Arterial inflammation on [18F]FDG PET/CT in melanoma patients treated with and without immune checkpoint inhibitors: CHECK-FLAME I.

BACKGROUND AND AIMS: Immune checkpoint inhibitors (ICIs) revolutionized cancer treatment. However, ICIs may increase the immune response to non-tumor cells, possibly resulting in increased arterial inflammation, raising the risk of atherosclerotic events. Nevertheless, malignancies may induce a pro-inflammatory state and the association between ICIs and arterial inflammation remains to be clarified. This study aims to assess differences in increase in arterial inflammation between patients with advanced melanoma treated with ICIs compared to a control group without ICIs. METHODS: Patients with advanced melanoma who underwent [18F]FDG PET/CT scans at baseline, 6 months (T1) and 18 months (T2) were included in this retrospective observational study. Arterial inflammation was evaluated in eight segments by calculating the target-to-background ratio (TBR). The primary study outcome was the difference in increase in mean TBRmax between patients treated with and without ICIs. RESULTS: We included 132 patients of whom 72.7 % were treated with ICIs. After exclusion for the use of anti-inflammatory medication, patients treated with ICIs showed a significant increase in mean TBRmax between baseline and T1 from 1.29 ± 0.12 to 1.33 ± 0.13 (p = 0.017), while in the control group, no change in mean TBRmax (1.30 ± 0.12 to 1.28 ± 0.10, p = 0.22) was observed (p = 0.027). During longer follow-up, mean TBRmax remained stable in both groups. Arterial inflammation increased significantly after ICI therapy in patients without active inflammation (p < 0.001) and in patients without calcifications (p = 0.013). CONCLUSIONS: A significant increase in arterial inflammation as measured on [18F]FDG PET/CT was observed in patients with advanced melanoma treated with ICIs only in the first six months after initiation of therapy, whereas no changes were observed in the control group. Moreover, arterial inflammation was mainly increased in patients without pre-existing inflammatory activity and with non-calcified lesions.

Computed tomography diagnosis of pulmonary infarction in acute pulmonary embolism.

INTRODUCTION: Pulmonary infarction is a common sequela of pulmonary embolism (PE) but lacks a diagnostic reference standard. CTPA in the setting of acute PE does not reliably differentiate infarction from other consolidations, such as reversible alveolar hemorrhage or atelectasis. We aimed to assess the diagnostic accuracy for recognizing pulmonary infarction on CT in the acute phase of PE, with follow-up CT as reference. MATERIALS AND METHODS: Initial and follow-up CT scans of 33 patients with acute PE were retrospectively assessed. Two radiologists independently evaluated the presence and size of suspected pulmonary infarction on the initial CT. Confirmation of infarction was established by detection of residual densities on follow-up CT. Sensitivity, specificity and interobserver variability were calculated. RESULTS: In total, 60 presumed infarctions were found in 32 patients, of which 34 infarctions in 21 patients could be confirmed at follow-up. On patient-level, observers' sensitivity/specificity were 91 %/9 %, and 73 %/46 %, respectively, with interobserver agreement by Kappa's coefficient of 0.17. Confirmed infarctions were usually larger than false positive lesions (median approximate volume of 6.6 mL [IQR 0.84-21.3] vs. 1.3 mL [IQR 0.57-6.5], p = 0.040), but still small. An occluding thrombus in a supplying vessel was predictive for confirmed infarction (OR 11, 95%CI 2.1-55), but was not discriminative. CONCLUSIONS: Pulmonary infarction is a common finding in acute PE, and generally small. Radiological identification of infarction was challenging, with considerable interobserver variability. Complete obstruction of the supplying (sub)segmental pulmonary artery was found as the strongest predictor for pulmonary infarction but was not demonstrated to be discriminative.

Relation between Coronary Artery Calcium Score and Cardiovascular Events in Hodgkin Lymphoma Survivors: A Cross-Sectional Matched Cohort Study.

