Research Progress on the Pathogenesis of Aortic Aneurysm and Dissection in Metabolism.

Aortic aneurysm and dissection are complicated diseases having both high prevalence and mortality. It is usually diagnosed at advanced stages and posing diagnostic and therapeutic challenges due to the limitations of current detecting methods for aortic dissection used in clinics. Metabonomics demonstrated its great potential capability in the early diagnosis and personalized treatment of several diseases. Emerging evidence suggests that metabolic disorders including amino acid metabolism, glycometabolism, and lipid metabolism disturbance are involved in the pathogenesis of aortic aneurysm and dissection by affecting multiple functional aortic cells. The purpose of this review is to provide new insights into the metabolism alterations and their related regulatory mechanisms with a focus on recent advances and findings and provide a theoretical basis for the diagnosis, prevention, and drug development for aortic aneurysm and dissection.

Insights into elastic fiber fragmentation: Mechanisms and treatment of aortic aneurysm in Marfan syndrome.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutations in fibrillin 1 (FBN1) gene. These mutations result in defects in the skeletal, ocular, and cardiovascular systems. Aortic aneurysm is the leading cause of premature mortality in untreated MFS patients. Elastic fiber fragmentation in the aortic vessel wall is a hallmark of MFS-associated aortic aneurysms. FBN1 mutations result in FBN1 fragments that also contribute to elastic fiber fragmentation. Although recent research has advanced our understanding of MFS, the contribution of elastic fiber fragmentation to the pathogenesis of aneurysm formation remains poorly understood. This review provides a comprehensive overview of the molecular mechanisms of elastic fiber fragmentation and its role in the pathogenesis of aortic aneurysm progression. Increased comprehension of elastic fragmentation has significant clinical implications for developing targeted interventions to block aneurysm progression, which would benefit not only individuals with Marfan syndrome but also other patients with aneurysms. Moreover, this review highlights an overlooked connection between inhibiting aneurysm and the restoration of elastic fibers in the vessel wall with various aneurysm inhibitors, including drugs and chemicals. Investigating the underlying molecular mechanisms could uncover innovative therapeutic strategies to inhibit elastin fragmentation and prevent the progression of aneurysms.

Association of HIV infection with clinical features and outcomes of patients with aortic aneurysms.

Data on the characteristics and outcomes of hospitalized patients with aortic aneurysms (AA) and HIV remain scarce. This is a cohort study of hospitalized adult patients with a diagnosis of AA from 2013 to 2019 using the US National Inpatient Readmission Database. Patients with a diagnosis of HIV were identified. Our outcomes included trends in hospitalizations and comparison of clinical characteristics, complications, and mortality in patients with AA and HIV compared to those without HIV. Among 1,905,837 hospitalized patients with AA, 4416 (0.23%) were living with HIV. There was an overall age-adjusted increase in the rate of HIV among patients hospitalized with AA over the years (14-29 per 10,000 person-years; age-adjusted p-trend < 0.001). Patients with AA and HIV were younger than those without HIV (median age: 60 vs 76 years, p < 0.001) and were less likely to have a history of smoking, hypertension, dyslipidemia, diabetes mellitus, and obesity. Thoracic aortic aneurysms were more prevalent in those with HIV (37.5% vs 26.7%, p < 0.001). On multivariable logistic regression, HIV was not associated with increased risk of aortic rupture (OR: 0.79; 95% CI: 0.61-1.01, p = 0.06), acute aortic dissection (OR: 0.73; 95% CI: 0.51-1.06, p = 0.3), readmissions (OR: 1.04; 95% CI: 0.95-1.13, p = 0.4), or aortic repair (OR: 0.89; 95% CI: 0.79-1.00, p = 0.05). Hospitalized patients with AA and HIV had a lower crude mortality rate compared to those without HIV (OR: 0.75 (0.63-0.91), p = 0.003). Hospitalized patients with AA and HIV likely constitute a distinct group of patients with AA; they are younger, have fewer traditional cardiovascular risk factors, and a higher rate of thoracic aorta involvement. Differences in clinical features may account for the lower mortality rate observed in patients with AA and HIV compared to those without HIV.

Insights on aortic aneurysm and dissection: Role of the extracellular environment in vascular homeostasis.

