Chemokine Receptor 2 Targeted PET/CT Imaging Distant Metastases in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and treatment-refractory malignancies. The lack of an effective screening tool results in the majority of patients being diagnosed at late stages, which underscores the urgent need to develop more sensitive and specific imaging modalities, particularly in detecting occult metastases, to aid clinical decision-making. The tumor microenvironment of PDAC is heavily infiltrated with myeloid-derived suppressor cells (MDSCs) that express C-C chemokine receptor type 2 (CCR2). These CCR2-expressing MDSCs accumulate at a very early stage of metastasis and greatly outnumber PDAC cells, making CCR2 a promising target for detecting early, small metastatic lesions that have scant PDAC cells. Herein, we evaluated a CCR2 targeting PET tracer (68Ga-DOTA-ECL1i) for PET imaging on PDAC metastasis in two mouse models. Positron emission tomography/computed tomography (PET/CT) imaging of 68Ga-DOTA-ECL1i was performed in a hemisplenic injection metastasis model (KI) and a genetically engineered orthotopic PDAC model (KPC), which were compared with 18F-FDG PET concurrently. Autoradiography, hematoxylin and eosin (H&E), and CCR2 immunohistochemical staining were performed to characterize the metastatic lesions. PET/CT images visualized the PDAC metastases in the liver/lung of KI mice and in the liver of KPC mice. Quantitative uptake analysis revealed increased metastasis uptake during disease progression in both models. In comparison, 18F-FDG PET failed to detect any metastases during the time course studies. H&E staining showed metastases in the liver and lung of KI mice, within which immunostaining clearly demonstrated the overexpression of CCR2 as well as CCR2+ cell infiltration into the normal liver. H&E staining, CCR2 staining, and autoradiography also confirmed the expression of CCR2 and the uptake of 68Ga-DOTA-ECL1i in the metastatic foci in KPC mice. Using our novel CCR2 targeted radiotracer 68Ga-DOTA-ECL1i and PET/CT, we demonstrated the sensitive and specific detection of CCR2 in the early PDAC metastases in two mouse models, indicating its potential in future clinical translation.

Summary: SNMMI Procedure Standard/EANM Practice Guideline for Estrogen Receptor Imaging of Patients with Breast Cancer Using 16α-[18F]Fluoro-17ß-Estradiol PET.

The estrogen receptor (ER), a steroid hormone receptor important in female physiology, is a significant contributor to breast carcinogenesis and progression and, as such, is an important therapeutic target. Approximately 70% of breast cancers will express ER at presentation, and the determination of ER expression by tissue assay, usually by immunohistochemistry, is part of the standard of care for newly diagnosed breast cancer. ER expression is important in guiding the approach to treatment, especially with the increase in relevant systemic therapies. The ER-targeting imaging agent 16α-[18F]fluoro-17ß-estradiol ([18F]FES) is approved for clinical use by regulatory agencies in France and the United States. Multiple studies suggest the advantages of [18F]FES PET in assessing tumor ER expression, the ability of both qualitative and quantitative [18F]FES PET measures to predict response to ER-targeted therapy, and the ability of [18F]FES PET to clarify equivocal staging and restaging results in patients with ER-expressing cancers. [18F]FES PET/CT may also be helpful in staging invasive lobular breast cancer and low-grade ER-expressing invasive ductal cancers and, in some cases, may be a substitute for biopsy. The Society of Nuclear Medicine and Molecular Imaging and the European Association of Nuclear Medicine in June 2023 released a procedure standard/practice guideline for [18F]FES PET ER imaging of patients with breast cancer. The goal of the standard/guideline is to assist physicians in recommending, performing, interpreting, and reporting the results of [18F]FES PET studies for patients with breast cancer and to provide clinicians with the best available evidence, inform them about areas where robust evidence is lacking, and help them deliver the best possible diagnostic efficacy and study quality for their patients. Also reviewed are standardized quality control, quality assurance, and imaging procedures for [18F]FES PET. The authors emphasize the importance of precision, accuracy, repeatability, and reproducibility for both clinical management of patients and for use of [18F]FES PET in multicenter trials. A standardized imaging procedure, in combination with already published appropriate-use criteria, will help promote the use of [18F]FES PET and enhance subsequent research. This brief summary article reviews the content of the joint standard/guideline, which is available in its entirety at https://www.snmmi.org/ClinicalPractice/content.aspx?ItemNumber=6414&navItemNumbe=10790.

