核医学分子显像在ICI相关心肌炎中的应用与进展

… emission tomography (PET) computed tomography (CT) has not been prospectively evaluated and compared to EMB in ICI myocarditis [2,4]. The rationale for using FDG PET is that …

Visual Abstract

… ICI-myocarditis is low (1%) 1 but milder troponin rises are more common and ICI-myocarditis needs excluding to continue ICI … PET in patients with suspected ICI-associated myocarditis. …

… Heterogeneous lower myocardial perfusion and diffuse 18F-FDG uptake (not shown… (ICI)–associated myocarditisinduced heart failure. 68Ga-FAPI PET imaging may be used to detect ICI…

In recent years, a wide range of cancer immunotherapies have been developed and have become increasingly important in cancer treatment across multiple oncologic diseases. In particular, immune checkpoint inhibitors (ICIs) offer promising options to improve patient outcomes. However, a major limitation of these treatments consists in the development of immune-related adverse events (irAEs) occurring in potentially any organ system and affecting up to 76% of the patients. The most frequent toxicities involve the skin, gastrointestinal tract, and endocrine system. Although mostly manageable, potentially life-threatening events, particularly due to neuro-, cardiac, and pulmonary toxicity, occur in up to 30% and 55% of the patients treated with ICI-monotherapy or -combination therapy, respectively. Imaging, in particular computed tomography (CT), magnetic resonance imaging (MRI), and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG-PET/CT), plays an important role in the detection and characterization of these irAEs. In some patients, irAEs can even be detected on imaging before the onset of clinical symptoms. In this context, it is particularly important to distinguish irAEs from true disease progression and specific immunotherapy related response patterns, such as pseudoprogression. In addition, there are irAEs which might be easily confused with other pathologies such as infection or metastasis. However, many imaging findings, such as in immune-related pneumonitis, are nonspecific. Thus, accurate diagnosis may be delayed underling the importance for adequate imaging features characterization in the appropriate clinical setting in order to provide timely and efficient patient management. 18F-FDG-PET/CT and radiomics have demonstrated to reliably detect these toxicities and potentially have predictive value for identifying patients at risk of developing irAEs. The purpose of this article is to provide a review of the main immunotherapy-related toxicities and discuss their characteristics on imaging.

Objective: Checkpoint inhibitors (ICIs) have gained importance in recent years regarding the treatment of a variety of oncologic diseases. The possibilities of diagnosing cardiac adverse autoimmune effects of ICIs are still limited. We aimed to implement FAPI PET/CT imaging in detecting ICI-associated myocarditis. Methods: In a retrospective study, FAPI PET/CT scans of 26 patients who received ICIs from 01/2017 to 10/2019 were analyzed. We compared tracer enrichment in the heart of patients without any signs of a cardiac disease (n = 23) to three patients with suspected ICI-associated myocarditis. To exclude any significant coronary heart disease, cardiac catherization was performed. All three patients' myocardial biopsies were examined for inflammatory cells. Results: Three patients showed clinical manifestations of an ICI syndrome including myocarditis with elevated levels of hsTnT (175 pg/ml, 1,771 pg/ml, 157 pg/ml). Further cardiological assessments revealed ECG abnormalities, lymphocyte infiltration of the myocardium in the biopsies or wall motion abnormalities in echocardiography. These patients' FAPI PET/CTs showed cardiac enrichment of the marker which was less distinct or absent in patients receiving ICIs without any signs of immunological adverse effects or cardiac impairment (n = 23) [Median SUV myocarditis patients: 1.79 (IQR: 1.65, 1.85), median SUV non-myocarditis patients: 1.15 (IQR: 0.955, 1.52)]. Conclusions: Apart from the successful implementation of ICIs in oncological treatments, ICI-associated myocarditis is still a challenging adverse effect. FAPI PET/CT may be used in order to identify affected patients at an early stage. Moreover, when integrated into cancer stage diagnostics, it contributes to cardiac risk stratification besides biomarker, ECG and echocardiography.