Aortic aneurysm and dissection (AAD) is a life-threatening medical condition associated with high morbidity and mortality rates. Important mechanisms underlying AAD are the dysregulation of vascular homeostasis and adverse remodeling. Vascular homeostasis maintains normal physiological function. Various physical, chemical, biological, and other internal or external environmental changes dysregulate vascular homeostasis, leading to vascular degeneration and aggravated aortic injury. This process is dependent on the communication between homeostatic mechanisms and the extracellular environment, such as local inflammatory cytokines, vasoactive substances, and hemodynamics. In this article, we summarize recent reports by Chinese researchers who studied the pathogenic mechanisms of AAD mainly from the perspective of communication of the extracellular environment with vascular homeostasis and improving diagnostic methods and therapeutic options for patients with AAD. This review aims to provide a roadmap for AAD that encompasses its pathogenesis and clinical aspects. We hope to facilitate future studies on the development of effective treatments and preventive therapies, and thus improve patient outcomes.

Aortic Wall Inflammation in the Pathogenesis, Diagnosis and Treatment of Aortic Aneurysms.

The role of inflammation in the development of aortic aneurysms is emerging, along with the potential diagnostic and therapeutical potential of this correlation. Abdominal aorta aneurysms have a strong inflammatory substrate since atherosclerosis, which is undoubtedly linked to inflammation, is also a predisposing factor to their formation. Yet, data have emerged that the development of thoracic aorta aneurysms involves several inflammatory pathways, although they were previously referred to as a non-inflammatory disease. Since aortic aneurysms are mainly asymptomatic during their clinical course until their complications-which may be lethal-serum biomarkers for their early diagnosis are a necessity. Studies highlight that inflammation molecules may have a critical role in that direction. In addition, imaging techniques that trace aortic wall inflammation are developed in order to predict aneurysm growth rates and sites vulnerable of rupture. Several anti-inflammatory agents have been also studied in animal models and clinical trials for the treatment of aortic aneurysms. This review highlights the role of inflammation in pathogenesis, diagnosis and treatment of aortic aneurysms.

Investigations into the Potential of Using Open Source CFD to Analyze the Differences in Hemodynamic Parameters for Aortic Dissections (Healthy versus Stanford Type A and B).

BACKGROUND: The objective of this study was to develop a method to evaluate the effects of an aortic dissection on hemodynamic parameters by conducting a comparison with that of a healthy (nondissected) aorta. Open-source software will be implemented, no proprietary software/application will be used to ensure accessorily and repeatability, in all the data analysis and processing. Computed tomography (CT) images of aortic dissection are used for the model geometry segmentation. Boundary conditions from literature are implemented to computational fluid dynamics (CFD) to analyze the hemodynamic parameters. METHODS: A numerical simulation model was created by obtaining accurate 3-dimensional geometries of aortae from CT images. In this study, CT images of 8 cases of aortic dissection (Stanford type-A and type-B) and 3 cases of healthy aortae are used for the actual aorta model geometry segmentation. These models were exported into an open-source CFD software, OpenFOAM, where a simplified pulsating flow was simulated by controlling the flow pressure. Ten cycles of the pulsatile flow (0.50 sec/cycle) conditions, totaling 5 sec, were calculated. RESULTS: The pressure distribution, wall shear stress (WSS) and flow velocity streamlines within the aorta and the false lumen were calculated and visualized. It was found that the flow velocity and WSS had a high correlation in high WSS areas of the intermittent layer between the true and false lumen. Most of the Stanford type-A dissections in the study showed high WSS, over 38 Pa, at the systole phase. This indicates that the arterial walls in type-A dissections are more likely to be damaged with pulsatile flow. CONCLUSIONS: Using CFD to estimate localized high WSS areas may help in deciding to treat a type-A or B dissection with a stent graft to prevent a potential rupture.

Alternative therapeutic strategy for existing aortic aneurysms using mesenchymal stem cell-derived exosomes.

