Multimodality imaging in cardio-oncology: the added value of CMR and CCTA

During the last 30 years, we have assisted to a great implementation in anticancer treatment with a subsequent increase of cancer survivors and decreased mortality. This has led to an ongoing interest about the possible therapy-related side-effects and their management to better guide patients therapy and surveillance in the chronic and long-term setting. As a consequence cardio-oncology was born, involving several different specialties, among which radiology plays a relevant role. Till the end of August 2022, when European Society of Cardiology (ESC) developed the first guidelines on cardio-oncology, no general indications existed to guide diagnosis and treatment of cancer therapy-related cardiovascular toxicity (CTR-CVT). They defined multimodality imaging role in primary and secondary prevention strategies, cancer treatment surveillance and early CTR-CVT identification and management. Cardiac computed tomography angiography (CCTA) has acquired a central role in coronary assessment, as far as coronary artery disease (CAD) exclusion is concerned; but on the side of this well-known application, it also started to be considered in left ventricular function evaluation, interstitial fibrosis quantification and cardiac perfusion studies. Cardiac magnetic resonance (CMR), instead, has been acknowledged as the gold standard alternative to trans-thoracic echocardiography (TTE) poor acoustic window in quantification of heart function and strain modifications, as well as pre- and post-contrast tissue characterization by means of T1-T2 mapping, early Gadolinium enhancement (EGE), late Gadolinium enhancement (LGE) and extracellular volume (ECV) evaluation. Our review is intended to provide a focus on the actual role of CMR and CCTA in the setting of a better understanding of cardiotoxicity and to draw some possible future directions of cardiac imaging in this field, starting from the recently published ESC guidelines.


BACKGROUND AND DEFINITION
During the last 30 years, we have assisted to a great implementation in anticancer treatment with a subsequent huge increase of cancer survivors. 1,2This has led to an ongoing interest about the possible therapy-related side effects and their management to better guide patients therapy and surveillance in the chronic and long-term setting. 3For this purpose, a new discipline was born, namely, cardiooncology 4 , involving several different specialties, among which radiology plays a relevant role in both cardiotoxicity identification and follow-up through multimodality imaging.
Over the past decades, different definitions have been used to describe cancer therapy-related cardiovascular toxicity (CTR-CVT), generating confusion and misdiagnosis.Among them, the most common is the one given by the American Society of Echocardiography, describing cancer treatment-related cardiac dysfunction as a decrease in left ventricular ejection fraction (LVEF) of >10% to a value <53%. 5Nowadays, the consensus statement of the International Cardio-Oncology Society (IC-OS) 6 has overcome these issues with a specific definition of cancer therapyrelated cardiac dysfunction (CTRCD) as cardiomyopathy, heart failure (HF), myocarditis, vascular toxicity, hypertension (HTN), cardiac arrhythmias, and corrected QT interval prolongation induced by anticancer therapy.For CTR-CVT-induced pericardial and valvular heart diseases, definitions are the same used for the general population.
Till the end of August 2022, no international guidelines have existed to guide diagnosis and therapy of CTR-CVT, when the first European Society of Cardiology (ESC) guidelines on cardio-oncology were developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and IC-OS. 7 already stated, multimodality imaging plays a central role in primary and secondary prevention strategies, cancer treatment surveillance and early CTR-CVT identification and management.Our review will mainly focus on the actual role of cardiac magnetic resonance (CMR) and cardiac computed tomography angiography (CCTA) in the setting of a better understanding of cardiotoxicity predictive factors, early diagnosis, treatment, and follow-up. 8