Fluorine-18-Labeled Fluoroestradiol PET/CT: Current Status, Gaps in Knowledge, and Controversies-AJR Expert Panel Narrative Review.

PET/CT using 16α-[18F]-fluoro-17ß-estradiol (FES) noninvasively images tissues expressing estrogen receptors (ERs). FES has undergone extensive clinicopathologic validation for ER+ breast cancer and received FDA approval in 2020 for clinical use as an adjunct to biopsy in patients with recurrent or metastatic ER+ breast cancer. Clinical use of FES PET/CT is increasing, but is not widespread in the United States. This AJR Expert Panel Narrative Review explores the present status and future directions of FES PET/CT, including image interpretation, existing and emerging uses, knowledge gaps, and current controversies. Specific controversies discussed include whether both FES PET/CT and FDG PET/CT are warranted in certain scenarios, whether further workup is required after negative FES PET/CT results, whether FES PET/CT findings should inform endocrine therapy selection, and whether immunohistochemistry should remain the standalone reference standard for determining ER status for all breast cancers. Consensus opinions from the panel include agreement with the appropriate clinical uses of FES PET/CT published by a multidisciplinary expert workgroup in 2023; anticipated expanded clinical use of FES PET/CT for staging ER-positive invasive lobular carcinomas and low-grade invasive ductal carcinomas pending ongoing clinical trial results; and the need for further research regarding use of FES PET/CT for ER-expressing nonbreast malignancies.

Molecular imaging of bone metastasis.

Recent advances in molecularly targeted modular designs for in vivo imaging applications has thrusted open possibilities of investigating deep molecular interactions non-invasively and dynamically. The shifting landscape of biomarker concentration and cellular interactions throughout pathological progression requires quick adaptation of imaging agents and detection modalities for accurate readouts. The synergy of state of art instrumentation with molecularly targeted molecules is resulting in more precise, accurate and reproducible data sets, which is facilitating investigation of several novel questions. Small molecules, peptides, antibodies and nanoparticles are some of the commonly used molecular targeting vectors that can be applied for imaging as well as therapy. The field of theranostics, which encompasses joint application of therapy and imaging, is successfully leveraging the multifunctional use of these biomolecules [[1], [2]]. Sensitive detection of cancerous lesions and accurate assessment of treatment response has been transformative for patient management. Particularly, since bone metastasis is one of the dominant causes of morbidity and mortality in cancer patients, imaging can be hugely impactful in this patient population. The intent of this review is to highlight the utility of molecular positron emission tomography (PET) imaging in the context of prostate and breast bone metastatic cancer, and multiple myeloma. Furthermore, comparisons are drawn with traditionally utilized bone scans (skeletal scintigraphy). Both these modalities can be synergistic or complementary for assessing lytic- and blastic- bone lesions.

A Projection-Domain Low-Count Quantitative SPECT Method for α-Particle-Emitting Radiopharmaceutical Therapy.

Single-photon emission-computed tomography (SPECT) provides a mechanism to estimate regional isotope uptake in lesions and at-risk organs after administration of α-particle-emitting radiopharmaceutical therapies (α-RPTs). However, this estimation task is challenging due to the complex emission spectra, the very low number of detected counts (~20 times lower than in conventional SPECT), the impact of stray-radiation-related noise at these low counts, and the multiple image-degrading processes in SPECT. The conventional reconstruction-based quantification methods are observed to be erroneous for α-RPT SPECT. To address these challenges, we developed a low-count quantitative SPECT (LC-QSPECT) method that directly estimates the regional activity uptake from the projection data (obviating the reconstruction step), compensates for stray-radiation-related noise, and accounts for the radioisotope and SPECT physics, including the isotope spectra, scatter, attenuation, and collimator-detector response, using a Monte Carlo-based approach. The method was validated in the context of 3-D SPECT with 223Ra, a commonly used radionuclide for α-RPT. Validation was performed using both realistic simulation studies, including a virtual clinical trial, and synthetic and 3-D-printed anthropomorphic physical-phantom studies. Across all studies, the LC-QSPECT method yielded reliable regional-uptake estimates and outperformed the conventional ordered subset expectation-maximization (OSEM)-based reconstruction and geometric transfer matrix (GTM)-based post-reconstruction partial-volume compensation methods. Furthermore, the method yielded reliable uptake across different lesion sizes, contrasts, and different levels of intralesion heterogeneity. Additionally, the variance of the estimated uptake approached the Cramér-Rao bound-defined theoretical limit. In conclusion, the proposed LC-QSPECT method demonstrated the ability to perform reliable quantification for α-RPT SPECT.

