A Randomized Prospective Non-Inferiority Trial of Sentinel Lymph Node Biopsy in Early Breast Cancer: Blue Dye Compared with Indocyanine Green Fluorescence Tracer.

BACKGROUND: Indocyanine green (ICG) is a promising tracer for sentinel lymph node biopsy in early breast cancer. This randomized study was conducted to evaluate sentinel lymph node biopsy with ICG compared with blue dye as a tracer in woman with early breast cancer without any sign of lymph node invasion. METHODS: Between January 2019 and November 2020, 240 consecutive women with early breast cancer were enrolled and randomized to sentinel lymph node biopsy using ICG or blue dye. The primary endpoint was the sentinel lymph node detection rate in both arms. RESULTS: ICG was used in 121 patients and detected sentinel lymph nodes in all patients (detection rate, 100%; 95% CI: 96.9-100.0) while blue dye was used in 119 patients and detected sentinel lymph nodes in 116 patients (detection rate: 97.5%, 95% CI: 92.9-99.1). This analysis indicated the non-inferiority of ICG vs. blue dye tracer (90%CI: -1.9-6.9; p = 0.0009). CONCLUSION: ICG represents a new promising tracer to detect sentinel lymph nodes in early breast cancer with a detection rate similar to other conventional tracers, and is associated with easy learning and low cost. Our result suggest that this technique is a good alternative to avoid radioactive isotope manipulation.

Sentinel lymph node mapping with patent blue dye in patients with breast cancer: a retrospective single institution study.

BACKGROUND: Since the end of the last century, sentinel lymph node biopsy (SLNB) has replaced axillary lymph node dissection (ALND) as standard of care for axillary staging in early breast cancer in patients without any clinical sign of axillary lymph node infiltration. The worldwide most frequently used mapping method consists in the injection of radioactive technetium-99 isotope alone or in combination with blue dye. As a specific infrastructure and dedicated personnel are needed for the use of a radioactive tracer, the CHC in Liege (Belgium) decided to test the use of patent blue dye alone to detect sentinel lymph nodes in a large consecutive cohort of patients and compared the results with radioactive mapping methods and guidelines recommendations. METHODS: Patent blue dye was used in 456 consecutive patients with early breast cancer who underwent conservative breast cancer surgery or radical mastectomy between 1/1/2000 and 31/12/2007 in a community hospital (CHC Liège, Belgium). After SLNB, an ALND was performed in each patient. RESULTS: Sentinel lymph nodes were identified in 444 patients among the 456 patients evaluated by this mapping method during this time period, which represents a detection rate of 97.4%. Infiltrated lymph nodes were detected in 32.7% of patients (149/456) while in the 444 patients with sentinel lymph nodes identified and resected, 137 patients have at last one positive lymph node (30.9%). The false negative rate was 4.9% and the predictive negative value was 97.7% with the blue dye mapping method. CONCLUSIONS: In addition of the simplicity of the method and the large economic advantage, SNLB using blue dye alone showed a quite acceptable performance in our retrospective analysis concerning its ability to find the SLN as well as its reliability to remove the good ones.

From modified radical mastectomy to infra-radical mastectomy: a phase I study for surgical de-escalation focusing on pathological analyses.

