGalNAc) units (CCA α-16-DOTA-Y 3+ ; molecular weight: 9059 Da). Pretargeting [ 177 Lu]LuDOTA-Bn with CCA α-16-DOTA-Y 3+ to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [ 177 Lu]LuDOTA-Bn for blood, tumor, liver, spleen, and kidneys of 11.7, 468, 9.97, 5.49, and 13.3 cGy/MBq, respectively. Tumor-to-normal tissues absorbed-dose ratios (i.e., TIs) ranged from 40 (e.g., for blood and kidney) to about 550 for stomach.

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.)

Mesh-type and voxel-based computational phantoms comprise the current state of the art for internal dose assessment via Monte Carlo simulations but excel in different aspects, with mesh-type phantoms offering advantages over their voxel counterparts in terms of their flexibility and realistic representation of detailed patient- or subject-specific anatomy. We have developed PARaDIM (pronounced "paradigm": Particle and Heavy Ion Transport Code System-Based Application for Radionuclide Dosimetry in Meshes), a freeware application for implementing tetrahedral mesh-type phantoms in absorbed dose calculations. It considers all medically relevant radionuclides, including α, β, γ, positron, and Auger/conversion electron emitters, and handles calculation of mean dose to individual regions, as well as 3-dimensional dose distributions for visualization and analysis in a variety of medical imaging software. This work describes the development of PARaDIM, documents the measures taken to test and validate its performance, and presents examples of its uses. Methods: Human, small-animal, and cell-level dose calculations were performed with PARaDIM and the results compared with those of widely accepted dosimetry programs and literature data. Several tetrahedral phantoms were developed or adapted using computer-aided modeling techniques for these comparisons. Results: For human dose calculations, agreement of PARaDIM with OLINDA 2.0 was good-within 10%-20% for most organs-despite geometric differences among the phantoms tested. Agreement with MIRDcell for cell-level S value calculations was within 5% in most cases. Conclusion: PARaDIM extends the use of Monte Carlo dose calculations to the broader community in nuclear medicine by providing a user-friendly graphical user interface for calculation setup and execution. PARaDIM leverages the enhanced anatomic realism provided by advanced computational reference phantoms or bespoke image-derived phantoms to enable improved assessments of radiation doses in a variety of radiopharmaceutical use cases, research, and preclinical development. PARaDIM can be downloaded freely at www.paradim-dose.org., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

A six-transmembrane epithelial antigen of prostate-1 (STEAP1) is a newly identified target in prostate cancer. The use of radio-labeled STEAP1-targeting antibodies with positron emission tomography (PET) may allow for detection of sites of metastatic prostate cancer and may refine patient selection for antigen-directed therapies. This was a prospective study in seven patients with metastatic castration-resistant prostate cancer who had at least one archival biopsy that was STEAP1-positive by immunohistochemistry. Patients received intravenous injections of ∼185 MBq and 10 mg of [ 89 Zr]Zr-DFO-MSTP2109A, a humanized IgG1 monoclonal antibody directed against STEAP1. PET/CT images, blood samples, and whole-body counts were monitored longitudinally in six patients. Here, we report on safety, biodistribution, pharmacokinetics, dose estimates to normal tissues, and initial tumor targeting for this group of patients. There was no significant acute or subacute toxicity. Favorable biodistribution and enhanced lesion uptake (in both bone and soft tissue) were observed on imaging using a mass of 10 mg of DFO-MSTP2109A. The best lesion discrimination was seen at the latest imaging time, a median of 6 days postadministration. Pharmacokinetics showed a median serum T 1/2 β of 198 h, volume of central compartment of 3.54 L (similar to plasma volume), and clearance of 19.7 mL/h. The median biologic T 1/2 for whole-body retention was 469 h. The highest mean absorbed doses to normal organs (mGy/MBq) were 1.18, 1.11, 0.78, 0.73, and 0.71 for liver, heart wall, lung, kidney, and spleen, respectively. Excellent targeting of metastatic prostate sites in both bone and soft tissue was observed, with an optimal imaging time of 6 days postadministration. The liver and heart were the normal organs that experienced the highest absorbed doses. The pharmacokinetics were similar to other antibodies without major cross-reactivity with normal tissues. A more detailed analysis of lesion targeting in a larger patient population with correlation to immunohistology and standard imaging modalities has been reported.