Background: Immune checkpoint inhibitors (ICIs) have changed the landscape in oncology, providing effective cancer management for a growing population. However, by promoting an immunological attack on cancer cells, healthy cells may be harmed in the process. Increased awareness of ICI-associated myocarditis (ICIMy) as one of the most fatal immune-related adverse events has led to efforts to improve the diagnosis and treatment of this condition. The purpose of this review is to summarize the current state of knowledge regarding ICIMy. Methods: We performed a literature search in Pubmed and Scopus with the relevant keywords, screened the titles and abstracts of the results, and reviewed the selected publications using pre-established criteria. Main findings: Although ICIMy’s cumulative incidence is below 0.5% in clinical trials, real-world data reveal a higher incidence of up to 4%. Underlying pathophysiologic mechanisms include T cell clonal expansion, molecular mimicry, and increased inflammatory cytokine signaling pathways leading to ICIMy. The clinical presentation can vary from asymptomatic to fulminant cardiac death and is often accompanied by musculoskeletal adverse events. Emerging diagnostic tools with prognostic value include global longitudinal strain assessment and multiple PET-CT modalities. The mainstay of treatment includes holding the immunotherapy, prompt high-dose methylprednisolone, and close cardiovascular observation. Fulminant and refractory cases benefit from additional immunomodulatory therapies. Principal conclusions: Although ICIMy is a rare adverse event, its non-specific presentation warrants a high level of suspicion. Once ICIMy is considered a likely diagnosis, immunomodulatory therapies should be initiated promptly.

Background Myocardial programmed death-ligand 1 (PD-L1) expression is implicated in immune checkpoint inhibitor (ICI)-associated myocarditis. Measurement of myocardial PD-L1 expression may have potential use as a mechanistic and predictive biomarker. The aim of this study was to determine non-invasive assessment of myocardial PD-L1 expression using [^99mTc]-labelled anti-PD-L1 single-domain antibody (NM-01) SPECT/CT. Methods Thoracic [^99mTc]NM-01 SPECT/CT was performed in lung cancer patients ( n  = 10) at baseline and 9-weeks following anti-programmed cell death protein 1 (PD-1) therapy. Baseline and 9-week left ventricular and right ventricular to blood pool ratios (LV_max:BP) and (RV_max:BP) were measured. LV_max was compared to background skeletal muscle (muscle_max). Intra-rater reliability was determined by intraclass correlation coefficient (ICC) and Bland–Altman analysis. Results Mean LV_max:BP values were 2.76 ± 0.67 at baseline vs 2.55 ± 0.77 at 9 weeks ( p  = 0.42). Mean RV_max:BP was 1.82 ± 0.32 at baseline vs 1.76 ± 0.45 at 9 weeks ( p  = 0.67). Myocardial PD-L1 expression was at least threefold greater than skeletal muscle at baseline for the LV (LV_max to muscle_max 3.71 ± 0.77 vs 0.98 ± 0.20 ( p  < 0.001)) and at least twofold for the RV (LV_max to muscle_max 2.49 ± 0.63 vs 0.98 ± 0.20 ( p  < 0.001)). There was excellent intra-rater reliability for LV_max:BP with ICC 0.99 (95% confidence interval 0.94–0.99, p  < 0.001), mean bias -0.05 ± 0.14 (95% limits of agreement -0.32 to 0.21). There were no major adverse cardiovascular events or myocarditis during follow-up. Conclusion This study is the first to report PD-L1 expression of the heart that can be quantified non-invasively without invasive myocardial biopsy, with high reliability and specificity. This technique can be applied to investigate myocardial PD-L1 expression in ICI-associated myocarditis and cardiomyopathies. Clinical trial registration PD-L1 Expression in Cancer (PECan) study (NCT04436406). https://clinicaltrials.gov/ct2/show/NCT04436406 June 18th, 2020.