Frequency of Hepatic Metastatic Disease in Patients with Stage IV Breast Cancer Is Similar for Steatotic and Non-Steatotic Livers.

Background: Breast cancer is the most common non-cutaneous malignancy and the second leading cause of cancer mortality in the United States. Breast cancer is a heterogeneous disease; diagnosis at an early stage renders it potentially curable, whereas advanced metastatic disease carries a worse prognosis. Objectives: To investigate whether hepatic steatosis (HS) is associated with liver metastases in patients with newly diagnosed stage IV female breast cancer patients (either de novo metastatic breast cancer or recurrent metastatic breast cancer) using non-contrast computed tomography (CT) as a marker of HS. Design: Retrospective analysis. Methods: We retrospectively identified 168 patients with stage IV breast cancer with suitable imaging from a prospectively maintained oncologic database. Three radiologists manually defined hepatic regions of interest on non-contrast CT images, and attenuation data were extracted. HS was defined as a mean attenuation <48 Hounsfield units. The frequency of hepatic metastatic disease was calculated for patient with and without HS. Relationships between HS and various patient (age, body mass index, race) and tumor (hormone receptor status, HER2 status, tumor grade) characteristics were also analyzed. Results: There were 4 patients with liver metastasis in the HS group (41 patients) versus 20 patients with liver metastases in the non-HS group (127 patients). The difference in frequencies of liver metastases among patients with (9.8%) versus without (15.7%) hepatic steatosis (odds ratio = 1.72 [0.53-7.39]) was not statistically significant (P = .45). Body mass index was significantly higher (P = .01) among patients with hepatic steatosis (32.2 ± 7.3 vs 28.8 ± 7.1 kg/m2). Otherwise, there were no significant differences between patients with versus without HS with respect to regarding age, race, hormone receptor status, HER2 status, or tumor grade. Conclusion: The frequency of hepatic metastatic disease in patients with stage IV breast cancer is similar for steatotic and non-steatotic livers.

Summary: Appropriate Use Criteria for Estrogen Receptor-Targeted PET Imaging with 16α-18F-Fluoro-17ß-Fluoroestradiol.

PET imaging with 16α-18F-fluoro-17ß-fluoroestradiol (18F-FES), a radiolabeled form of estradiol, allows whole-body, noninvasive evaluation of estrogen receptor (ER). 18F-FES is approved by the U.S. Food and Drug Administration as a diagnostic agent "for the detection of ER-positive lesions as an adjunct to biopsy in patients with recurrent or metastatic breast cancer." The Society of Nuclear Medicine and Molecular Imaging (SNMMI) convened an expert work group to comprehensively review the published literature for 18F-FES PET in patients with ER-positive breast cancer and to establish appropriate use criteria (AUC). The findings and discussions of the SNMMI 18F-FES work group, including example clinical scenarios, were published in full in 2022 and are available at https://www.snmmi.org/auc Of the clinical scenarios evaluated, the work group concluded that the most appropriate uses of 18F-FES PET are to assess ER functionality when endocrine therapy is considered either at initial diagnosis of metastatic breast cancer or after progression of disease on endocrine therapy, the ER status of lesions that are difficult or dangerous to biopsy, and the ER status of lesions when other tests are inconclusive. These AUC are intended to enable appropriate clinical use of 18F-FES PET, more efficient approval of FES use by payers, and promotion of investigation into areas requiring further research. This summary includes the rationale, methodology, and main findings of the work group and refers the reader to the complete AUC document.

Observer-study-based approaches to quantitatively evaluate the realism of synthetic medical images.