The Society of Nuclear Medicine and Molecular Imaging convened a task group to examine the evidence for the risk of carcinogenesis from low-dose radiation exposure and to assess evidence in the scientific literature related to the overall validity of the linear no-threshold (LNT) hypothesis and its applicability for use in risk assessment and radiation protection. In the low-dose and dose-rate region, the group concluded that the LNT hypothesis is invalid as it is not supported by the available scientific evidence and, instead, is actually refuted by published epidemiology and radiation biology. The task group concluded that the evidence does not support the use of LNT either for risk assessment or radiation protection in the low-dose and dose-rate region.

Ionizing radiation has contributed enormously to dramatic improvements in medical care. The potential risks of radiation-based medical imaging have, however, drawn considerable attention in recent years. Although such concern is beneficial in terms of critical evaluation and optimization of imaging procedures, it can create the misconception that radiation is the only risk of medical imaging. In contrast to expression of radiation risks, quantitative estimates of the benefits of medical imaging are notably lacking. Expression of benefit in purely qualitative terms vs. expression of risk in quantitative, and thus apparently more concrete, terms may contribute to a biased judgement of the relative benefits and risks of medical imaging among health care professionals as well as the public. This paper, therefore, quantitatively compares the benefits of diagnostic imaging in several cases, based on actual mortality or morbidity data if ionizing radiation were not employed, with the linear no-threshold model derived (i.e., theoretical) estimates of radiogenic cancer mortality and illustrates the large benefit-to-risk ratios typical of medical imaging procedures.

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.

18 F-fluorodihydrotestosterone ( 18 F-FDHT) is a radiolabeled analog of the androgen receptor's primary ligand that is currently being credentialed as a biomarker for prognosis, response, and pharmacodynamic effects of new therapeutics. As part of the biomarker qualification process, we prospectively assessed its reproducibility and repeatability in men with metastatic castration-resistant prostate cancer. Methods: We conducted a prospective multiinstitutional study of metastatic castration-resistant prostate cancer patients undergoing 2 (test/retest) 18 F-FDHT PET/CT scans on 2 consecutive days. Two independent readers evaluated all examinations and recorded SUVs, androgen receptor-positive tumor volumes, and total lesion uptake for the most avid lesion detected in each of 32 predefined anatomic regions. The relative absolute difference and reproducibility coefficient (RC) of each metric were calculated between the test and retest scans. Linear regression analyses, intraclass correlation coefficients (ICCs), and Bland-Altman plots were used to evaluate repeatability of 18 F-FDHT metrics. The coefficient of variation and ICC were used to assess interobserver reproducibility. Results: Twenty-seven patients with 140 18 F-FDHT-avid regions were included. The best repeatability among 18 F-FDHT uptake metrics was found for SUV metrics (SUV max, SUV mean , and SUV peak ), with no significant differences in repeatability among them. Correlations between the test and retest scans were strong for all SUV metrics ( R 2 ≥ 0.92; ICC ≥ 0.97). The RCs of the SUV metrics ranged from 21.3% (SUV peak ) to 24.6% (SUV max ). The test and retest androgen receptor-positive tumor volumes and TLU, respectively, were highly correlated ( R 2 and ICC ≥ 0.97), although variability was significantly higher than that for SUV (RCs > 46.4%). The prostate-specific antigen levels, Gleason score, weight, and age did not affect repeatability, nor did total injected activity, uptake measurement time, or differences in uptake time between the 2 scans. Including the most avid lesion per patient, the 5 most avid lesions per patient, only lesions 4.2 mL or more, only lesions with an SUV of 4 g/mL or more, or normalizing of SUV to area under the parent plasma activity concentration-time curve did not significantly affect repeatability. All metrics showed high interobserver reproducibility (ICC > 0.98; coefficient of variation < 0.2%-10.8%). Conclusion: Uptake metrics derived from 18 F-FDHT PET/CT show high repeatability and interobserver reproducibility., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

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.