BACKGROUND: Several studies demonstrated the therapeutic potential of mesenchymal stem cell-derived exosomes (MSC-exs) based on their anti-inflammatory properties. The objective was to determine the therapeutic effects of MSC-exs on aortic aneurysms (AAs) caused by atherosclerosis. RESEARCH DESIGN AND METHODS: Apolipoprotein E knockout mice with AAs induced by angiotensin II were injected with MSC-exs or saline as a control. The change in the diameter of the aorta was measured. The expression of AA-related proteins and the histology of the aortic wall were investigated at 1 week after treatment. MicroRNA and protein profiles of MSC-exs were examined. RESULTS: MSC-exs significantly attenuated AA progression (2.04 ± 0.20 mm in the saline group and 1.34 ± 0.13 mm in the MSC-ex group, P = 0.004). In the MSC-ex group, the expression of IL-1ß, TNF-α and MCP-1 decreased, and expression of IGF-1 and TIMP-2 increased. MSC-ex induced the M2 phenotype in macrophages and suppressed the destruction of the elastic lamellae in the aortic wall. MSC-exs contained high levels of 10 microRNAs that inhibit AA formation and 13 proteins that inhibit inflammation and promote extracellular matrix synthesis. CONCLUSIONS: MSC-ex might be a novel alternative therapeutic tool for treatment of existing AAs.

Association of Mental Health Disorders and Aortic Dissection.

INTRODUCTION: Mental health disorders (MHD), including substance abuse, have been associated with aortic dissection (AD). Aneurysmal degeneration in the residual untreated aorta after both open and endovascular treatment is not uncommon in AD. Thus, diligent long-term follow-up is necessary and MHD may play a role in treatment plan and surveillance. The impact of MHD on management, outcomes and follow-up after AD treatment is unknown and here we sought to evaluate these associations. METHODS: A retrospective review was performed on all patients diagnosed with Stanford Type A and B dissections from 2008 to 2018 at a tertiary referral center. MHD was defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). Patient demographics, procedural characteristics, and outcomes were analyzed. RESULTS: A total of 649 non-traumatic aortic dissections were identified in the study timeframe. The cohort consisted of 51% Type A (n = 334) dissection and 49% Type B (n = 315) dissection. Mental health disorders were present in 49.3% of the cohort. Notably, the timing of MHD diagnosis relative to development of AD is unknown in the majority of patients. Within the Type A population, a MHD was present in 50.6% (N = 162) of patients, of which the most common indication for MHD was the presence of antidepressant or antipsychotic medication (28.6%). In patients with Type A dissections, the presence of a MHD did not significantly affect the rate of index hospitalization intervention (68%) or long-term mortality (12.5% in patients with a MHD). Within the Type B population, a MHD was present in 49.4% (n = 158) of patients, of which the most common indication for MHD was the presence of antidepressant or antipsychotic medication (30.5%). In patients with Type B dissections, the presence of a MHD did not significantly affect the rate of index hospitalization intervention (50.3% in patients with a MHD) or long-term mortality (10.1% in patients with a MHD). The overall participation in follow-up care was not significantly decreased based on the presence of a MHD compared to those without a MHD (1.66 ± 2.16 years vs. 1.68 ± 2.20 years, P = 0.93). CONCLUSION: MHD is more prevalent in AD patients than in the general population, but demonstrating a causal relationship between MHD and development/progression of AD is challenging. Despite a high prevalence of MHD in AD patients, in-hospital mortality and follow-up compliance was similar to non-MHD patients.

Differences in the clinical presentation, management, and in-hospital outcomes of acute aortic dissection in patients with and without end-stage renal disease.

BACKGROUND: Few studies have evaluated the clinical presentation, management, and outcomes of patients with end-stage renal disease (ESRD) presenting with acute aortic dissection (AAD) in real-world clinical practice. Thus, this study investigated the clinical characteristics, management, and outcomes of AAD patients with ESRD. METHODS: A total of 217 patients were included. We evaluated the differences in the clinical features, management, and in-hospital outcomes of patients with and without a history of ESRD presenting with AAD. RESULTS: A history of ESRD was present in 71 of 217 patients. Patients with ESRD had atypical clinical manifestations (p < 0.001) and were more likely to be managed medically compared with patients without ESRD (p = 0.002). Hypertension and type B aortic dissection were significantly more common among patients with ESRD. Moreover, patients with ESRD had lower leucocyte and platelet counts than patients without ESRD in laboratory findings (p < 0.001). However, hospitalization days and in-hospital mortality were similar between the two groups (p > 0.05). Multivariate analysis identified Type A aortic dissection as an independent predictor of in-hospital mortality among patients without ESRD (OR, 13.68; 95% CI, 1.92 to 98.90; P = 0.006). CONCLUSIONS: This study highlights differences in the clinical characteristics, management, and outcomes of AAD patients with ESRD. These patients usually have atypical symptoms and more comorbid conditions and are managed more conservatively. However, these patients have no in-hospital survival disadvantage over those without ESRD. Further studies are needed to better understand and optimize care for patients with ESRD presenting with AAD.