Objective.Synthetic images generated by simulation studies have a well-recognized role in developing and evaluating imaging systems and methods. However, for clinically relevant development and evaluation, the synthetic images must be clinically realistic and, ideally, have the same distribution as that of clinical images. Thus, mechanisms that can quantitatively evaluate this clinical realism and, ideally, the similarity in distributions of the real and synthetic images, are much needed.Approach.We investigated two observer-study-based approaches to quantitatively evaluate the clinical realism of synthetic images. In the first approach, we presented a theoretical formalism for the use of an ideal-observer study to quantitatively evaluate the similarity in distributions between the real and synthetic images. This theoretical formalism provides a direct relationship between the area under the receiver operating characteristic curve, AUC, for an ideal observer and the distributions of real and synthetic images. The second approach is based on the use of expert-human-observer studies to quantitatively evaluate the realism of synthetic images. In this approach, we developed a web-based software to conduct two-alternative forced-choice (2-AFC) experiments with expert human observers. The usability of this software was evaluated by conducting a system usability scale (SUS) survey with seven expert human readers and five observer-study designers. Further, we demonstrated the application of this software to evaluate a stochastic and physics-based image-synthesis technique for oncologic positron emission tomography (PET). In this evaluation, the 2-AFC study with our software was performed by six expert human readers, who were highly experienced in reading PET scans, with years of expertise ranging from 7 to 40 years (median: 12 years, average: 20.4 years).Main results.In the ideal-observer-study-based approach, we theoretically demonstrated that the AUC for an ideal observer can be expressed, to an excellent approximation, by the Bhattacharyya distance between the distributions of the real and synthetic images. This relationship shows that a decrease in the ideal-observer AUC indicates a decrease in the distance between the two image distributions. Moreover, a lower bound of ideal-observer AUC = 0.5 implies that the distributions of synthetic and real images exactly match. For the expert-human-observer-study-based approach, our software for performing the 2-AFC experiments is available athttps://apps.mir.wustl.edu/twoafc. Results from the SUS survey demonstrate that the web application is very user friendly and accessible. As a secondary finding, evaluation of a stochastic and physics-based PET image-synthesis technique using our software showed that expert human readers had limited ability to distinguish the real images from the synthetic images.Significance.This work addresses the important need for mechanisms to quantitatively evaluate the clinical realism of synthetic images. The mathematical treatment in this paper shows that quantifying the similarity in the distribution of real and synthetic images is theoretically possible by using an ideal-observer-study-based approach. Our developed software provides a platform for designing and performing 2-AFC experiments with human observers in a highly accessible, efficient, and secure manner. Additionally, our results on the evaluation of the stochastic and physics-based image-synthesis technique motivate the application of this technique to develop and evaluate a wide array of PET imaging methods.

FDG PET/CT-based Response Assessment in Malignancies.

Response is the logical outcome measure of a treatment in a clinical or research setting. Objective response assessment involves the use of a test to segregate patients who are likely to experience improved survival from those who are not. Early and accurate response assessment is critical for determining therapy effectiveness in clinical settings, for effective trial designs comparing two or more therapies, and for modulating treatment on the basis of response (ie, response-adapted therapy). 2-[fluorine 18]fluoro-2-deoxy-d-glucose (FDG) PET/CT can provide both functional and structural information about a disease process. It has been used at several stages of patient management, including imaging-based tumor response assessment, for various malignancies. FDG PET/CT can be used to differentiate patients with lymphoma who have a residual mass but no residual disease after treatment (ie, complete responders) from those who have a residual mass and residual disease after treatment. Similarly, in solid malignancies, the functional changes in glucose uptake and metabolism precede the structural changes (commonly seen as tumor shrinkage) and necrosis. Response assessment criteria have been developed on the basis of findings on FDG PET/CT images and are continuously being revised to ensure standardization and improve their predictive performance. Published under a CC BY 4.0 license. Quiz questions for this article are available through the Online Learning Center.

Adverse Clinical Events at the Injection Site Are Exceedingly Rare After Reported Radiopharmaceutical Extravasation in Patients Undergoing 99mTc-MDP Whole-Body Bone Scintigraphy: A 12-Year Experience.