In what we believe to be a first-in-human study, we evaluated the safety and dosimetry of 89 Zr-pertuzumab PET/CT for human epidermal growth factor receptor 2 (HER2)-targeted imaging in patients with HER2-positive breast cancer. Methods: Patients with HER2-positive breast cancer and evidence of distant metastases were enrolled in an institutional review board-approved prospective clinical trial. Pertuzumab was conjugated with deferoxamine and radiolabeled with 89 Zr. Patients underwent PET/CT with 74 MBq of 89 Zr-pertuzumab in a total antibody mass of 20-50 mg of pertuzumab. PET/CT, whole-body probe counts, and blood drawing were performed over 8 d to assess pharmacokinetics, biodistribution, and dosimetry. PET/CT images were evaluated for the ability to visualize HER2-positive metastases. Results: Six patients with HER2-positive metastatic breast cancer were enrolled and administered 89 Zr-pertuzumab. No toxicities occurred. Dosimetry estimates from OLINDA demonstrated that the organs receiving the highest doses (mean ± SD) were the liver (1.75 ± 0.21 mGy/MBq), the kidneys (1.27 ± 0.28 mGy/MBq), and the heart wall (1.22 ± 0.16 mGy/MBq), with an average effective dose of 0.54 ± 0.07 mSv/MBq. PET/CT demonstrated optimal imaging 5-8 d after administration. 89 Zr-pertuzumab was able to image multiple sites of malignancy and suggested that they were HER2-positive. In 2 patients with both known HER2-positive and HER2-negative primary breast cancers and brain metastases, 89 Zr-pertuzumab PET/CT suggested that the brain metastases were HER2-positive. In 1 of the 2 patients, subsequent resection of a brain metastasis proved HER2-positive disease, confirming that the 89 Zr-pertuzumab avidity was a true-positive result for HER2-positive malignancy. Conclusion: This first-in-human study demonstrated safety, dosimetry, biodistribution, and successful HER2-targeted imaging with 89 Zr-pertuzumab PET/CT. Potential clinical applications include assessment of the HER2 status of lesions that may not be accessible to biopsy and assessment of HER2 heterogeneity., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose To assess the clinical safety, pharmacokinetics, and tumor imaging characteristics of fluorine 18-(2S,4R)-4-fluoroglutamine (FGln), a glutamine analog radiologic imaging agent. Materials and Methods This study was approved by the institutional review board and conducted under a U.S. Food and Drug Administration-approved Investigational New Drug application in accordance with the Helsinki Declaration and the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Between January 2013 and October 2016, 25 adult patients with cancer received an intravenous bolus of FGln tracer (mean, 244 MBq ± 118, <100 μg) followed by positron emission tomography (PET) and blood radioassays. Patient data were summarized with descriptive statistics. FGln biodistribution and plasma amino acid levels in nonfasting patients (n = 13) were compared with those from patients who fasted at least 8 hours before injection (n = 12) by using nonparametric one-way analysis of variance with Bonferroni correction. Tumor FGln avidity versus fluorodeoxyglucose (FDG) avidity in patients with paired PET scans (n = 15) was evaluated with the Fisher exact test. P < .05 was considered indicative of a statistically significant difference. Results FGln PET depicted tumors of different cancer types (breast, pancreas, renal, neuroendocrine, lung, colon, lymphoma, bile duct, or glioma) in 17 of the 25 patients, predominantly clinically aggressive tumors with genetic mutations implicated in abnormal glutamine metabolism. Acute fasting had no significant effect on FGln biodistribution and plasma amino acid levels. FGln-avid tumors were uniformly FDG-avid but not vice versa (P = .07). Patients experienced no adverse effects. Conclusion Preliminary human FGln PET trial results provide clinical validation of abnormal glutamine metabolism as a potential tumor biomarker for targeted radiotracer imaging in several different cancer types. © RSNA, 2018 Online supplemental material is available for this article. Clinical trial registration no. NCT01697930.