BACKGROUND: Thoracic radiotherapy is one of the corner stones of HL treatment, but it is associated with increased risk of cardiovascular events. As HL is often diagnosed at a young age, long-term follow-up including screening for coronary artery disease (CAD) is recommended. OBJECTIVES: This study aims to evaluate the presence of coronary artery calcium score (CACS) in relation to cardiovascular events in HL patients treated with thoracic radiotherapy compared to a non-cancer control group. METHODS: Consecutive HL patients who underwent evaluation for asymptomatic CAD with coronary computed tomography angiography > 10 years after thoracic irradiation were included. The study population consisted of 97 HL patients matched to 97 non-cancer patients on gender, age, cardiovascular risk factors, and statin use. RESULTS: Mean age during CT scan in the HL population was 45.5 ± 9.9 and in the non-cancer population 45.5 ± 10.3 years. CACS was elevated (defined as >0) in 49 (50.5%) HL patients and 30 (30.9%) control patients. HL survivors had an odds ratio of 2.28 [95% CI: 1.22-4.28] for having a CACS > 0 compared to the matched population (p = 0.006). Prevalence of CACS > 90th percentile differed significantly: 17.1% in HL survivors vs. 4.6% in the matched population (p = 0.009). Non-obstructive coronary artery stenosis was more prevalent in the HL population than in the control population (45.7% vs. 28.4%, respectively, p = 0.01). During follow-up of 8.5 [5.3; 9.9] years, nine HL patients experienced an event including two patients with a CACS of zero. No events occurred in the control population. CONCLUSION: In a matched study population, HL survivors have a higher prevalence of a CACS > 0 and an increased risk of cardiovascular events after thoracic irradiation compared to a matched non-cancer control group.

A percutaneous treatment strategy of an adult patient with a bicuspid aortic valve, coarctation of the aorta, and an exceptionally large aneurysm of a collateral artery: Case report and literature overview.

Coarctation of the aorta (CoA) is a congenital heart defect that is associated with a bicuspid aortic valve (BAV), ascending aorta dilatation, intracerebral aneurysms, and premature atherosclerotic disease. The first presentation during late adulthood is rare and is frequently driven by late sequelae. Hypertrophic collateral arteries can develop aneurysms which are at risk for spontaneous rupture, however, treatment recommendations for these aneurysms are scarce. Here, we describe the clinical course and percutaneous treatment strategy of a patient with a late diagnosis of a pin-point CoA, a BAV with moderate regurgitation, and an exceptionally large aneurysm of a collateral artery. A 59-year-old woman was diagnosed with Streptococcus bovis endocarditis of a BAV with moderate aortic valve regurgitation and small vegetation (<5 mm) on the non-coronary cusp. Work-up revealed hypertension and adenocarcinoma in situ of the ascending colon, considered the bacteremia porte d'entrée, for which a curative hemicolectomy was performed. Echocardiography showed a narrowing of the aorta distal from the origin of the left subclavian artery with the antegrade diastolic flow with a pathognomonic "sawtooth" pattern and an estimated pressure gradient of >70 mmHg. Computed tomography angiography (CTA) showed a network of well-developed collateral arteries and a levoatriocardinal vein. One of the collateral arteries arising from the left subclavian artery revealed an exceptionally large aneurysmatic dilation (29 × 24 × 24 mm). The invasive assessment confirmed a hemodynamically significant CoA. Treatment involved balloon dilatation and placement of a covered stent at the site of the pin-point CoA and a percutaneous coronary intervention (PCI) of the stenosis in the left anterior descending artery. No residual gradient over the CoA was observed. Antihypertensive drugs could be discontinued, and CTA performed 4 months later showed regression and thrombosis of the numerous collaterals and, importantly, thrombosis of the large aneurysm. This case illustrates the late diagnosis of CoA with associated congenital heart defects and late sequelae including hypertension, BAV endocarditis, coronary artery disease, and aneurysm formation of the extensive collateral network. The patient underwent pharmacological and percutaneous treatment, ultimately resulting in the alleviation of the CoA, normalization of the blood pressure, reduction of collateral flow, and thrombosis of the large aneurysm of the collateral artery.