The deleterious effects of high-dose radiation on normal tissue are sometimes extrapolated to diagnostic (SPECT and PET) radiopharmaceutical extravasation (RPE). It has been hypothesized that diagnostic RPE can have gradually evolving local tissue injury and a potentially increased risk of local dermatologic or oncologic diseases over a longer period. However, data on clinical adverse events after diagnostic RPE are limited. Therefore, our primary aim was to study the occurrence of short-term and long-term clinical adverse events in patients who underwent 99mTc-methylene diphosphonate (99mTc-MDP) whole-body bone scintigraphy (WBBS) with reported RPE. Methods: The records of 99mTc-MDP WBBS performed from June 2010 to January 2022 were retrospectively examined for RPE documented in the scan reports. The clinical records of patients with a documented RPE were extensively reviewed for any related short-term adverse events (within 2 wk of the WBBS: local symptoms and care sought for local dermatologic or musculoskeletal issues) and long-term adverse events (until the last follow-up: local deleterious effects and related consults for dermatology, plastic surgery, oncology, or orthopedics). Results: Retrospective review of the records of 31,679 99mTc-MDP WBBS studies showed RPE documented in 118 (0.37%). Medical records were not retrievable for 22 patients, yielding a final cohort of 96 patients with reported RPE. The median follow-up was 18.9 mo (interquartile range, 7.8-45.7 mo). Short-term events were noted in 4 patients, of whom one was asymptomatic. Of the 3 symptomatic patients, 2 experienced mild discomfort at the injection site, and 1 had tender swelling. Three of the 4 events were in patients who had a prior intravenous contrast extravasation for contrast-enhanced CT performed earlier during the day and a 99mTc-MDP injection later at the same site, likely leading to RPE. None of the long-term local events had any plausible link with the RPE event. Conclusion: Reported RPE was rare, and 3 patients (0.009%) had short-term local symptoms, all of which were likely related to the prior higher-volume intravenous contrast extravasation. The smaller-volume diagnostic radiopharmaceutical injections for WBBS are highly unlikely to cause local symptoms on their own. No patient had any long-term adverse event with a plausible link to the RPE.

Diagnostic Accuracy of 99mTc-Sestamibi SPECT/CT for Characterization of Solid Renal Masses.

Our objective was to assess the diagnostic accuracy of 99mTc-sestamibi SPECT/CT for characterizing solid renal masses. Methods: Imaging and clinical records of patients who underwent 99mTc-sestamibi SPECT/CT for clinical work-up of their solid renal masses from September 2018 to October 2021 were retrospectively reviewed. Histopathology formed the reference standard, and the diagnoses were categorized as malignant/concerning (renal cell carcinomas [RCCs] other than chromophobe histology) and benign/nonconcerning (oncocytic tumors including chromophobe RCC, other benign diagnoses) to calculate the sensitivity and specificity of 99mTc-sestamibi SPECT/CT and contrast-enhanced CT (ceCT). The clinical reads of the SPECT/CT images were used for visual classification of the lesions. Additionally, the SPECT images were manually segmented to obtain the maximum and mean counts of the lesion and adjacent renal cortex and maximum and mean lesion Hounsfield units. Results: 99mTc-sestamibi SPECT/CT was performed on 42 patients with 62 renal masses. A histopathologic diagnosis was available for 27 patients (18 male, 9 female) with 36 solid renal masses. ceCT findings were available for 20 of these patients. The most commonly identified single histologic type was clear cell RCC (13/36; 36.1%). Oncocytic tumors were the most common group of nonconcerning lesions (15/36), with oncocytoma as the predominant histologic type (n = 6). The sensitivity and specificity of SPECT/CT for diagnosing a nonconcerning lesion were 66.7% and 89.5%, respectively, compared with 10% and 75%, respectively, for ceCT. The lesion-to-kidney ratios for maximum and mean counts and maximum lesion Hounsfield units showed significant differences between the 2 groups (P < 0.05). The lesion-to-kidney mean count ratio at a cutoff of 0.46 showed a sensitivity and specificity of 87.5% and 86.67%, respectively, for detecting nonconcerning lesions, which was significantly higher than that of ceCT. Conclusion: The current literature on the utility of 99mTc-sestamibi SPECT/CT for characterization of solid renal masses is limited. We offer additional evidence of the incremental value of 99mTc-sestamibi SPECT/CT over ceCT for differentiating malignant or aggressive renal tumors from benign or indolent ones, thereby potentially avoiding overtreatment and its associated complications. Quantitative assessment can further increase the diagnostic accuracy of SPECT/CT and may be used in conjunction with visual interpretation.

First-in-Humans Evaluation of Safety and Dosimetry of 64Cu-LLP2A for PET Imaging.