Immune checkpoint inhibitors (ICI) boost the endogenous anticancer immunity, evoking long-lasting anticancer responses in a subset of patients with solid tumors. Simultaneously, ICI are also associated with serious toxicities, impacting treatment duration and the quality of life. The proposed processes underlying ICI-related toxicity include T-cell activation and recruitment to non-tumor tissues, involvement of other immune cells and fibroblasts and the host’ microbiome composition. However, the exact mechanisms of these processes remain incompletely understood, hindering clinicians’ ability to predict and identify ICI-related toxicity in the early stages of treatment. Molecular imaging may play a role as a non-invasive biomarker, providing a tool to study ICI-related toxicity. This review discusses the applications of molecular imaging to answer questions regarding the mechanisms, detection, and prediction of ICI-related toxicity. Potential targets and the current state of development of suitable imaging techniques are discussed.

The emerging use of immunotherapies in cancer treatment increases the risk of immunotherapy-related cardiotoxicity. In contrast to conventional chemotherapy, these novel therapies have expanded the forms and presentations of cardiovascular damage to a broad spectrum from asymptomatic changes to fulminant short- and long-term complications in terms of cardiomyopathy, arrythmia, and vascular disease. In cancer patients and, particularly, cancer patients undergoing (immune-)therapy, cardio-oncological monitoring is a complex interplay between pretherapeutic risk assessment, identification of impending cardiotoxicity, and post-therapeutic surveillance. For these purposes, the cardio-oncologist can revert to a broad spectrum of nuclear cardiological diagnostic workup. The most promising commonly used nuclear medicine imaging techniques in relation to immunotherapy will be discussed in this review article with a special focus on the continuous development of highly specific molecular markers and steadily improving methods of image generation. The review closes with an outlook on possible new developments of molecular imaging and advanced image evaluation techniques in this exciting and increasingly growing field of immunotherapy-related cardiotoxicity.

Advanced cardiac imaging techniques such as cardiovascular magnetic resonance (CMR) and positron emission tomography (PET) are widely used in clinical practice in patients with acute myocarditis and chronic inflammatory cardiomyopathies (I-CMP). We aimed to provide a review article with practical recommendations from the European Society of Cardiovascular Radiology (ESCR), in order to guide physicians in the use and interpretation of CMR and PET in clinical practice both for acute myocarditis and follow-up in chronic forms of I-CMP.

… /CT, which could interfere with the detection of FDG uptake in inflammatory region of myocarditis. Thus, similar to cardiac sarcoidosis imaging, dietary preparation to suppress normal …

… Non-invasive imaging of myocarditis using echocardiography … acute than in subacute or chronic myocarditis. Even in acute type… has been demonstrated in myocarditis caused by chronic …

… presence of myocarditis. These areas of hyperenhancement correspond to inflammation and … Myocarditis may be identified at PET/CT by the presence of increased metabolic activity in …

Simple Summary Recent advances in cancer therapy have spotlighted immune checkpoint inhibitors (ICIs) as a breakthrough in treating various cancers. These treatments, however, can lead to immune-related adverse events (irAEs) that mirror the body’s heightened immune response, affecting multiple organs. Recognizing and managing these irAEs is critical, and imaging modalities such as 18F-FDG PET/CT have emerged as a potential tool for early detection. This review delves into the capability of 18F-FDG PET/CT to identify irAEs, exploring the patterns of metabolic activation indicative of these events. While highlighting the current utility of PET/CT scans in oncology for tracking therapy response and irAEs, the review also speculates on future directions, suggesting a potential role in refining immunotherapy strategies and enhancing patient care. The insights obtained could transform patient monitoring during ICI therapy, potentially improving outcomes by facilitating prompt management of irAEs. Abstract Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized contemporary oncology, presenting efficacy in various solid tumors and lymphomas. However, ICIs may potentially overstimulate the immune system, leading to immune-related adverse events (irAEs). IrAEs may affect multiple organs, such as the colon, stomach, small intestine, kidneys, skin, lungs, joints, liver, lymph nodes, bone marrow, brain, heart, and endocrine glands (e.g., pancreas, thyroid, or adrenal glands), exhibiting autoimmune inflammation. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is commonly used in oncology for staging and assessment of therapy responses, but it may also serve as a tool for detecting irAEs. This review aims to present various patterns of metabolic activation associated with irAEs due to ICI treatment, identifiable through 18F-FDG PET/CT. It describes the advantages of early detection of irAEs, but also presents the challenges in differentiating them from tumor progression. It also delves into aspects of molecular response assessment within the context of pseudoprogression and hyperprogression, along with typical imaging findings related to these phenomena. Lastly, it summarizes the role of functional PET imaging in oncological immunotherapy, speculating on its future significance and limitations.