Endobronchial ultrasound for T4 staging in patients with resectable NSCLC.

BACKGROUND: In lung cancer patients, accurate assessment of mediastinal and vascular tumor invasion (stage T4) is crucial for optimal treatment allocation and to prevent unnecessary thoracotomies. We assessed the diagnostic accuracy of linear endobronchial ultrasound (EBUS) for T4-status in patients with centrally located lung cancer. METHODS: This is a retrospective study among consecutive patients who underwent EBUS for diagnosis and staging of lung cancer in four hospitals in The Netherlands (Amsterdam, Leiden), Italy (Bologna) and Poland (Zakopane) between 04-2012 and 04-2019. Patients were included if the primary tumor was detected by EBUS and subsequent surgical-pathological staging was performed, which served as the reference standard. T4-status was extracted from EBUS and pathology reports. Chest CT's were re-reviewed for T4-status. RESULTS: 104 patients with lung cancer in whom EBUS detected the primary tumour, and who underwent subsequent surgical-pathological staging were included. 36 patients (35 %) had T4-status, based on vascular (n = 17), mediastinal (n = 15), both vascular and mediastinal (n = 3), or oesophageal invasion (n = 1). For EBUS, sensitivity, specificity, PPV and NPV for T4-status were (n = 104): 63.9 % (95 %CI 46.2-79.2 %), 92.6 % (83.7-97.6 %), 82.1 % (65.6-91.7 %), and 82.9 % (75.7-88.2 %), respectively. For chest CT (n = 72): 61.5 % (95 %CI 40.6-79.8 %), 37.0 % (23.2-52.5 %), 35.6 % (27.5-44.6 %), and 63.0 % (47.9-75.9 %), respectively. When combining CT and EBUS with concordant T4 status (n = 33): 90.9 % (95 %CI 58.7-99.8 %), 77.3 % (54.6-92.20 %), 66.7 % (47.5-81.6 %), and 94.4 % (721-99.1%), respectively. CONCLUSION: Both EBUS and CT alone are inaccurate for assessing T4-status as standalone test. However, combining a negative EBUS with a negative CT may rule out T4-status with high certainty.

The Clinical Spectrum of Kommerell's Diverticulum in Adults with a Right-Sided Aortic Arch: A Case Series and Literature Overview.

BACKGROUND: Kommerell's diverticulum is a rare vascular anomaly characterized as an outpouch at the onset of an aberrant subclavian artery. In the variant of a right-sided aortic arch, the trachea and esophagus are enclosed dorsally by the arch. In the configuration of an aberrant left subclavian artery, a Kommerell's diverticulum and persisting ductus arteriosus or ductal ligament enclose the lateral side, forming a vascular ring which may result in (symptomatic) esophageal or tracheal compression. Spontaneous rupture of an aneurysmatic Kommerell's diverticulum has also been reported. Due to the rarity of this condition and underreporting in the literature, the clinical implications of a Kommerell's diverticulum are not well defined. CASE SUMMARY: We describe seven consecutive adult patients with a right-sided aortic arch and an aberrant course of the left subclavian artery (arteria lusoria), and a Kommerell's diverticulum, diagnosed in our tertiary hospital. One patient had severe symptoms related to the Kommerell's diverticulum and underwent surgical repair. In total, two of the patients experienced mild non-limiting dyspnea complaints and in four patients the Kommerell's diverticulum was incidentally documented on a computed tomography (CT) scan acquired for a different indication. The size of the Kommerell's diverticulum ranged from 19 × 21 mm to 30 × 29 mm. In the six patients that did not undergo surgery, a strategy of periodic follow-up with structural imaging was pursued. No significant growth of the Kommerell's diverticulum was observed and none of the patients experienced an acute aortic syndrome to date. DISCUSSION: Kommerell's diverticulum in the setting of a right-sided aortic arch with an aberrant left subclavian artery is frequently associated with tracheal and esophageal compression and this may result in a varying range of symptoms. Guidelines on management of Kommerell's diverticulum are currently lacking. This case series and literature overview suggests that serial follow-up is warranted in adult patients with a Kommerell's diverticulum with small dimensions and no symptoms, however, that surgical intervention should be considered when patients become symptomatic or when the diameter exceeds 30 mm in the absence of symptoms.