There remains an unmet need for molecularly targeted imaging agents for multiple myeloma (MM). The integrin very late antigen 4 (VLA4), is differentially expressed in malignant MM cells and in pathogenic inflammatory microenvironmental cells. [64Cu]Cu-CB-TE1A1P-LLP2A (64Cu-LLP2A) is a VLA4-targeted, high-affinity radiopharmaceutical with promising utility for managing patients diagnosed with MM. Here, we evaluated the safety and human radiation dosimetry of 64Cu-LLP2A for potential use in MM patients. Methods: A single-dose [natCu]Cu-LLP2A (Cu-LLP2A) tolerability and toxicity study was performed on CD-1 (Hsd:ICR) male and female mice. 64Cu-LLP2A was synthesized in accordance with good-manufacturing-practice-compliant procedures. Three MM patients and six healthy participants underwent 64Cu-LLP2A-PET/CT or PET/MRI at up to 3 time points to help determine tracer biodistribution, pharmacokinetics, and radiation dosimetry. Time-activity curves were plotted for each participant. Mean organ-absorbed doses and effective doses were calculated using the OLINDA software. Tracer bioactivity was evaluated via cell-binding assays, and metabolites from human blood samples were analyzed with analytic radio-high-performance liquid chromatography. When feasible, VLA4 expression was evaluated in the biopsy tissues using 14-color flow cytometry. Results: A 150-fold mass excess of the desired imaging dose was tolerated well in male and female CD-1 mice (no observed adverse effect level). Time-activity curves from human imaging data showed rapid tracer clearance from blood via the kidneys and bladder. The effective dose of 64Cu-LLP2A in humans was 0.036 ± 0.006 mSv/MBq, and the spleen had the highest organ uptake, 0.142 ± 0.034 mSv/MBq. Among all tissues, the red marrow demonstrated the highest residence time. Image quality analysis supports an early imaging time (4-5 h after injection of the radiotracer) as optimal. Cell studies showed statistically significant blocking for the tracer produced for all human studies (82.42% ± 13.47%). Blood metabolism studies confirmed a stable product peak (>90%) up to 1 h after injection of the radiopharmaceutical. No clinical or laboratory adverse events related to 64Cu-LLP2A were observed in the human participants. Conclusion: 64Cu-LLP2A exhibited a favorable dosimetry and safety profile for use in humans.

Post COVID-19 syndrome with impairment of flow-mediated epicardial vasodilation and flow reserve.

AIMS: The aim of this study is to evaluate whether post-acute sequelae of COVID-19 cardiovascular syndrome (PASC-CVS) is associated with alterations in coronary circulatory function. MATERIALS AND METHODS: In individuals with PASC-CVS but without known cardiovascular risk factors (n = 23) and in healthy controls (CON, n = 23), myocardial blood flow (MBF) was assessed with 13 N-ammonia and PET/CT in mL/g/min during regadenoson-stimulated hyperemia, at rest, and the global myocardial flow reserve (MFR) was calculated. MBF was also measured in the mid and mid-distal myocardium of the left ventricle (LV). The Δ longitudinal MBF gradient (hyperemia minus rest) as a reflection of an impairment of flow-mediated epicardial vasodilation, was calculated. RESULTS: Resting MBF was significantly higher in PASC-CVS than in CON (1.29 ± 0.27 vs. 1.08 ± 0.20 ml/g/min, p ≤ .024), while hyperemic MBFs did not differ significantly among groups (2.46 ± 0.53 and 2.40 ± 0.34 ml/g/min, p = .621). The MFR was significantly less in PASC-CVS than in CON (1.97 ± 0.54 vs. 2.27 ± 0.43, p ≤ .031). In addition, there was a Δ longitudinal MBF gradient in PASC-CVS, not observed in CON (-0.17 ± 0.18 vs. 0.04 ± 0.11 ml/g/min, p < .0001). CONCLUSIONS: Post-acute sequelae of COVID-19 cardiovascular syndrome may be associated with an impairment of flow-mediated epicardial vasodilation, while reductions in coronary vasodilator capacity appear predominantly related to increases in resting flow in women deserving further investigations.

[18F]-Labeled PARP-1 PET imaging of PSMA targeted alpha particle radiotherapy response.

The growing interest and clinical translation of alpha particle (α) therapies brings with it new challenges to assess target cell engagement and to monitor therapeutic effect. Noninvasive imaging has great potential to guide α-treatment and to harness the potential of these agents in the complex environment of disseminated disease. Poly(ADP) ribose polymerase 1 (PARP-1) is among the most abundantly expressed DNA repair enzymes with key roles in multiple repair pathways-such as those induced by irradiation. Here, we used a third-generation PARP1-specific radiotracer, [18F]-PARPZ, to delineate castrate resistant prostate cancer xenografts. Following treatment with the clinically applied [225Ac]-PSMA-617, positron emission tomography was performed and correlative autoradiography and histology acquired. [18F]-PARPZ was able to distinguish treated from control (saline) xenografts by increased uptake. Kinetic analysis of tracer accumulation also suggests that the localization of the agent to sites of increased PARP-1 expression is a consequence of DNA damage response. Together, these data support expanded investigation of [18F]-PARPZ to facilitate clinical translation in the ⍺-therapy space.