Introduction: Capsular contracture after breast reconstruction is a morbid complication, occurring in 30.0% to 47.5% of patients undergoing postoperative radiotherapy. Although it is well known that radiation increases rate of capsular contracture, there are few well-established animal models that faithfully replicate standard-of-care clinical practice, that is, prosthesis placement at the time of mastectomy followed by delayed radiotherapy. To better recapitulate current clinical practice, we developed a murine model in which the implant sites were irradiated 10 days postoperatively, rather than at time of surgery., Methods: Hemispherical implants were created from polydimethylsiloxane and implanted bilaterally in the subcutaneous dorsa of 20 C57Bl/6 mice. Mice were randomized to 5 treatment groups, differing in irradiation dose: 0 to 40 Gy. Ten days postoperatively, irradiation was performed using 250-kVp x-rays (XRAD225Cx, Precision X-ray, North Branford, Conn). In 1 mouse per group, dosimeters were placed subcutaneously to measure the delivered absorbed dose. Thirty-one days postoperatively, the mice were sacrificed and examined grossly, and periprosthetic tissues were removed for histologic analysis of periprosthetic capsule thickness and cellular deposition., Results: Total radiation dose was calculated by the treatment planning software and confirmed by the in vivo dosimeters. Physical examination of the irradiated region demonstrated evidence of local radiation delivery, including circular patterns of hair blanching and thinning directly over the implants. Furthermore, histologic analysis of the irradiated epidermis demonstrated dose-dependent radiation changes including keratin whorls and patches of uneven epidermal thickness. There was no statistically significant difference in capsule thickness among the groups. Mice in the 30 and 40 Gy groups endured complications including shortness of breath, coagulopathy, and death, signs of systemic radiation poisoning., Conclusions: There was no evidence of increased periprosthetic capsule thickness with localized irradiation, irrespective of dose up to 20 Gy. These results differ from those previously published, which demonstrated increased capsule thickness with 10 Gy irradiation. Given the evidence of local radiation delivery, we believe that the lack of increase in capsule thickness observed in our experiment is a real phenomenon and demonstrate the difficulty in creating an easily reproducible rodent model that mimics the effects of postmastectomy implant-based reconstruction and irradiation.

Background: High-risk and recurrent medulloblastoma (MB) is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell-surface disialoganglioside GD2 on MB. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular 131 I-labeled 3F8 in patients with MB on a phase II clinical trial., Methods: Patients with histopathologically confirmed high-risk or recurrent MB were eligible for cRIT. After determining adequate cerebrospinal fluid (CSF) flow, patients received 2 mCi (where Ci is Curie) 124 I-3F8 or 131 I-3F8 with nuclear imaging for dosimetry, followed by up to four therapeutic (10 mCi/dose) 131 I-3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hr plus region-of-interest analyses on serial imaging scans. Disease evaluation included pre- and posttherapy brain/spine magnetic resonance imaging approximately every 3 months for the first year after treatment, and every 6-12 months thereafter., Results: Forty-three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment-related deaths occurred. Toxicities related to drug administration included acute bradycardia with somnolence, headache, fatigue, and CSF pleocytosis consistent with chemical meningitis and dystonic reaction. Total CSF absorbed dose was 1,453 cGy (where Gy is Gray; 350.0-2,784). Median overall survival from first dose of cRIT was 24.9 months (95% confidence interval [CI]:16.3-55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (hazard ratio: 0.40, 95% CI: 0.18-0.88, P = 0.024)., Conclusions: cRIT with 131 I-3F8 is safe, has favorable dosimetry to CSF, and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high-risk or recurrent MB., (© 2017 Wiley Periodicals, Inc.)