Deleting myeloid IL-10 receptor signalling attenuates atherosclerosis in LDLR-/- mice by altering intestinal cholesterol fluxes.

Inflammatory responses and cholesterol homeostasis are interconnected in atherogenesis. Interleukin (IL)-10 is an important anti-inflammatory cytokine, known to suppress atherosclerosis development. However, the specific cell types responsible for the atheroprotective effects of IL-10 remain to be defined and knowledge on the actions of IL-10 in cholesterol homeostasis is scarce. Here we investigated the functional involvement of myeloid IL-10-mediated atheroprotection. To do so, bone marrow from IL-10 receptor 1 (IL-10R1) wild-type and myeloid IL-10R1-deficient mice was transplanted to lethally irradiated female LDLR-/- mice. Hereafter, mice were given a high cholesterol diet for 10 weeks after which atherosclerosis development and cholesterol metabolism were investigated. In vitro, myeloid IL-10R1 deficiency resulted in a pro-inflammatory macrophage phenotype. However, in vivo significantly reduced lesion size and severity was observed. This phenotype was associated with lower myeloid cell accumulation and more apoptosis in the lesions. Additionally, a profound reduction in plasma and liver cholesterol was observed upon myeloid IL-10R1 deficiency, which was reflected in plaque lipid content. This decreased hypercholesterolaemia was associated with lowered very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels, likely as a response to decreased intestinal cholesterol absorption. In addition, IL-10R1 deficient mice demonstrated substantially higher faecal sterol loss caused by increased non-biliary cholesterol efflux. The induction of this process was linked to impaired ACAT2-mediated esterification of liver and plasma cholesterol. Overall, myeloid cells do not contribute to IL-10-mediated atheroprotection. In addition, this study demonstrates a novel connection between IL-10-mediated inflammation and cholesterol homeostasis in atherosclerosis. These findings make us reconsider IL-10 as a beneficial influence on atherosclerosis.

Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions.

Macrophages are key immune cells found in atherosclerotic plaques and critically shape atherosclerotic disease development. Targeting the functional repertoire of macrophages may hold novel approaches for future atherosclerosis management. Here, we describe a previously unrecognized role of the epigenomic enzyme Histone deacetylase 3 (Hdac3) in regulating the atherosclerotic phenotype of macrophages. Using conditional knockout mice, we found that myeloid Hdac3 deficiency promotes collagen deposition in atherosclerotic lesions and thus induces a stable plaque phenotype. Also, macrophages presented a switch to anti-inflammatory wound healing characteristics and showed improved lipid handling. The pro-fibrotic phenotype was directly linked to epigenetic regulation of the Tgfb1 locus upon Hdac3 deletion, driving smooth muscle cells to increased collagen production. Moreover, in humans, HDAC3 was the sole Hdac upregulated in ruptured atherosclerotic lesions, Hdac3 associated with inflammatory macrophages, and HDAC3 expression inversely correlated with pro-fibrotic TGFB1 expression. Collectively, we show that targeting the macrophage epigenome can improve atherosclerosis outcome and we identify Hdac3 as a potential novel therapeutic target in cardiovascular disease.

Reprogramming macrophages to an anti-inflammatory phenotype by helminth antigens reduces murine atherosclerosis.