CARDIOTOXICITY MANIFESTATIONS AND MECHANISMS
The most common clinical manifestations of CRT-CVT are acute and chronic HF, myocardial ischemia, electrophysiological disturbances, HTN, and vessel thromboembolism. 9We will briefly analyze them from a clinical and pathophysiological point of view.
HF is mostly induced by the administration of anthracyclines, cyclophosphamide, ifosfamide, bevacizumab, trastuzumab, and imatinib.From the pathophysiological point of view, free radical formation is recognized as the main mechanism of cardiotoxicity in anthracyclines treatment. 10Cyclophosphamide and ifosfamide are thought to cause direct endothelial injury by means of extravasation of toxic metabolites leading to cardiomyocytes damage, interstitial damage, and hemorrhage. 11Bevacizumab has been demonstrated to induce HF via uncontrolled HTN and inhibition of Vascular Endothelial Growth Factor (VEGF), 12 while Trastuzumab interferes with normal cardiomyocytes growth by inhibiting their epidermal growth factor receptor 2 (Erb2). 13ocardial ischemia is commonly diagnosed in cancer patients, particularly in those treated with antimetabolites, antimicrotubules, and monoclonal antibody-based tyrosine kinase inhibitors. 14From the pathophysiological point of view, coronary artery thrombosis, arteritis, and vasospasms are proposed as the main causative mechanisms of ischemia in antimetabolites and antimicrotubules therapy ( 15 ).Bevacizumab, instead, seems to cause myocardial ischemia through its anti-VEGF mechanism. 16adycardia and QT prolongation are the main electrophysiological disturbances found in CRT-CVT. 14They can be caused by anti-cancer-induced fibrosis and radiation therapy, directly affecting the heart conduction system. 17Concerning bradycardia, paclitaxel is considered as the main causative agent among chemotherapeutic drugs via its direct effect on Purkinje fibers or extracardiac autonomic control. 18QT prolongation causative mechanisms remain unknown and are still quite rare, especially related to small molecule tyrosine kinase inhibitors.
HTN is the most frequent comorbid condition reported in cancer patients. 19Studies have shown that it may be related to the VEGF inhibition, decreasing nitric oxide production in arterioles leading to increased vasoconstriction and peripheral vascular resistance. 20ncer patients commonly stay in a pro-thrombotic state, which is in some cases worsened by specific anticancer treatment, like alkylating agents and angiogenesis inhibitors, frequently resulting into vessels' thromboembolism. 21Cisplatin, for example, induces platelet activation and aggregation interfering with monocytes pro-coagulant activity and elevating von-Willebrand factor levels. 22inical manifestations for chemotherapeutic agents are reported in Table 1.

Cardiotoxicitiy in immunotherapy
In the last decades, immunotherapy has become of common use in the treatment of various diseases, such as non-small cell lung cancer, renal cell carcinoma, and both Hodgkin and non-Hodgkin lymphoma.Checkpoint inhibitor immunotherapy (also known as immune checkpoint inhibitors [ICI]) is immunomodulatory antibodies that are used to enhance the immune system.These agents have substantially improved the prognosis for patients with advanced malignancy.Despite clinical benefit, ICI are associated with a broad spectrum of side effects that are caused mainly by their activity on the immune system: these side effects are known as immune-related adverse events (IrAEs) with various manifestations including cardiotoxicity in up to 1% of patients. 23s manifestation typically includes hypotension, arrhythmia, and left ventricular dysfunction, typically in the setting of cytokine release syndrome.
Of significant interest for the role of advanced imaging is the occurrence of acute ICI induced myocarditis, whose incidence is documented around 0.04-1.14%and which has been associated with a worsening of mortality. 24,25Clinical features are extremely variable, in terms of disease onset and severity of manifestations, ranging from fatal myocarditis to transient myocardial edema.Median interval time from first treatment to disease presentation is typically 1-2 months, but cases of delayed onset have been reported up to one year. 26e underlying pathophysiology for ICI-associated myocarditis is not yet fully understood.
One possible mechanism is that T cells could target an antigen shared by both the tumor and the heart.Preclinical studies in mouse models have demonstrated that PD-1 protects the heart against T-cell-mediated inflammation and that PD-1-deficient mice develop myocarditis.Similarly, CTLA-4-deficient mice also developed autoimmune myocarditis with infiltration of CD4+ and CD8+ T lymphocytes in the myocardium.Deletion of the CTLA-4 and PD-1 axis led to autoimmune myocarditis, which suggests that PD-1/PDL1 and CTLA-4 play important roles in limiting T-cell-mediated autoimmune myocarditis.
Other mechanisms underlying ICI-mediated cardiotoxicity include pericardial inflammation by ICI-stimulated cytotoxic T-cells and myocardial ischemia.Indeed, ICI-associated inflammation may act on atherosclerotic coronary plaques and trigger fibrous cap rupture, leading to acute myocardial infarction.A second possible underlying mechanism of ICI-associated acute myocardial ischemia is coronary spasm causing ST elevation secondary to PD-1 inhibitor (pembrolizumab) treatment.The exact mechanism of coronary spasm remains unclear but may be related to systemic inflammatory response syndrome.A third explanation for ICI-related acute MI is the direct activation of T-cell-mediated coronary vasculitis in the absence of atherosclerosis.An indirect effect of ICIs on the coronary vasculature via a sudden release of large amounts of catecholamine from the adrenal glands or postganglionic sympathetic nerves in the heart, could result in catecholamine-mediated myocardial stunning (Tako-tsubo syndrome). 27most all cardiovascular adverse reactions, especially myocarditis, are firstly clinically suspected with cardiac enzymes and ECG alteration, but most of the evidence suggest CV imaging is requested to perform an accurate diagnosis.For this purpose, trans-thoracic echocardiography (TTE) and CMR are interchangeably indicated by 2022 ESC guidelines, but a specific and exclusive role of CMR could be postulated on the basis of modified Lake Louise Criteria accuracy. 28