Trastuzumab with chemotherapy improves clinical outcomes in patients with human epidermal growth factor receptor 2 (HER2)-positive esophagogastric adenocarcinoma (EGA). Despite the therapeutic benefit, responses are rarely complete, and most patients develop progression. To our knowledge, this is the first report evaluating 89 Zr-trastuzumab in HER2-positive EGA; here, we evaluate the safety, pharmacokinetics, biodistribution, and dosimetry 89 Zr-trastuzumab. Methods: Trastuzumab was conjugated with deferoxamine and radiolabeled with 89 Zr. A mean activity of 184 MBq was administered to 10 patients with metastatic HER2-positive EGA. PET imaging, whole-body probe counts, and blood draws were performed to assess pharmacokinetics, biodistribution, and dosimetry. Results: No clinically significant toxicities were observed. At the end of infusion, the estimated 89 Zr-trastuzumab in plasma volume was a median 102% (range, 78%-113%) of the injected dose. The median biologic half-life T 1/2β was 111 h (range, 78-193 h). The median biologic whole-body retention half-life was 370 h (range, 257-578 h). PET images showed optimal tumor visualization at 5-8 d after injection. The maximum tumor SUV ranged from no to minimal uptake in 3 patients to a median of 6.8 (range, 2.9-22.7) for 20 lesions in 7 patients. Dosimetry estimates from OLINDA showed that the organs receiving the highest absorbed doses were the liver and heart wall, with median values of 1.37 and 1.12 mGy/MBq, respectively. Conclusion: 89 Zr-trastuzumab imaging tracer is safe and provides high-quality images in patients with HER2-positive EGA, with an optimal imaging time of 5-8 d after injection., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

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.)

To protect bone marrow from overirradiation, the maximum permissible activity (MPA) of 131 I to treat thyroid cancer is that which limits the absorbed dose to blood (as a surrogate of marrow) to less than 200 cGy. The conventional approach (method 1) requires repeated γ-camera whole-body measurements along with blood samples. We sought to determine whether reliable MPA values can be obtained by simplified procedures. Methods: Data acquired over multiple time points were examined retrospectively for 65 thyroid cancer patients, referred to determine 131 I uptake and MPA for initial treatment after thyroidectomy ( n = 39), including 17 patients with compromised renal function and 22 patients with known ( n = 16) or suspected ( n = 6) metastases. The total absorbed dose to blood (D Total ) was the sum of mean whole-body γ-ray dose component (D γ ) from uncollimated γ-camera measurements and dose due to β emissions (D β ) from blood samples. Method 2 estimated D Total from D β alone, method 3 estimated D Total from D γ alone, and method 4 estimated D Total from a single 48-h γ-camera measurement. MPA was computed as 200 cGy/D Total for each D Total estimate. Results: Method 2 had the strongest correlation with conventional method 1 ( r = 0.98) and values similar to method 1 (21.0 ± 13.7 cGy/GBq vs. 21.0 ± 14.1 cGy/GBq, P = 0.11), whereas method 3 had a weaker ( P = 0.001) correlation ( r = 0.94) and method 4 had the weakest ( P < 0.0001) correlation ( r = 0.69) and lower dose (16.3 ± 14.8 cGy/GBq, P < 0.0001). Consequently, correlation with method 1 MPA was strongest for method 2 MPA ( r = 0.99) and weakest for method 4 ( r = 0. 75). Method 2 and method 1 values agreed equally well regardless of whether patients had been treated with 131 I previously or had abnormal renal function. Conclusion: Because MPA based on blood measurements alone is comparable to MPA obtained with combined body counting and blood sampling, blood measurements alone are sufficient for determining MPA., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Hypoxic tumors exhibit increased resistance to radiation, chemical, and immune therapies. 18 F-fluoromisonidazole ( 18 F-FMISO) PET is a noninvasive, quantitative imaging technique used to evaluate the magnitude and spatial distribution of tumor hypoxia. In this study, pharmacokinetic analysis (PKA) of 18 F-FMISO dynamic PET extended to 3 h after injection is reported for the first time, to our knowledge, in stage III-IV non-small cell lung cancer (NSCLC) patients. Methods: Sixteen patients diagnosed with NSCLC underwent 2 PET/CT scans (1-3 d apart) before radiation therapy: a 3-min static 18 F-FDG and a dynamic 18 F-FMISO scan lasting 168 ± 15 min. The latter data were acquired in 3 serial PET/CT dynamic imaging sessions, registered with each other and analyzed using pharmacokinetic modeling software. PKA was performed using a 2-tissue, 3-compartment irreversible model, and kinetic parameters were estimated for the volumes of interest determined using coregistered 18 F-FDG images for both the volume of interest-averaged and the voxelwise time-activity curves for each patient's lesions, normal lung, and muscle. Results: We derived average values of 18 F-FMISO kinetic parameters for NSCLC lesions as well as for normal lung and muscle. We also investigated the correlation between the trapping rate ( k 3 ) and delivery rate ( K 1 ), influx rate ( K i ) constants, and tissue-to-blood activity concentration ratios (TBRs) for all tissues. Lesions had trapping rates 1.6 times larger, on average, than those of normal lung and 4.4 times larger than those in muscle. Additionally, for almost all cases, k 3 and K i had a significant strong correlation for all tissue types. The TBR- k 3 correlation was less straightforward, showing a moderate to strong correlation for only 41% of lesions. Finally, K 1 - k 3 voxelwise correlations for tumors were varied, but negative for 76% of lesions, globally exhibiting a weak inverse relationship (average R = -0.23 ± 0.39). However, both normal tissue types exhibited significant positive correlations for more than 60% of patients, with 41% having moderate to strong correlations (R > 0.5). Conclusion: All lesions showed distinct 18 F-FMISO uptake. Variable 18 F-FMISO delivery was observed across lesions, as indicated by the variable values of the kinetic rate constant K 1 Except for 3 cases, some degree of hypoxia was apparent in all lesions based on their nonzero k 3 values., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