Pilot Study: PARP1 Imaging in Advanced Prostate Cancer.

PURPOSE: PARP inhibitor (PARPi) therapy is approved for patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) genomic aberrations. However, only a fraction of patients with BRCA1/2 mutations respond to PARPi therapy. In this pilot study, we assess PARP-1 expression in prostate cancer patients with and without HRR genomic alternations using a novel PARP-based imaging agent. PROCEDURES: Nine advanced prostate cancer patients were studied with PET/CT and [18F]FluorThanatrace (FTT), an analogue of the PARPi rucaparib. Images were analyzed using maximum standardized uptake values (SUVmax). PARP expression was assessed by immunohistochemistry (IHC) when feasible (n = 4). RESULTS: We found great variability in FTT uptake (SUVmax range: 2.3-15.4). Patients with HRR mutations had a significantly higher SUVmax (p = 0.0379) than patients with non-HRR mutations although there was an overlap in FTT uptake between groups. Three patients without HRR and one with HRR mutations had similarly high PARP1 IHC expression. CONCLUSIONS: FTT-PET/CT may serve as an alternate biomarker for PARP1 expression and a potential method for PARPi treatment selection.

An Exploratory Study of Neoadjuvant Cetuximab Followed by Cetuximab and Chemoradiotherapy in Women With Newly Diagnosed Locally Advanced Cervical Cancer.

OBJECTIVES: This study explored the feasibility of cetuximab with chemoradiation in women with cervical carcinoma and evaluated fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) to assess early response to cetuximab (NCT00292955). PATIENTS AND METHODS: Eligible patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVB invasive carcinoma of the uterine cervix were treated on 1 of 3 dose levels (DL). DL1 consisted of neoadjuvant cetuximab, then concurrent radiotherapy with cetuximab 250 mg/m2/cisplatin 40 mg/m2, followed by weekly cetuximab. DL2 consisted of radiotherapy with cetuximab 200 mg/m2 and cisplatin 30 mg/m2. DL3 consisted of radiotherapy with cetuximab 250 mg/m2 and cisplatin 30 mg/m2. Patients underwent 18F-FDG-PET/CT before treatment, after neoadjuvant cetuximab, and at the end of treatment. RESULTS: Of the 21 patients enrolled, 9, 3, and 9 were treated in DL1, DL2, and DL3, respectively. DL1 required dose reductions due to gastrointestinal toxicities. DL2 and 3 were tolerated with 1 dose-limiting toxicity (grade 4 renal failure) at DL3. Following 3 weekly treatments of neoadjuvant cetuximab in DL1, 7 patients had maximum standardized uptake value changes on 18F-FDG-PET/CT consistent with response to cetuximab. Of the 12 patients with locally advanced disease, eleven evaluable patients had no evidence of disease on 18F-FDG-PET/CT at treatment end. Five-year progression-free survival and overall survival rates for all patients were 57.5% and 58.5%, respectively. CONCLUSIONS: Cetuximab with cisplatin 30 mg/m2 and radiotherapy was tolerated. 18F-FDG-PET/CT demonstrated early evidence of response to neoadjuvant cetuximab. With advances in precision oncology and the recent approval of pembrolizumab in metastatic cervical cancer, dual-target inhibition with an epidermal growth factor receptor inhibitor may be a promising treatment in the future.

18F-FDG PET/CT Staging of Head and Neck Cancer: Interobserver Agreement and Accuracy-Results from Multicenter ACRIN 6685 Clinical Trial.

To our knowledge, no prior multicenter clinical trial has reported interobserver agreement of 18F-FDG PET/CT scans for staging of clinical N0 neck in head and neck cancer. Methods: A total of 287 participants were recruited. For visual analysis, positive nodal uptake of 18F-FDG was defined as uptake visually greater than activity seen in the blood pool. Results: The negative predictive value of the 18F-FDG PET/CT for N0 clinical neck was 86% or above for visual assessment (95% CI, 86%-88%) for the 2 central readers and above 90% (95% CI, 90%-95%) for SUVmax for central reads and site reads dichotomized at the optimal cutoff value of 1.8 and the prespecified cutoff value of 3.5, respectively. The κ coefficients between the 2 expert readers and between central reads and site reads varied between 0.53 and 0.78. Conclusion: The NPV of the 18F-FDG PET/CT for N0 clinical neck was 86% or above for visual assessment and above 90% for SUVmax cut points of 1.8 and 3.5 with moderate to substantial agreements.