IMAGING STATE OF THE ART Insight into ESC 2022 international guidelines
First guidelines in cardioncology were released by ESC on August 2022, 7 , aiming at giving all the healthcare professionals the instruments to take care of oncologic patients before, during and after cancer treatment as far as the cardiovascular system is concerned.They represent a consensus on definition, diagnosis, treatment, and prevention of CTR-CVT.Guidelines include clear indications regarding the role and the appropriate use of different imaging modalities in various clinical scenarios, namely, cardiovascular toxicity risk stratification before anticancer therapy and cardiovascular surveillance during treatment (Figure 1) .
Advanced cardiovascular imaging can be used to identify patients with sub-clinical cardiovascular diseases, directly influencing therapeutic decisions and representing a time zero reference for changes during treatment. 29,30ESC guidelines confer a primary role to TTE in the baseline evaluation of heart function and structure prior to chemotherapy, 31 while CMR role is limited to the evaluation of LVEF in patients with poor acoustic window.
Moreover, whenever TTE is misleading in identifying specific cardiovascular disease, like hypertrophic cardiomyopathy, CMR has to be considered for further risk assessment.
CCTA and/or CMR are also suggested to identify subclinical coronary artery disease (CAD) by means of coronary calcium score quantification and to detect intracardiac masses. 32Patients with symptomatic CAD should be tested with functional imaging for myocardial ischemia, like stress-CMR, while in patients with low-intermediate risk of CAD, CCTA represents the standard test to rule out the pathology. 33rdiac imaging also exerts a relevant role in decision-making during anti-cancer therapy. 34Accurate imaging techniques are requested for this aim, like 3D echocardiography or CMR. 35hoice of favourite imaging technique depends on the local availability and expertise; no strict indication favors TTE over CMR at this point but the same imaging modality is recommended over the entire follow-up to allow a precise comparison. 36TTE is still recommended for left ventricular function and GLS assessment to detect cardiac dysfunction, 37  of poor image quality or non-diagnostic TTE, CMR has to be considered 38 (Figure 2).