BACKGROUND: Despite that breast conservative therapy became the standard of care in breast cancer, modified radical mastectomy, a large mutilating surgery, is still required for an important number of patients. In order to improve the quality of life and the psychological aspects of a surgery involving the femininity of woman, we developed a new less invasive procedure called infra-radical mastectomy. It aims to save the neckline of patients by the maintenance of the peripheral skin-fatty flap that constitutes the base for implantation of the breast. This phase I study analyzed the feasibility of this procedure using outcome of anatomo-pathological analyses as primary endpoint. METHODS: Between March 2015 and July 2017, all women with operable breast cancer without signs of lymph node invasion were invited to participate in the study in the 2 participating institutions. After a water-assisted dissection of the peri-glandular space, an enucleation of the breast was performed by a cold knife which represents the infra-radical mastectomy. A peri-glandular re-excision (PGR) of the skin and the fat tissue surrounding the gland was then achieved to obtain an MRM. This PGR underwent a careful pathological examination (10 samples per patient). Moreover, the tissue volume and the skin surface of the PGR were quantified. RESULTS: A total of 53 patients (median age: 60 years) were prospectively recruited. The pathological analysis of peri-glandular biopsies revealed none residual invasive carcinoma, 1% of biopsies contained focal ductal carcinoma in situ (DCIS) and 0.4% atypical hyperplasia corresponding to 4 and 2 patients respectively. These 4 patients with residual DCIS were preoperatively diagnosed with extensive DCIS. On average after an infra-radical mastectomy, 37% of the volume and 53% of the skin surface of a complete modified radical mastectomy were sparred. CONCLUSIONS: The evaluation of biopsies from peri-glandular tissue suggests that infra-radical mastectomy should be further evaluated except for patients diagnosed with extensive DCIS which must be excluded of this infra-radical approach. Additional work is needed to evaluate cosmetic outcome and impact on quality of life, the need of radiotherapy and the oncological long-term outcome.

Positron Emission Tomography/Computed Tomography Predicts and Detects Complications After Endovascular Repair of Abdominal Aortic Aneurysms.

Purpose: To assess if aortic 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT) could play a role in predicting complications after endovascular aneurysm repair (EVAR). Materials and Methods: This study involved 2 cohorts of men with abdominal aortic aneurysm treated by EVAR: those who underwent a PET/CT scan before EVAR (n=17) and those who had a PET/CT during follow-up (n=34). Uptake of FDG was measured as the standardized uptake value (SUV). D-dimer, a marker of fibrinolysis, was measured in blood drawn concomitantly with the PET/CT. Results: A significant uptake of FDG in the aneurysm wall was detected by PET/CT before EVAR in 6 of 17 patients. During the first year after EVAR, type II endoleaks developed in 5 of these FDG+ patients vs 3 of 11 FDG- patients (p=0.04). Two of the FDG+ patients had continued sac growth and required conversion to open repair. A significant association between sac growth rate, SUV, and the presence of endoleak was found in the 34 patients who underwent PET/CT after EVAR. Finally, D-dimer was significantly increased in patients with both endoleak and positive PET/CT in the post-EVAR group. Conclusion: This study suggests that the presence of FDG uptake in the aortic wall might be a useful tool to predict patients at high risk of developing post-EVAR complications.

Abdominal Aortic Aneurysm (AAA): Is There a Role for the Prevention and Therapy Using Antioxidants?

BACKGROUND: Abdominal aortic aneurysm (AAA) is a degenerative disease that causes mortality in people aged > 65 years. Increased reactive oxygen species (ROS) and oxidative stress seem to play a pivotal role in AAA pathogenesis. Several sources of ROS have been identified in aortic tissues using experimental models: inflammation, increased activity of NAD(P)H or NOX, over-expression of inducible nitric oxide synthase (iNOS), uncoupled endothelial nitric oxide synthase (eNOS), platelets activation and iron release from hemoglobin. OBJECTIVES: Human studies confirmed that oxidative stress and endothelial dysfunction, an important source of ROS production, were well associated with AAA development. Reducing oxidative stress by antioxidants can therefore be a good strategy for limiting AAA development. The objective of the present study is to review literature data favoring or not such a hypothesis. There is currently no evidence showing that strategies using classical low molecular weight antioxidants (vitamins C and E, ß- carotene) as target for ROS is effective to reduce human AAA progression. However, recent epidemiological data have highlighted the positive role of a diet enriched in fruits which contain high amounts of antioxidant polyphenols. By their ability to restore endothelial function and also their capacity to stimulate enzymatic antioxidants through activation of the Keap1/Nrf2/ARE pathway, polyphenols can represent a promising treatment target for reducing human AAA progression. CONCLUSION: Clinical studies are therefore urgently necessary to confirm the potential beneficial effect of polyphenols in preventing or limiting AAA.