Coronary circulatory function with increasing obesity: A complex U-turn.

AIMS: The aim of this investigation was to explore and characterize alterations in coronary circulatory function in function of increasing body weight with medically controlled cardiovascular risk factors and, thus, "metabolically" unhealthy obesity. MATERIALS AND METHODS: We prospectively enrolled 106 patients with suspected CAD but with normal stress-rest myocardial perfusion on 13 N-ammonia PET/CT and with medically controlled or no cardiovascular risk factors. 13 N-ammonia PET/CT concurrently determined myocardial blood flow (MBF) during pharmacologically induced hyperaemia and at rest. Based on body mass index (BMI), patients were grouped into normal weight (BMI: 20.0-24.9 kg/m2 , n = 22), overweight (BMI: 25.0-29.9 kg/m2 , n = 27), obese (BMI: 30.0-39.9 kg/m2 , n = 31), and morbidly obese (BMI ≥ 40kg/m2 , n = 26). RESULTS: Resting MBF was comparable among groups (1.09 ± 0.18 vs. 1.00 ± 0.15 vs. 0.96 ± 0.18 vs.. 1.06 ± 0.31 ml/g/min; p = .279 by ANOVA). Compared to normal weight individuals, the hyperaemic MBF progressively decreased in in overweight and obese groups, respectively (2.54 ± 0.48 vs. 2.02 ± 0.27 and 1.75 ± 0.39 ml/g/min; p < .0001), while it increased again in the group of morbidly obese individuals comparable to normal weight (2.44 ± 0.41 vs. 2.54 ± 0.48 ml/g/min, p = .192). The BMI of the study population correlated with the hyperaemic MBF in a quadratic or U-turn fashion (r = .34, SEE = 0.46; p ≤ .002). CONCLUSIONS: The U-turn of hyperaemic MBF from obesity to morbid obesity is likely to reflect contrasting effects of abdominal versus subcutaneous adipose tissue on coronary circulatory function indicative of two different disease entities, but needing further investigations.

18F-FDG PET in Myocardial Viability Assessment: A Practical and Time-Efficient Protocol.

We assessed image quality using a practical and time-efficient protocol for intravenous glucose loading and insulin injection before administration of 18F-FDG for PET myocardial viability evaluation in patients with ischemic cardiomyopathy (ICM), with and without type 2 diabetes mellitus. Methods: The metabolic preparation period (MPP) or optimal cardiac 18F-FDG uptake was determined from the time of intravenous infusion of 12.5 or 25 g of 50% dextrose to the time of 18F-FDG injection. Cardiac 18F-FDG image quality was evaluated according to a 5-point scoring system (from 5, excellent, to 1, nondiagnostic) by 2 independent observers. In cases of disagreement, consensus was achieved in a joint reading. Fifteen patients with ICM who underwent oral glucose loading and intravenous insulin administration served as a reference for MPP comparisons. Results: Fifty-nine consecutive patients (age, 63 ± 10 y; 48 men and 11 women) underwent rest 99mTc-tetrofosmin SPECT/CT and 18F-FDG PET/CT for the evaluation of myocardial viability. 18F-FDG image quality was scored as excellent in 42%, very good in 36%, good in 17%, fair in 3%, and nondiagnostic in 2%. When diabetic and nondiabetic patients were compared, the quality scores were excellent in 29% versus 76%, very good in 41% versus 18%, good in 24% versus 6%, fair in 4% versus 0%, and nondiagnostic in 2% versus 0%. The mean (±SD) quality score was 4.12 ± 0.95, and overall it was better in nondiabetic than in diabetic patients (4.71 ± 0.59 vs. 3.88 ± 0.96; P < 0.0001). Notably, the average MPP was significantly less with intravenous glucose loading than with oral glucose loading (51 ± 15 min vs. 132 ± 29 min; P < 0.0001), paralleled by higher insulin doses (6.3 ± 2.2 U vs. 2.0 ± 1.69 U; P < 0.001). Conclusion: Using a practical and time-efficient protocol for intravenous glucose loading and insulin administration before 18F-FDG injection reduces the MPP by 61% as compared with an oral glucose challenge and affords good-to-excellent image quality in 95% of ICM patients.