but in case
A specific indication for CMR exists as far as cardiovascular surveillance for multiple myeloma (MM) targeted therapy is concerned.Proteasome inhibitors (PI) -bortezomib, carfilzomib, and ixazomib -have become a mainstay for MM treatment. 391][42][43] Among them, HF with preserved ejection fraction is frequently associated with cardiac amyloidosis in MM but also to PI therapy; in this setting, a baseline CMR before treatment initiation followed by TTE every three cycles of PI is the commonly accepted surveillance protocol. 7rrent imaging role in clinical practice CCTA CCTA is a widely available imaging technique for the evaluation of coronary anatomy and pathology, which can be exploited in the setting of secondary prevention, as far as CAD rule-out is concerned.
Pre-existing CAD has been demonstrated to contribute to an increased risk of cardiovascular toxicity in patients undergoing anti-cancer treatment. 44Despite this knowledge, while clear recommendation exists to rule out CAD in case of first evidence of HF with reduced ejection fraction, no guidelines recommend a pre-treatment evaluation of CAD.Due to its high sensitivity in excluding CAD, CCTA is now widely used to exclude coronary stenosis in patients with exposure to cardiotoxic anticancer treatment and newly developed reduced LVEF. 45Non-contrast CT provides information about calcium burden within the coronary arteries as a reliable predictor of cardiovascular risk 46 ; it can be used to drive cardio-protective therapy before and during cytotoxic anticancer treatment like anthracyclines as proposed by the society of Cardiovascular Computed Tomography and the Society of Thoracic Radiology. 47 example of CAD rule-out by CCTA is shown in Figure 2.

CCTA limitations
As already stated, CCTA value in Cardioncology field is nowadays confined to CAD rule-out in case of reduced LVEF, playing a limited role in all the other possible clinical scenarios, according to ESC 2022 guidelines.( 7 No strong evidences exist about CCTA role in cardiac function assessment and tissue characterization, where CMR is still superior.As far as tissue characterization is concerned, which is the main early markers of cardiotoxicity, future CCTA technology, like Photon Counting CT, may lead to CCTA as a competitive imaging modality in CTR-CVT early recognition and prevention. 48Radiation exposure issues still represent a major limitation to CCTA use, although new multidetector machine already maximally reduce dose. 49

CMR -Functional evaluation and tissue characterization
Due to its high spatial and temporal resolution, CMR is a highly accurate modality to measure LVEF without any geometrical assumption.According to the American Society of Echocardiography, CTR-CVT occurs whenever LVEF decreases below normal values (53%) or more than 10% without other recognized causes. 50Mendelez et al 51 studied a cohort of more than 100 patients undergoing potentially cardio-toxic chemotherapy, mainly anthracyclines, and found out that 20% of the population developed a significant drop in LVEF.
The spectrum of tissue abnormalities characterizing myocardial toxic effects of chemotherapy ranges from tissue edema and necrosis to the development of focal replacement and interstitial fibrosis.CMR has also been recognized as a significant prognostic tool in various clinical settings, which can be easily extended to the field of cardio-oncology. 52e of multiparametric CMR imaging allows to comprehensively explore the various faces and phases of the process, by means of a combination of conventional sequences with more recently developed T1/T2 mapping imaging 36,53 (Figure 3).These include the quantification of ECV, as an indirect biomarker of tissue fibrosis and interstitial space expansion.