The pretargeting system based on the inverse electron demand Diels-Alder reaction (IEDDA) between trans-cyclooctene (TCO) and tetrazine (Tz) combines the favorable pharmacokinetic properties of radiolabeled small molecules with the affinity and specificity of antibodies. This strategy has proven to be an efficient method for the molecularly targeted delivery of pharmaceuticals, including isotopes for radiological imaging. Despite encouraging results from in vivo PET imaging studies, this promising system has yet to be thoroughly evaluated for pretargeted radioimmunotherapy (PRIT). Toward that end, we synthesized two novel 177 Lu-labeled tetrazine-bearing radioligands. Next, we compared the usefulness of our ligands for PRIT when paired with TCO-modified 5B1-a human, anti-CA19.9 mAb-in preclinical murine models of pancreatic cancer. The exemplary ligand, 177 Lu-DOTA-PEG 7 -Tz, showed rapid (4.6 ± 0.8% ID/g at 4 hours) and persistent (16.8 ± 3.9% ID/g at 120 hours) uptake in tumors while concurrently clearing from blood and nontarget tissues. Single-dose therapy studies using 5B1-TCO and varying amounts of 177 Lu-DOTA-PEG 7 -Tz (400, 800, and 1,200 μCi) showed that our system elicits a dose-dependent therapeutic response in mice bearing human xenografts. Furthermore, dosimetry calculations suggest that our approach is amenable to clinical applications with its excellent dosimetric profile in organs of clearance (i.e., liver and kidneys) as well as in dose-limiting tissues, such as red marrow. This study established that a pretargeted methodology utilizing the IEDDA reaction can rapidly and specifically deliver a radiotherapeutic payload to tumor tissue, thus illustrating its excellent potential for clinical translation. Mol Cancer Ther; 16(1); 124-33. ©2016 AACR., (©2016 American Association for Cancer Research.)

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.