Aortic aneurysms and dissections: Unmet needs from physicians and engineers perspectives.

The treatment of aortic disease is complex, requiring cardiothoracic and vascular surgeons to make pre-, post- and intraoperative decisions directly influencing patient survival and well-being. Despite tremendous advancement in vascular surgery and endovascular techniques in the last two decades, along with the abundance of research in the field, many unmet needs and unanswered questions remain. Tight collaboration between engineers and physicians is a keystone in translating new tools, techniques, and devices into practice. Here, we have gathered our perspective, as physicians and engineers, in several pressing issues associated with the diagnosis and treatment of aortic aneurysms and dissection, referring to the current knowledge and practice, signifying unmet needs as well as future directions.

Culture-Negative Mycotic Aortic Aneurysms Probably Have a Less Severe Clinical Nature Than Culture-Positive Counterparts.

BACKGROUND: Mycotic aortic aneurysm constitutes a potentially devastating disease that necessitates prompt suspicion and diagnosis. There is no exact consensus for treatment, but removal of infected tissues and prolonged use of antimicrobials based on the identified causative microorganisms seem widely acceptable and have been similarly practiced worldwide. However, some patients still show no identified microorganisms. In this study, we sought to determine whether there are any clinical significance or differences of note in culture-negative mycotic aortic aneurysms. METHODS: Between October 2003 and August 2018, 71 patients were identified as treated for mycotic aortic aneurysms at a single tertiary institution. Review of medical records and imaging studies were completed to collect the following information: demographics, previous medical/surgical history regarding potential infection sources, laboratory and radiologic findings, clinical presentations, treatment method, and morbidity and mortality rates. For analysis, patients were categorized into two groups: the blood and/or tissue culture-positive (CP) group and the blood and/or tissue culture-negative (CN) group. The latter was further divided as CN with identified microorganism by molecular biologic methods [CN(+)] and CN with no identified microorganism [CN(-)]. RESULTS: More patients in the CP group were symptomatic than were in the CN(+) group (100% vs. 80%; P = 0.034). However, identification of causative microorganisms did not result in a difference in symptom status upon comparing the [CP + CN(+)] and [CN(-)] groups. Inflammatory markers were the most elevated in the CP group and least elevated in the CN(-) group. The aneurysm growth rate seemed slower in the CN(-) group than in the CN(+) and CP groups (1.3 vs. 3.4 vs. 9 mm/month respectively). Aneurysm rupture at initial presentation was more prevalent in the CP group (33.3%). 18F-Fluorodeoxyglucose-positron emission tomography showed increased uptake regardless of whether or not the microorganisms were identified. Early mortality and disease-specific mortality rates during the follow-up period were higher in the CP group but without statistical significance. CONCLUSIONS: Compared with the CP group, the CN groups appeared clinically less severe, and also exhibited a relatively less devastating course as exhibited by the slower aneurysm expansion rate and smaller number of ruptured aneurysms at the initial presentation.

In-hospital outcomes and long-term survival of women of childbearing age with aortic dissection.

OBJECTIVE: In the present study, we defined the outcomes and effects of pregnancy in a cohort of women of childbearing age with acute aortic dissection (AAD). METHODS: We reviewed our database of AAD to identify all eligible female patients. Women aged <45 years were included. Data on pregnancy timing with respect to the occurrence of dissection, the demographic data, dissection extent, dissection treatment, dissection-related outcomes, overall maternal and fetal mortality, and genetic testing results were analyzed. RESULTS: A total of 62 women aged <45 years had presented to us with AAD from 1999 to 2017. Of the 62 women, 37 (60%) had had a history of pregnancy at AAD. Of these 37 patients, 10 (27%) had had a peripartum aortic dissection, defined as dissection during pregnancy or within 12 months postpartum. Of the 10 AADs, 5 were type A and 5 were type B. Three patients had presented with AAD during pregnancy (one in the second and two in the third trimester). Five patients (50%) had developed AAD in the immediate postpartum period (within 3 months) and two (20%) in the late postpartum period. For the immediate postpartum AADs (<3 months), four of the five patients delivered via cesarean section. Of these 10 peripartum AADs, 3 (30%) had occurred in patients with known Marfan syndrome. In-hospital mortality for those with peripartum AAD was 10% (1 of 10). Fetal mortality was 20% (2 of 10). CONCLUSIONS: The frequency of aortic dissection in women of childbearing age at our institution was low. However, pregnancy might increase the risk of those young women genetically predisposed to dissection events. From these data, this risk appears to be greatest in the immediate postpartum period, even for those who undergo cesarean section. Close clinical and radiographic surveillance is required for all women with suspected aortopathy, especially in the third trimester and early postpartum period.