The best approach to evaluate myocardial toxic effects of chemotherapy is represented by 10 use of quantitative imaging techniques.Myocardial tissue mapping is, accordingly, the favourite approach for the quantification of special extent of tissue damage in diffuse disease or in the presence of subtle regional tissue changes, potentially missed with conventional sequences like late gadolinium enhancement (LGE) and T 2 -weighted STIR.
As a general rule, an increase in pre-contrast T1 is associated with myocardial edema, inflammation, and fibrosis, 54 while increase in T2 relaxation time is associated with acute myocardial edema, being a water-sensitive process. 55Generally speaking, cardiotoxic drug exposure has been associated with an increase in both native T1 and T2 relaxation time 56 (Figure 4).As an early acute hallmark of cardiotoxicity, many studies stress the pivotal role of increased T2 relaxation time. 57Anthracyclines and trastuzumab treatment in HER-2 positive breast cancer patients is associated with an elevated T2 mapping still at a subclinical stage of cardiotoxicity without any LVEF decrease. 58Another evidence of early T2 changes as possible hallmark of subclinical cardiotoxicity comes from Lustberg and colleagues, who demonstrated that patients with breast cancer treated with anthracyclines showed no LVEF changes after the first chemotherapy cycle associated with a progressive significant increase in T2 relaxation time over time. 59A huge effort has been done to understand and describe temporal evolution of tissue characterization in patients undergoing potentially cardiotoxic chemotherapy.Haslbauer et al 60 observed early cardiotoxic changes in the form of native T1 and T2 progressive increase during the first month of therapy, followed by a late normalization of T2 time with a permanently elevated non-contrast T1, as a sign of myocardial fibrosis.This work ended up in the definition of an algorithm defining cardiac changes during anticancer treatment and able to detect cardiotoxicity in 84% of cases: early involvement characterized by native T1 >/=2 SD and native T2 >/=2 SD and late involvement with native T1>/=2 SD and normal T2 with or without GLS 17%.More significantly, non-contrast tissue characterization outperformed functional evaluation and GLS in detecting early cardiotoxicity.
Tissue characterization also includes the use of qualitative/semiquantitative methods based on the administration of gadolinium contrast agents.The presence of early Gadolinium enhancement (EGE) and/or LGE is a hallmark of underlying pathologic processes like inflammation, edema, and myocardial fibrosis 61,62 also associated with cardiotoxic chemotherapy.More specifically, some studies found EGE to be predictive of LVEF decline after the first month of anthracyclines therapy, 63 LGE pattern associated with trastuzumab and anthracyclines-induced myocardial fibrosis has been described as non-ischemic-subepicardial contrast enhancement. 64,65ECV has the great advantage to detect diffuse myocardial fibrosis even when it is not correctly identified by LGE sequences, as confirmed by a good correlation of ECV values with histological specimens. 66ECV increase in the acute setting may be caused by inflammation and interstitial edema 53 and persistently high ECV values in the long term is reasonable due to edema turning into interstitial fibrosis. 67