… intra-cardiac masses, and cardiac sarcoidosis. … ,18F-FDG PET/CT was able to detect ICI-induced myocarditis despite unremarkable electrocardiography, echocardiography, and cardiac …

Simple Summary Immunotherapy has been introduced as a standard of care for several cancers, and its use is on the rise. However, the enhanced immune system frequently causes immune-related adverse events. Depending on the affected organ and tissue and the severity of the toxicity, immunotherapy is generally held, and steroids or immunosuppressive agents are introduced, impacting cancer treatment. Therefore, prompt identification of toxicity at an early stage and multidisciplinary management are mandatory. Since imaging is crucial to guide clinicians in managing immune-related adverse events, this imaging-based review presents the most frequent complications identifiable on imaging. Clues for identification and the most important differential diagnoses are discussed to enhance knowledge among imaging specialists and clinicians regarding these complications. Abstract Immunotherapy has revolutionized oncology care, improving patient outcomes in several cancers. However, these therapies are also associated with typical immune-related adverse events due to the enhanced inflammatory and immune response. These toxicities can arise at any time during treatment but are more frequent within the first few months. Any organ and tissue can be affected, ranging from mild to life-threatening. While some manifestations are common and more often mild, such as dermatitis and colitis, others are rarer and more severe, such as myocarditis. Management depends on the severity, with treatment being held for >grade 2 toxicities. Steroids are used in more severe cases, and immunosuppressive treatment may be considered for non-responsive toxicities, along with specific organ support. A multidisciplinary approach is mandatory for prompt identification and management. The diagnosis is primarily of exclusion. It often relies on imaging features, and, when possible, cytologic and/or pathological analyses are performed for confirmation. In case of clinical suspicion, imaging is required to assess the presence, extent, and features of abnormalities and to evoke and rule out differential diagnoses. This imaging-based review illustrates the diverse system-specific toxicities associated with immune checkpoint inhibitors and chimeric antigen receptor T-cells with a multidisciplinary perspective. Clinical characteristics, imaging features, cytological and histological patterns, as well as the management approach, are presented with insights into radiological tips to distinguish these toxicities from the most important differential diagnoses and mimickers—including tumor progression, pseudoprogression, inflammation, and infection—to guide imaging and clinical specialists in the pathway of diagnosing immune-related adverse events.

18F‐FDG PET/CT scanning is routinely performed to stage and evaluate the treatment response in many malignancies. Immunotherapy is a rapidly growing treatment option for many cancers, and both clinicians and imaging specialists need to be familiar with 18F‐FDG PET/CT imaging characteristics unique to patients on this type of treatment. In particular, many immune‐related adverse events (irAEs) can be detected on 18F‐FDG PET/CT and early accurate identification is critical to reduce treatment related morbidity and incorrect interpretation of malignant disease status. This pictorial essay reviews frequently encountered irAEs in clinical practice and their appearances on 18F‐FDG PET/CT along with a brief discussion on pseudoprogression and hyperprogression.