Managing Vascular Surgery Emergencies and Referrals During the COVID-19 Pandemic at a Tertiary Centre in Oman.

OBJECTIVES: This study aimed to discuss the different challenges faced while managing emergency vascular surgery cases during the COVID-19 pandemic and how these challenges were overcome. METHODS: This study details 14 emergency cases that were managed during a period of one month from mid-March to mid-April at Sultan Qaboos University Hospital, Muscat, Oman. The cases included acute limb ischaemia, critical limb ischaemia, type B dissection of the thoracic aorta, thoraco-abdominal aneurysm, critical internal carotid artery stenosis, trauma, infected arteriovenous forearm loop graft and thrombosed arteriovenous fistulas. RESULTS: Only one patient was confirmed to have COVID-19. Five were negative for COVID-19 while the remaining eight were not tested. Various strategies on how the vascular surgical team accommodated changes in hospital protocols and nationwide lockdown are discussed in detail. CONCLUSIONS: With the judicious use of personal protective equipment and consumable surgical and endovascular devices, communication with support services and other hospitals and implementation of triage protocols, it was possible to manage vascular surgery emergencies effectively.

Epidemiology of aortic dissection.

Aortic dissection remains a highly morbid diagnosis. The treatment of aortic dissection has undergone several paradigm shifts since it was first understood. However, despite the robust research in treatment, the epidemiology of aortic dissection is limited. In this review, we discuss the historical perspectives of aortic dissection with a review of risk factors and presentation. We review the trends in incidence during the past 40 years, with consideration for sex, race, and ethnicity in admission. We further focus our discussion of the classically described Type B aortic dissection treatment. Lastly, we review the impact of long-term events, readmissions, cost assessments, and quality of life studies of patients with aortic dissection. Care for those with aortic dissection remains a long-term challenge for providers and a multispecialty approach is needed for complete patient management.

Aortic aneurysm and aortic graft infection related to Mycobacterium bovis after intravesical Bacille Calmette-Guérin therapy-a case series.

BACKGROUND: So called "mycotic" aortic aneurysms account for only 0.7 to 1.3% of all aortic aneurysms and are commonly caused by Staphylococcus aureus and Salmonella species. Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is part of the therapy of non-muscle-invasive bladder cancer (NMIBC). CASE PRESENTATION: We report a case series of three patients with a mycobacterial graft infection related to BCG after surgical treatment of a presumed mycotic aortic aneurysm as an extremely rare complication after NMIBC treatment. All three patients developed aortic aneurysm after BCG instillation and subsequent mycobacterial graft infection. CONCLUSION: Diagnosis requires a high degree of suspicion because of its nonspecific symptoms and imaging. The pathogen is not detected by standard microbiological testing. Treatment includes triple antimycobacterial therapy and radical surgical interventions. Graft preservation may be considered if no anastomosis is involved.

Long-term fate of aortic branches in patients with aortic dissection.