CMR limitations
Major CMR limitations derive from its costs and exam tolerability by patients, for which reason TTE still represents the first imaging modality of choice in Cardioncology according to ESC 2022 guidelines. 7A limited tolerability of the exam does not allow to perform it in claustrophobic or patients unable to maintain apnea.Despite all the possible application of CMR in function assessment, tissue characterization and strain evaluation, still limited robust evidences exist about their changes in Cardiotoxicity, to allow for accurate diagnosis and prevention of CTR-CVT.

Potential future imaging role CCTA -ECV quantification
Despite its exclusively approved role in CAD rule-out, literature evidence suggests possible CCTA use for left ventricular function evaluation, cardiac perfusion studies, and tissue characterization.
Multiple studies demonstrated extracellular volume (ECV) increase in patients treated with cardiotoxic chemotherapy compared to matched control population, 68 and CMR quantification of late gadolinium enhancement was validated as a gold standard non-invasive method for the identification of focal myocardial fibrosis in the setting of ischemic and non-ischemic cardiomyopathy. 69In the last 20 years also CCTA has been used for the assessment of cardiac fibrosis by means of ECV quantification.The same imaging protocol as CMR has been adopted with a non-contrast low-dose ECG-gated CCTA acquisition followed by multiple imaging after contrast administration at a given time delay, usually around 10 min. 70A good correlation was found between CCTA findings and both CMR ECV and histological fibrosis 71,72 also in cancer patients undergoing anthracycline chemotherapy regimens. 73CCTA-based ECV calculation has also some drawbacks, namely, the increased radiation dose delivered to the patients along with difficulty in image registration and segmentation.These aspects seem to be possibly overcome by the introduction of dual source energy CCT: reduced radiation dose through the elimination of pre-contrast images, improvement of image quality by beam hardening artefact reduction, and less wrong image registration. 74,75R -Functional evaluation with strain From a functional perspective, subtle early tissue changes following chemotherapy may induce regional wall motion impairments that can be detected using advanced strain CMRbased imaging.This technique is based on the principle of tracking tissue voxel motion using standard steady-state free precession sequences.76 In the last years, left ventricular GLS merged as a more accurate index of left ventricular dysfunction, as demonstrated by the SUCCOR (Strain sUrveillance of Chemotherapy for improving Cardiovascular Outcomes) international multicenter prospective randomized controlled trial.Echocardiographic GLS-guided cardioprotective therapy better prevents chemotherapy-induced cardiotoxicity in comparison with LVEF in a high-risk population receiving cardiotoxic chemotherapy.77 CMR studies have proposed myocardial global longitudinal circumferential and radial strain to describe LV dysfunction, also in patients who have undergone anthracyclines and trastuzumab therapy.78,79 A prospective study conducted by Drafts et al 77 demonstrated an early subclinical deterioration in global circumferential strain (GCS) in patients receiving lowmoderate dose of anthracyclines along with subclinical decline of LVEF, proving GCS as an early predictor of cardiotoxicity.An example of the utility of CMR longitudinal circumferential and radial strain as an early marker of cardio-toxicity is shown in Figure 5. CMR can play a central role in early stages, when normal LVEF does not exclude CTR-CVT, and deformation parameters, like GLS, can identify early systolic impairment with good accuracy.80,81 Their evaluation is recommended in all patients screened before cardiotoxic cancer treatment initiation to stratify CTR-CVT risk and to identify significant changes during treatment.82 Among the different values of CMR strain, GLS and GCS are the most used because of less technical limitations with respect to global radial strain (GRS).83 In the specific case of anthracyclines, decline in LVEF and deterioration of strain (GLS, GCS, GRS) values has been postulated to be associated with an atrophic remodeling of myocardium induced by DNA oxidative damage.[84][85][86] Coherently, several studies have also demonstrated a significant decrease in left ventricular mass after anthracycline therapy. 87 Souza et al 88 introduced a new method of measuring cardiomyocytes size with CMR, the intracellular water lifetime.It demonstrated a decrease in left ventricular mass due to cardiomyocytes atrophy in females treated with anthracyclines for breast cancer.Another study found an association between left ventricular mass decline, increased risk of cardiac events and HF symptoms more than LVEF decline.89 CMR and the paradigm of ICI-related myocarditis Among all possible myocardial inflammation, ICI-related myocarditis represents a specific pathological entity from a clinical, radiological, and histopathological point of view.Differently from non-ICI myocarditis, less than 50% of cases present with a decreased ventricular function and relevant LGE.
Most of patients developing ICI myocarditis show atypical patterns of LGE, without any association with pathology prognosis, meaning LGE approach is necessary but not sufficient for their evaluation. 90antitative parametric T1 and T2 mapping, as well ECV, seem to represent a real instrument to avoid underdiagnoses and overcome this inconsistency, in such a way to allow for a proper and prompt diagnosis of a pathology which brings a relevant mortality into the general population. 91cent studies, like the one of Paaladinesh et al, 92 demonstrate a better correlation between T1 and T2 mapping and both clinical and histological ICI-induced myocarditis characteristics.T1 mapping alterations are significantly correlated with symptom severity as well as to the histological specimen; even better and more significantly than T2 mapping, T1 mapping alteration seems to be correlated with the incidence of major cardiovascular adverse events.
An example of ICI-induced myocarditis is shown in Figure 6.
This opens to the possibility of designing specific CMR protocols, centered on quantitative parametric mapping, with a diagnostic and prognostic role from the pre-subclinical stages to the full-blown pathology.

SUGGESTED WORKFLOW FOR CTR-CVT
Despite the recently published ESC guidelines, on the basis of an accurate review of the new risk assessment tools from Cardioncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardioncology Society, 93 we propose a novel baseline risk assessment flowchart for patient's candidate to potential cardiotoxic therapy, according to our Institution's clinical routine (Figure 7).
A baseline Calcium Score quantification on a non-contrast ECGgated chest CT performed during the cancer staging phase is strongly suggested according to the strong evidence correlation between coronary calcification and increased risk for a major adverse cardiac event. 94