Circulating microRNAs signature correlates with positive [18F]fluorodeoxyglucose-positron emission tomography in patients with abdominal aortic aneurysm.

BACKGROUND: Prediction of abdominal aortic aneurysm (AAA) rupture is a challenging issue. Small noncoding microRNAs (miRNAs) are potent regulators of gene expression and are considered as valuable circulating biomarkers. Recently, [18F]fluorodeoxyglucose (FDG) uptake detected by positron emission tomography (PET) in AAA was correlated with cellular and molecular alterations involved in wall instability and its potential rupture. Our study aimed at identifying circulating miRNAs correlated with a positive PET that could help discriminate patients at high risk of rupture. METHODS: The level of 372 miRNAs was evaluated by polymerase chain reaction array in plasma from 35 AAA patients displaying no FDG uptake (A0) and 22 patients with a positive PET uptake (A+). The modulated miRNAs were validated by quantitative polymerase chain reaction and measured in aneurysmal tissues from both groups of patients. RESULTS: Six circulating miRNAs were found significantly modulated in A+ vs A0 patients. They were significantly correlated not only between them but also with the intensity of FDG uptake. Two of them correlated also with the AAA diameter. These miRNAs displayed significant discriminating power between the A+ and A0 groups as determined by receiver operating characteristic curves. Three downregulated circulating miRNAs (miR-99b-5p, miR-125b-5p, and miR-204-5p) were also significantly reduced in the aneurysmal tissue, specifically in the FDG-uptake site, compared with a negative zone in the same aneurysm and with A0 aneurysms. They were further significantly inversely correlated with the expression, at the positive uptake site, of some of their potential gene targets, most notably matrix metalloproteinase 13. CONCLUSIONS: Six miRNAs were identified as potential new circulating biomarkers of PET+ AAA. Three of these were similarly modulated in the metabolically active aneurysmal wall and might be directly involved in AAA instability.

Therapeutic Applications of Prostaglandins and Thromboxane A2 Inhibitors in Abdominal Aortic Aneurysms.

BACKGROUND: Abdominal aortic aneurysm (AAA) is one of the leading causes of death in western countries. Surgery is still, at the present time, the sole treatment that has however a significant mortality and cost rate. Many pharmacological agents are under investigation aiming to reduce growth and prevent AAA rupture. These drugs target different pathological pathways and, notably, the excessive production of prostanoids by cyclooxygenases (COX). Intra-aneurysmal thrombus plays an adverse key role in the progression of AAA, platelets being a primary source of prostanoids as thromboxane A2. OBJECTIVE: In this review, we summarize studies targeting prostanoids production and down-stream pathways in cardiovascular diseases, and more specifically in AAA. RESULTS AND CONCLUSION: Various inhibitors of COX or antagonists of prostanoids receptors have been investigated in AAA animal models with conflicting results. In human AAA, only a few number of studies focused on anti-platelet therapy mostly using acetylsalicylic acid (aspirin, ASA), a COX1 inhibitor. Finally, we report preliminary promising results of a model of AAA in rats receiving a thromboxane A2 inhibitor, BM-573 that induced a reduction of aneurysmal growth.

A novel SMAD3 mutation caused multiple aneurysms in a patient without osteoarthritis symptoms.

Heterozygous mutations in the SMAD3 gene were recently described as the cause of a form of non-syndromic familial aortic thoracic aneurysm and dissection (FTAAD) transmitted as an autosomal dominant disorder and often associated with early-onset osteoarthritis. This new clinical entity, called aneurysms-osteoarthritis syndrome (AOS) or Loeys-Dietz syndrome 3 (LDS3), is characterized by aggressive arterial damages such as aneurysms, dissections and tortuosity throughout the arterial tree. We report, here, the case of a 45 year-old man presenting multiple visceral arteries and abdominal aortic aneurysms but without dissection of the thoracic aorta and without any sign of osteoarthritis. Exome-sequencing revealed a new frameshift heterozygous c.455delC (p.Pro152Hisfs*34) mutation in the SMAD3 gene. This deletion is located in the exon 3 coding for the linker region of the protein and causes a premature stop codon at positions 556-558 in the exon 4. The same mutation was found in the proband's mother and sister who had open surgery for abdominal aortic aneurysm and in one of his children who was 5 year-old and did not present aneurysm yet.