OBJECTIVE: Late morbidity and mortality related to aortic branches in patients with aortic dissection (AD) have not been well described. We investigated the fate of aortic branches in a population cohort of patients with newly diagnosed AD. METHODS: We used the Rochester Epidemiology Project record linkage system to identify all Olmsted County, Minnesota, residents with a diagnosis of AD from 1995 to 2015. Only patients with >30 days of available follow-up imaging studies were included in the present analysis. The primary outcome was freedom from any branch-related event (any intervention, aneurysm, malperfusion, rupture, or death occurring after the acute phase >14 days). The secondary outcome was the diameter change in the aortic branches. Univariate and multivariable Cox proportional hazards models were used to identify the predictors of branch-related events. Univariate and multivariate linear regression models were used to assess the aortic branch growth rate. RESULTS: Of 77 total incident AD cases, 58 patients who had survived and had imaging follow-up studies available were included, 28 (48%) with type A and 30 (52%) with type B AD. The presentation was acute in 39 patients (67%), 6 (10%) of whom had had branch malperfusion. Of 177 aortic branches involved by the AD, 81 (46%) had arisen from the true lumen, 33 (19%) from the false lumen, and 63 (36%) from both. After the acute phase, freedom from any branch-related event at 15 years was 48% (95% confidence interval [CI], 32%-70%). A total of 31 branch-related events had occurred in 19 patients within 15 years, including 12 interventions (76% freedom; 95% CI, 63%-92%), 10 aneurysms (67% freedom; 95% CI, 50%-90%), 8 cases of malperfusion (76% freedom; 95% CI, 61%-94%), and 1 rupture (94% freedom; 95% CI, 84%-100%). No branch-related deaths had occurred. Type B AD (hazard ratio [HR], 3.5; 95% CI, 1.1-10.8; P = .033), patency of the aortic false lumen (HR, 6.8; 95% CI, 1.1-42.2; P = .038), and malperfusion syndrome at presentation (HR, 6.0; 95% CI, 1.3-28.6; P = .023) were predictors of late aortic branch-related events. The overall growth rate of aortic branches was 1.3 ± 3.0 mm annually. Patency of the aortic false lumen, initial branch diameter, and Marfan syndrome were significantly associated with diameter increase. CONCLUSIONS: In patients with AD, aortic branch involvement was responsible for significant long-term morbidity, without any related mortality. Type B AD, patency of the aortic false lumen, and malperfusion syndrome at presentation resulted in a greater risk of branch events during the long-term follow-up. Dilatation of the aortic branches was observed in one third of cases during follow-up, especially in the case of a patent aortic false lumen or the presence of Marfan syndrome.

Percutaneous Closure of a Giant Aortic Pseudoaneurysm Using Multimodality Imaging Guidance.

Ascending aortic pseudoaneurysm is a rare, life-threatening complication of cardiac surgery. Surgical management is recommended, however, transcatheter techniques offer a less invasive alternative. We describe successful percutaneous closure, guided by using multimodality imaging, in a patient with high surgical risk.

The value of 18F-FDG-PET-CT in the management of infective native aortic aneurysms.

OBJECTIVE: The objective of this systematic literature review was to explore the value of positron emission tomography combined with low-dose computed tomography (18F-FDG-PET-CT) in the diagnostics of infective native aortic aneurysm (INAA). METHODS: A systematic literature review was performed using the search terms mycotic- and infected aortic aneurysms in Medline and Sciencedirect databases, published between 1 January 2000 and 1 January 2020. Using the PRISMA statement, articles were scrutinized according to a predefined protocol including: timing of 18F-FDG-PET-CT examination, the maximum standardized uptake value (SUVmax), additional findings on examination, and findings on repeated scanning of 18F-FDG-PET-CT. RESULTS: Four studies were included in the analysis, comprising a total of 11 patients. Two studies were single case reports, and two were small case series, all were graded to be of low quality with high risk of bias. All patients were examined with a preoperative 18F-FDG-PET-CT, and 10 (91%) had increased 18F-FDG uptakes. The median SUVmax value was 6.53, range 4.46-9.23. The mean duration of antibiotic therapy prior to 18F-FDG-PET-CT was not known. Two patients were examined with repeated 18F-FDG-PET-CT examinations after treatment, where a decrease in SUVmax values could be demonstrated after successful treatment. CONCLUSION: The literature on 18F-FDF-PET/CT for diagnosing infective native aortic aneurysms is scarce. However, there might be a role for 18F-FDF-PET/CT in the management of the disease, in particular for patients with clinical suspicion of INAA without convincing findings on CT. SUVmax values ranging from 4.5 to 6.5 could be guiding and suggestive of metabolic activity in agreement of INAA. However, further conclusions on its usefulness, robustness and specific SUVmax values are premature, and a definitive cut-off value is probably not attainable.