This study aimed to determine the organ-specific accuracy of [18F]FDG-PET/CT in identifying immune-related adverse events (irAEs) in patients with high-risk (stage III/IV) surgically resected melanoma treated with an adjuvant immune checkpoint inhibitor (ICI) and determine the incidence of irAEs within the first year after starting treatment. This registry-based study included individuals who had undergone surgical removal of melanoma and were undergoing adjuvant ICI treatment (either nivolumab or pembrolizumab). The study specifically enrolled patients who had undergone both a baseline and at least one subsequent follow-up [18F]FDG-PET/CT scan. Follow-up scans were performed every third month in the first year after surgery to screen for disease recurrence. We retrospectively compared the follow-up scans with baseline scans to identify irAEs. Clinical information on irAEs was obtained from medical records and served as a reference standard for determining the accuracy of [18F]FDG-PET/CT. A total of 123 patients with 363 [18F]FDG-PET/CT scans were included, and 65 patients (52.8%) developed irAEs. In decreasing order, the organ-specific incidences of irAEs were: skin 26/65 (40%), muscle and joints 21/65 (32.3%), intestines 13/65 (20%), thyroid gland 12/65 (18.5%), lungs 4/65 (6.2%), and heart 2/65 (3.1%). The sensitivities and specificities of [18F]FDG-PET/CT for diagnosing irAEs were: skin 19% (95% CI: 7–39%) and 95% (88–98%), muscles and joints 71% (48–89%) and 83% (75–90%), intestines 100% (75–100%) and 85% (77–91%); thyroid gland 92% (62–99%) and 95% (89–98%), lungs 75% (19–99%) and 90% (83–95%), and heart 50% (13–99%) and 97% (92–99%), respectively. [18F]FDG-PET/CT generally had moderate to high sensitivities (except for skin and heart) and specificities in diagnosing irAEs in patients receiving adjuvant ICI; this could be suggested to be systematically assessed and reported in scan reports.

… Myositis as an irAE usually involves skeletal muscle in the extremities but may also affect ocular … FDG-PET scan is used in IIM and ICI-myositis/-myocarditis and uptake reflective of …

BACKGROUND Programmed death receptor-1 blocking antibodies (anti-PD1) are a new standard of care in many cancer types. Patients benefit from improved survival but have the risk of immune-related adverse events (irAE). We evaluated if medical imaging procedures, used for anti-tumour response assessment, can detect irAEs. MATERIALS AND METHODS All consecutive patients treated with anti-PD1 and with a medical imaging acquisition performed within 2 weeks with irAEs ≥2 were retrospectively included. Data were gathered from June 2014 to February 2017, and a central review was performed. The primary and secondary end-points were i) to evaluate the overall detection rate of irAEs by medical imaging and ii) to provide a comprehensive radiological description of irAEs. RESULTS Fifty-three patients (31 women, 22 men; average age: 61 years) were included. The primary tumour was melanoma (n = 32), lung cancer (n = 18) and other (n = 3). Patients were treated with nivolumab (n = 27) or pembrolizumab (n = 26). Of 74 medical imaging procedures analysed (ratio = 1.4 medical imaging per patient), 55 irAE were detected. The detection rate was overall: 74% (95 confidence interval: 63-84%), positron emission tomography with 18F-fludeoxyglucose integrated with computed tomography (18F-FDG PET/CT): 83% (n = 10/12), magnetic resonance imaging: 83% (n = 5/6), computed tomography scan: 79% (n = 19/24), ultrasonography: 70% (n = 19/27), standard X-rays: 40% (n = 2/5), lung/mediastinum: 100% (n = 7/7), enterocolitis: 100% (n = 8/8), hypophysitis: 100% (n = 3/3), thyroiditis: 75% (n = 15/20), hepatitis: 67% (n = 2/3), arthralgia or arthritis: 40% (n = 2/5) and pancreas: 28% (n = 2/7). CONCLUSION Medical imaging detected 74% of irAE in patients treated with anti-PD1. Beyond response assessment, medical imaging can detect irAE and guide towards specific management. We described the most frequent sites and patterns of imaging findings.