Atherosclerosis is a lipid-driven inflammatory disease of the vessel wall, characterized by the chronic activation of macrophages. We investigated whether the helminth-derived antigens [soluble egg antigens (SEAs)] could modulate macrophage inflammatory responses and protect against atherosclerosis in mice. In bone marrow-derived macrophages, SEAs induce anti-inflammatory macrophages, typified by high levels of IL-10 and reduced secretion of proinflammatory mediators. In hyperlipidemic LDLR(-/-) mice, SEA treatment reduced plaque size by 44%, and plaques were less advanced compared with PBS-injected littermate controls. The atheroprotective effect of SEAs was found to be mainly independent of cholesterol lowering and T-lymphocyte responses but instead could be attributed to diminished myeloid cell activation. SEAs reduced circulating neutrophils and inflammatory Ly6C(high) monocytes, and macrophages showed high IL-10 production. In line with the observed systemic effects, atherosclerotic lesions of SEA-treated mice showed reduced intraplaque inflammation as inflammatory markers [TNF-α, monocyte chemotactic protein 1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and CD68], neutrophil content, and newly recruited macrophages were decreased. We show that SEA treatment protects against atherosclerosis development by dampening inflammatory responses. In the future, helminth-derived components may provide novel opportunities to treat chronic inflammatory diseases, as they diminish systemic inflammation and reduce the activation of immune cells.

Distribution of macrophage polarization markers in human atherosclerosis.

OBJECTIVE: Macrophages are decisive in the chronic inflammatory processes that drive atherogenesis. The purpose of this study was to explore the presence and spatial distribution of polarized macrophage populations in human atherosclerosis. METHODS & RESULTS: We used transcriptomics and immunohistochemistry to analyze macrophage subset dynamics in successive stages of atherogenesis. Developing lesions progressively accumulated both M1 and M2 cells, as was signified by the enhanced expression of associated markers at the transcriptional and protein level. Histologically, these markers were confined to overlapping, but spatially distinct CD68(+) areas of the intima. We subsequently quantified the presence of these markers in relation to morphological determinants of plaque stability. In line with their pro-inflammatory characteristics, M1 macrophages dominated the rupture-prone shoulder regions of the plaque over M2 polarized cells, while the fibrous caps of lesions showed no significant differences between subsets. In contrast, vascular adventitial tissue displayed a pronounced M2 activation profile. As expected, areas of intraplaque hemorrhage clearly associated with CD163 staining. Rather than being limited to complicated lesions, this M2 marker was also readily detectable in stable plaques. Finally, foamy macrophages displayed an ambiguous repertoire that incorporates individual M1 and M2 markers. CONCLUSION: M1 and M2 macrophage populations are present throughout atherogenesis. These subsets display disparity when it comes to their prevalence in morphological compartments of the vessel wall. Our current findings warrant continued investigation into the functional implications of polarized macrophage populations in human atherosclerosis.

Molecular pathways regulating macrophage polarization: implications for atherosclerosis.

Recent years have seen a tremendous development of our insight into the biology of atherosclerosis and its acute thrombotic manifestations. Inflammation now takes center stage among traditional risk factors as a decisive factor in cardiovascular risk. Consequently, its assessment and modulation have become key to clinical care and fundamental research alike. Plaque macrophages orchestrate many of the inflammatory processes that occur throughout atherogenesis. These cells are characteristically heterogeneous and adopt diverse activation states in response to micro-environmental triggers. In this review, macrophage-mediated inflammation in atherosclerosis sets the scene for a discussion of the gene regulatory mechanisms that facilitate and shape polarized macrophage phenotypes. When applicable, we consider these factors within the context of atherosclerosis and reflect on opportunities for future application.

Macrophage heterogeneity: relevance and functional implications in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease involving many cell types with a well-accepted key role for macrophages. A wide array of different properties and functional characteristics are attributed to macrophages present in the atherosclerotic plaque. As an increasing body of evidence strengthens the consensus that macrophages comprise a heterogeneous population, several co-existing subtypes with diverse, even opposing specialties have already been described in fields like parasitology, tumour biology and metabolic disorders. However, macrophage heterogeneity within atherosclerotic lesions has not been studied in detail yet. In this review we will introduce the characteristics of macrophage subsets in other pathologies and address the presence and possible roles of distinct macrophage subtypes in the rapidly evolving field of atherosclerosis. Finally, we make an effort to relate these subtypes to disease progression and explore a number of opportunities for novel diagnostic and therapeutic approaches.