Background: Hypoxic tumours exhibit increased resistance to radiation, chemical, and immune therapies. 18 F-fluoromisonidazole (FMISO) positron emission tomography (PET) is a non-invasive, quantitative imaging technique used to evaluate the presence and spatial distribution of tumour hypoxia. To facilitate the use of FMISO PET for identification of individuals likely to benefit from hypoxia-targeted treatments, we investigated the reproducibility of FMISO PET spatiotemporal intratumour distribution in patients with non-small cell lung cancer (NSCLC)., Methods: Ten patients underwent 18 F-fluorodeoxyglucose (FDG) PET/CT scans, followed by two FMISO PET/CT scans 1-2 days apart. Nineteen lesions in total were segmented from co-registered FDG PET image sets. Volumes of interest were also defined on normal contralateral lung and subscapularis muscle. The Pearson correlation coefficient r was calculated for mean standardized uptake values (SUV) within investigated volumes of interest and for voxels within tumour volumes (r TV ). The reproducibility of FMISO voxelwise distribution, SUV- and tumour-to-blood ratio (TBR)-derived indices was assessed using correlation and Bland-Altman analyses., Results: The SUV max , SUV mean , TBR max , and TBR mean were highly correlated (r ≥ 0.87, p < 0.001) and were reproducible to within 10-15 %. The mean r TV was 0.84 ± 0.10. 77 % of voxels identified as hypoxic on one FMISO scan were confirmed as such on the other FMISO scan. Mean voxelwise differences between TBR values as calculated from pooled data including all lesions were 0.9 ± 10.8 %., Conclusions: High reproducibility of FMISO intratumour distribution in NSCLC patients was observed, facilitating its use in determining the topology of the hypoxic tumour sub-volumes for dose escalation, in patient stratification strategies for hypoxia-targeted therapies, and in monitoring response to therapeutic interventions., Trial Registration: Current Controlled Trials NCT02016872.

Although spatially precise systems are now available for small-animal irradiations, there are currently limited software tools available for treatment planning for such irradiations. We report on the adaptation, commissioning, and evaluation of a 3-dimensional treatment planning system for use with a small-animal irradiation system. The 225-kV X-ray beam of the X-RAD 225Cx microirradiator (Precision X-Ray) was commissioned using both ion-chamber and radiochromic film for 10 different collimators ranging in field size from 1 mm in diameter to 40 × 40 mm(2) A clinical 3-dimensional treatment planning system (Metropolis) developed at our institution was adapted to small-animal irradiation by making it compatible with the dimensions of mice and rats, modeling the microirradiator beam orientations and collimators, and incorporating the measured beam data for dose calculation. Dose calculations in Metropolis were verified by comparison with measurements in phantoms. Treatment plans for irradiation of a tumor-bearing mouse were generated with both the Metropolis and the vendor-supplied software. The calculated beam-on times and the plan evaluation tools were compared. The dose rate at the central axis ranges from 74 to 365 cGy/min depending on the collimator size. Doses calculated with Metropolis agreed with phantom measurements within 3% for all collimators. The beam-on times calculated by Metropolis and the vendor-supplied software agreed within 1% at the isocenter. The modified 3-dimensional treatment planning system provides better visualization of the relationship between the X-ray beams and the small-animal anatomy as well as more complete dosimetric information on target tissues and organs at risk. It thereby enhances the potential of image-guided microirradiator systems for evaluation of dose-response relationships and for preclinical experimentation generally., (© The Author(s) 2015.)

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.

Unlabelled: (18)F-fluoromisonidazole dynamic PET (dPET) is used to identify tumor hypoxia noninvasively. Its routine clinical implementation, however, has been hampered by the long acquisition times required. We investigated the feasibility of kinetic modeling using shortened acquisition times in (18)F-fluoromisonidazole dPET, with the goal of expediting the clinical implementation of (18)F-fluoromisonidazole dPET protocols., Methods: Six patients with squamous cell carcinoma of the head and neck and 10 HT29 colorectal carcinoma-bearing nude rats were studied. In addition to an (18)F-FDG PET scan, each patient underwent a 45-min (18)F-fluoromisonidazole dPET scan, followed by 10-min acquisitions at 96 ± 4 and 163 ± 17 min after injection. Ninety-minute (18)F-fluoromisonidazole dPET scans were acquired in animals. Intratumor voxels were classified into 4 clusters based on their kinetic behavior using k-means clustering. Kinetic modeling was performed using the foregoing full datasets (FD) and repeated for each of 2 shortened datasets corresponding to the first approximately 100 min (SD1; patients only) or the first 45 min (SD2) of dPET data. The kinetic rate constants (KRCs) as calculated with a 2-compartment model for both SD1 and SD2 were compared with those derived from FD by correlation (Pearson), regression (Passing-Bablok), deviation (Bland-Altman), and classification (area-under-the-receiver-operating characteristic curve) analyses. Simulations were performed to assess uncertainties due to statistical noise., Results: Strong correlation (r ≥ 0.75, P < 0.001) existed between all KRCs deduced from both SD1 and SD2, and from FD. Significant differences between KRCs were found only for FD-SD2 correlations in patient studies. K1 and k3 were reproducible to within approximately 6% and approximately 30% (FD-SD1; patients) and approximately 4% and approximately 75% (FD-SD2; animals). Area-under-the-receiver-operating characteristic curve values for classification of patient clusters as hypoxic, using a tumor-to-blood ratio greater than 1.2, were 0.91 (SD1) and 0.86 (SD2). The percentage SD in estimating K1 and k3 from 45-min shortened datasets due to noise was less than 1% and between 2% and 12%, respectively., Conclusion: Using single-session 45-min shortened (18)F-fluoromisonidazole dPET datasets appears to be adequate for the identification of intratumor regions of hypoxia. However, k3 was significantly overestimated in the clinical cohort. Further studies are necessary to evaluate the clinical significance of differences between the results as calculated from full and shortened datasets., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