With this document, we provide a standard for PET/(diagnostic) CT imaging procedures in cardiovascular diseases that are inflammatory, infective, infiltrative, or associated with dysfunctional innervation (4Is). This standard should be applied in clinical practice and integrated in clinical (multicenter) trials for optimal procedural standardization. A major focus is put on procedures using [18F]FDG, but 4Is PET radiopharmaceuticals beyond [18F]FDG are also described in this document. Whilst these novel tracers are currently mainly applied in early clinical trials, some multicenter trials are underway and we foresee in the near future their use in clinical care and inclusion in the clinical guidelines. Finally, PET/MR applications in 4Is cardiovascular diseases are also briefly described. Diagnosis and management of 4Is-related cardiovascular diseases are generally complex and often require a multidisciplinary approach by a team of experts. The new standards described herein should be applied when using PET/CT and PET/MR, within a multimodality imaging framework both in clinical practice and in clinical trials for 4Is cardiovascular indications.

Imaging plays a crucial role in the clinical management of patients with inflammatory diseases, both for diagnosis and in evaluating treatment response. 2-deoxy-2-[18F]-fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) is a non-invasive imaging technique that is gaining prominence in the study of various infectious and inflammatory diseases. Advances in PET imaging technology, along with the development of new radiopharmaceuticals, have the potential to enhance the diagnostic accuracy of imaging in the evaluation of inflammation, allowing for the tracking of disease activity through mechanisms distinct from FDG. This narrative review aims to explore and discuss the emerging role of new PET/CT radiopharmaceuticals in the field of inflammation taking into account findings from recent studies in this setting. Preliminary promising findings are available in the literature regarding the potential usefulness of new radiotracers for investigating inflammatory diseases, especially in cardiovascular, neurological, rheumatological and pulmonary fields. In cardiovascular inflammation, different radiopharmaceuticals showed promising roles according to the disease evaluated, but globally the findings are preliminary and heterogeneous. Concerning cardiac sarcoidosis, somatostatin Receptor Subtype 2 (SSTR2)-ligands, translocator protein (TSPO) radiotracers, and hypoxic radiotracers were investigated but until now so strong evidence were available. About vasculitis, SSTR2-ligands and CXCR4 radiotracers showen the most promising findings, especially in the evaluation of treatment response. Regarding atherosclerosis and mycoarditis, we have positive preclinical studies but lack of evidence from a clinical point of view. For neuroinflammation, the available findings on new PET radiotracers are still limited even if TSPO PET seems the most promising due to the ability to image microglial activation. Instead, about lung and rheumatological inflammatory diseases, fibroblast activation protein inhibitors (FAPI) appear to be the most promising radiopharmaceutical, even better than [18F]FDG, although further solid data are needed. Emerging PET radiotracers showed promising results in detecting inflammatory diseases in different anatomical sites, but more robust and comprehensive studies are required for their clinical use.

… For the time being, cardiac PET/MRI emerges as potential clinical tool in the identification … of infiltrative cardiac diseases, such as sarcoidosis, acute or chronic myocarditis, and cardiac …

… of cancer imaging studies, 76 PET imaging studies of vascular inflammation should expand … trials are using 18 FDG PET to quantify reductions in carotid plaque inflammation after statin …

Inflammation is the key feature of myocarditis, which remains challenging to diagnose due to its complex etiology and nonspecific clinical presentation. In recent years, inflammation-targeted molecular imaging has become a research priority, and noninvasive monitoring of cardiac inflammation is expected to improve the accuracy of clinical diagnosis. This review focuses on the molecular imaging probes and targets for myocarditis in radionuclide imaging, ultrasound imaging, and magnetic resonance imaging (MRI), discussing the characteristics and applications of each probe-target combination and their potential limitations. Molecular targeted imaging approaches for inflammatory cell phenotypes, metabolic pathways, and endothelial cell markers hold significant potential for clinical translation and allow for early detection and treatment monitoring of myocarditis, thereby enabling better patient care and improving clinical outcomes.

… myocarditis, thyroiditis, arthritis and retroperitoneal fibrosis. … tumours, FAPI-PET tracers have demonstrated high diagnostic … ICI-associated myocarditis [17] and underwent myocardial …