IgG4-Related Disease Causing Rapid Evolution of a Severe Aortic Valvular Stenosis.

Immunoglobulin G4-related systemic disease (IgG4-RSD) is a recognized emerging entity characterized by chronic fibroinflammation that can affect every organ but rarely affects the cardiovascular system. We report a rare case of IgG4-RSD involving an aortic valve that resulted in rapid progression of an aortic valvular stenosis and was successfully treated by aortic valve replacement and corticosteroids.

Multimodality imaging assessment of the deleterious role of the intraluminal thrombus on the growth of abdominal aortic aneurysm in a rat model.

OBJECTIVES: To evaluate imaging changes occurring in a rat model of elastase-induced abdominal aortic aneurysm (AAA), with emphasis on the intraluminal thrombus (ILT) occurrence. METHODS: The post-induction growth of the AAA diameter was characterized using ultrasound in 22 rats. ILT was reported on 13 rats that underwent 14 magnetic resonance imaging (MRI) 2-18 days post-surgery, and on 10 rats that underwent 18 fluoro-deoxyglucose (FDG) positron emission tomography (PET)/microcomputed tomography examinations 2-27 days post-surgery. Logistic regressions were used to establish the evolution with time of AAA length, diameter, ILT thickness, volume, stratification, MRI and FDG PET signalling properties, and histological assessment of inflammatory infiltrates. RESULTS: All of the following significantly increased with time post-induction (p < 0.001): AAA length, AAA diameter, ILT maximal thickness, ILT volume, ILT iron content and related MRI signalling changes, quantitative uptake on FDG PET, and the magnitude of inflammatory infiltrates on histology. However, the aneurysm growth peak followed occurrence of ILT approximately 6 days after elastase infusion. CONCLUSION: Our model emphasizes that occurrence of ILT precedes AAA peak growth. Aneurysm growth is associated with increasing levels of iron, signalling properties changes in both MRI and FDG PET, relating to its biological activities. KEY POINTS: • ILT occurrence in AAA is associated with increasing FDG uptake and growth. • MRI signalling changes in ILT reflect activities such as haemorrhage and RBC trapping. • Monitoring ILT activities using MRI may require no exogenous contrast agent.

18F-FDG PET/CT in the Management of Aortitis.

BACKGROUND: Aortitis is a generic term defined as an inflammatory condition involving the aortic wall, of infectious or noninfectious origin. This inflammatory process may deteriorate the aortic wall, resulting in potentially life-threatening vascular complications. Therefore, it is important to establish a diagnosis as early as possible. PATIENTS AND METHODS: During a 4-year period, 428 consecutive patients referred to our department for aortic diseases underwent FDG PET/CT examinations. Among these, 18 patients (4.2%) were suspected to have aortitis. All of them had an initial positive FDG PET/CT uptake occurring in the aorta and major branches as evaluated by visual analysis of images and assessed with the final diagnosis of aortitis. During follow-up, after surgery and/or upon immunosuppressive treatment, each of these patients underwent a second PET/CT that was compared with the initial evaluation. In all cases, normalization of FDG uptake was correlated with clinical improvement. CONCLUSIONS: Our study aimed to illustrate the potential clinical value of functional monitoring with PET/CT in the management of aortitis. FDG PET/CT constitutes a valuable imaging modality to establish an early diagnosis, monitor disease progression and treatment, and evaluate vascular complication and relapse. We highlight the importance of an early detection of inflammatory large-vessel pathology, which may represent a major threat.

(Tissue PET) Vascular metabolic imaging and peripheral plasma biomarkers in the evolution of chronic aortic dissections.