While it is implicitly recognized that the benefits of diagnostic imaging far outweigh any theoretical radiogenic risks, quantitative estimates of the benefits are rarely, if ever, juxtaposed with quantitative estimates of risk. This alone - expression of benefit in purely qualitative terms versus expression of risk in quantitative, and therefore seemingly more certain, terms - may well contribute to a skewed sense of the relative benefits and risks of diagnostic imaging among healthcare providers as well as patients. The current paper, therefore, briefly compares the benefits of diagnostic imaging in several cases, based on actual mortality or morbidity data if ionizing radiation were not employed, with theoretical estimates of radiogenic cancer mortality based on the "linear no-threshold" (LNT) dose-response model., Competing Interests: The author declares no conflicts of interest.

Unlabelled: (90)Y has been used to label various new therapeutic radiopharmaceuticals. However, measuring the radiation dose delivered by (90)Y is challenging because of the absence of suitable γ emissions and its low abundance of positron emissions. For the treatment of prostate cancer, radiolabeled gastrin-releasing peptide receptor (GRPr) antagonists have yielded promising results in mouse models. In this study, we evaluated whether Cerenkov luminescence imaging (CLI) could be used to determine radiation doses of a (90)Y-labeled GRPr antagonist in nude mice., Methods: Mice bearing subcutaneous prostate cancer xenografts were injected with 0.74-18.5 MBq of the (90)Y-labeled GRPr antagonist DOTA-AR and underwent in vivo and ex vivo CLI at 1-48 h after injection. After imaging, animals were sacrificed, their tumors and organs were harvested, and the activity concentration was measured by liquid scintillation counting. In a second set of experiments, Cerenkov photon counts for tumor and kidney on in vivo CLI were converted to activity concentrations using conversion factors determined from the first set of experiments., Results: (90)Y-DOTA-AR concentration in the 3 tumor models ranged from 0.5% to 4.8% of the injected activity per gram at 1 h after injection and decreased to 0.05%-0.15 injected activity per gram by 48 h after injection. A positive correlation was found between tumor activity concentrations and in vivo CLI signal (r(2) = 0.94). A similar correlation was found for the renal activity concentration and in vivo Cerenkov luminescence (r(2) = 0.98). Other organs were not distinctly visualized on the in vivo images, but ex vivo CLI was also correlated with the radioactivity concentration (r(2) = 0.35-0.94). Using the time-activity curves from the second experiment, we calculated radiation doses to tumor and kidney of 0.33 ± 0.12 (range, 0.21-0.66) and 0.06 ± 0.01 (range, 0.05-0.08) Gy/MBq, respectively., Conclusion: CLI is a promising, low-cost modality to measure individual radiation doses of (90)Y-labeled compounds noninvasively. The use of Cerenkov imaging is expected to facilitate the development and comparison of (90)Y-labeled compounds for targeted radiotherapy., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)