FUTURE PERSPECTIVES AND PROGNOSTIC IMPLICATIONS
Regardless of these solid and consistent scientific bases, current CMR role is apparently limited to patients with poor acoustic TTE window, hypertrophic cardiomyopathy, and PI-induced MM, but its potential goes far beyond these applications.
While TTE is still recognized as the favourite imaging technique for baseline risk stratification, 7 CMR should be considered as a first-line imaging at least in patients at high/very high risk to develop CTR-CVT, in order to be able to precisely estimate ventricular volumes and function but also to perform tissue characterization and identify subclinical changes by means of mapping, LGE sequences and ECV evaluation.Whenever CMR results normal, patients may be followed-up clinically and according to the standard guideline; in the case of any pathological abnormalities, following investigations should be performed with CMR for the sake of reproducibility and precision.
ESC 2022 7 guidelines opened a new potential window for CMR application, but the pathway is still ongoing.
CCTA use in this setting still remains limited to CAD exclusion in low-intermediate risk patients 95 and all other possible applications for functional evaluation, GLS, LGE, and ECV quantification are not even mentioned for its poor availability and standardization.
The main potential strength of the introduction of CCTA in cardiovascular toxicity risk assessment and evaluation during therapy is that oncologic patients routinely undergo computed tomography exams for cancer staging, monitoring, and follow-up.This would mean maximizing the usefulness of an exam which cannot be bypassed in oncologic patients and adapting it to a double use: the purely oncologic staging and follow-up but also the possible complete cardiac evaluation in specific subsets of the population at risk of CTR-CVT.
Application of advanced cardiac imaging in oncology is an open field for research. 96More evidences are needed about the possible clinical role of the above-mentioned imaging findings in guiding multifactorial therapeutic pathways and decision.

FUNDING
Open access funding provided by BIBLIOSAN.

Figure 1 .
Figure 1.A table summarizing the main indications to CMR and CCTA according to ESC 2022 cardioncology guidelines.

Figure 2 .
Figure 2. 56-year-old female affected by diffuse large B cell lymphoma, treated with ipilimumab-nivolumab, presenting 50 days after treatment with a suspected myocarditis.She underwent CMR showing a focally increased T2 relaxation time in left anterior descending artery territory (a,b) with no evidence of LGE (no myocardial damage) (c).CCTA was performed to rule out CAD, showing a severe stenosis of left main coronary artery (e, red arrow), confirmed at invasive coronary angiography (f, red arrow).CCTA also shows large partially calcified anterior mediastinal lymphoadenopathy as a hallmark of previous radiotherapy (d, red arrow).

Figure 3 .
Figure 3. 48-year-old female affected by breast carcinoma studied with CMR at baseline and 3 months after anthracycline therapy.4 and 2 chamber functional evaluation (a,b before therapy and e,f after therapy) show a biventricular function drop and dilation correlated with a change in parametric mapping: c and d, respectively, show normal T1 and T2 parametric values (981 and 47 msec) and g,h chemotherapy induced increase in both T1 and T2 values (1086 and 57 msec).

Figure 4 .
Figure 4. 78-year-old female diagnosed with infiltrative breast carcinoma undergoing neoadjuvant chemotehrapy with anthracyclines who underwent CMR after TTE finding of increased trabeculation of the left ventricle.No morphological anomalies were found: LVEF was normal according to age reference values, as you can appreciate from 2 and 4 chamber view in the first row, but strain values were at lower limit of the normal range, as shown in the lower row images.

Figure 5 .
Figure 5. 38-year-old female affected by triple negative breast cancer during adjuvant chemotherapy with anthracyclines developing subjective dyspnea.CMR tissue characterization study shows increased native T1 (1040 ms) (a) and ECV (29%) (image b).No edema is found in T2 mapping (c) and inversion recovery sequences (d).

Figure 6 .
Figure 6.A 35-year-old male affected by metastatic melanoma under treatment with Ipilimumab developing chest discomfort and dyspnea after two weeks of treatment.No relevant ECG changes but increased high-sensitive Troponin was detected.Contrastenhanced CMR was performed showing increased T2 relaxation time (54.8 msec) in mid anterolateral LV wall (white arrow, (a), consensual increase in T1 relaxation time (1047 msec) (white arrow, (b) and atypical pattern of confluent almost transmural LGE (white arrow, (c), diagnostic for ICI-induced myocarditis.

Figure 7 .
Figure 7. Newly proposed indications to perform advanced cardiac imaging for baseline assessment before potentially cardiotoxic anticancer therapy.

Table 1 .
A table representing the main CRT-CVT clinical manifestations associated with the most common causative anticancer treatment 4 of 14 birpublications.org/bjr