AIMS: Despite adequate medical management, dissection of the descending aorta (type B) may develop complications, including aneurysmal progression and eventually rupture. Partial false lumen thrombosis has been identified as a marker of adverse evolution in chronic dissection. The aim of this study was to test the ability of complementary information, provided by (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) and peripheral biomarkers, to add pathophysiological significance and a prognostic value to morphological data. METHODS AND RESULTS: We explored serial aortic (18)F-FDG uptake by PET/CT imaging and plasma biomarkers in a series of 23 patients with type B dissection to predict complications from initial data and to investigate potential associations with aneurysmal expansion during follow-up. Complications occurred in 17 patients. Acute initial characteristics associated with complications were male gender (P = 0.021), arterial hypertension (P = 0.040), aortic dissection diameter (P = 0.0086), partial thrombosis of the false channel (P = 0.0046), and enhanced focal (18)F-FDG uptake (P = 0.045). During follow-up (mean 16.7 ± 8.0 months), aneurysmal expansion was associated with false lumen morphology (P< 0.0001), quantitative (18)F-FDG uptake, (P = 0.0029), elevated plasma concentrations of biomarkers of platelets (P-selectin, P = 0.0009) and thrombin activation (TAT complexes, P = 0.0075), and fibrinolysis (PAP complexes, P < 0.0001; D-dimers, P = 0.0006). Plasma markers of coagulation and fibrinolysis were related to false channel morphology, suggesting that thrombus biological dynamics may drive progressive expansion of type B dissections. CONCLUSION: Enhanced FDG uptake may be considered as a complementary imaging marker associated with secondary complications in type B dissections. During follow-up, aneurysmal progression is related to PET/CT and biomarkers of thrombus renewal and lysis.

Sex differences in abdominal aortic aneurysm: the role of sex hormones.

Abdominal aortic aneurysm (AAA) is a complex multifactorial disease with genetic and environmental components. AAA is more common in men, whereas women have a greater risk of rupture and more frequently have concomitant thoracic aortic aneurysms. Moreover, women are diagnosed with AAA about 10 years later and seem to be protected by female sex hormones. In this MEDLINE-based review of literature, we examined human and animal in vivo and in vitro studies to further deepen our understanding of the sexual dimorphism of AAA. We focus on the role of sex hormones during the formation and growth of AAA. Endogenous estrogens and exogenous 17ß-estradiol were found to exert favorable actions protecting from AAA in animal models, whereas exogenous hormone replacement therapy in humans had inconclusive results. Androgens, known to have detrimental effects in the vasculature, in sufficient levels maintain the integrity of the aortic wall through their anabolic actions and act differentially in men and women, whereas lower levels of testosterone have been associated with AAA in humans. In conclusion, sex differences remain an important area of AAA research, but further studies especially in humans are needed. Furthermore, differential molecular mechanisms of sex hormones constitute a potential therapeutic target for AAA.

Dissection of Iliac Artery in a Patient With Autosomal Dominant Polycystic Kidney Disease: A Case Report.

Autosomal dominant polycystic kidney disease (ADPKD) is a risk factor for several cardiovascular disorders such as intracranial aneurysm or aortic dissection, preferentially occurring at the thoracic or abdominal level. A 47-year-old man suffering from ADPKD had renal transplantation. Sixteen hours after surgery, he presented with left leg pain. Clinical and ultrasound examination revealed thrombosis of the external left iliac artery. Therefore, we decided to perform intra-arterial angiography to evaluate the possibility of an endovascular treatment. Aorto-femorography showed an obstruction of the external left iliac artery that was found during emergency surgery, consecutive to a dissection, which occurred following the surgery for kidney transplantation. The resected segment of the dissected vessel was analyzed by histology. Collagen fibers organization and density in the adventitia and smooth muscle cells density in the media were similar in the dissected and a normal artery from a healthy donor. By contrast, an almost complete disappearance and fragmentation of elastic lamellae were observed in the media of the dissected artery, most likely responsible for the weakening of the arterial wall and its dissection. Association between ADPKD and single dissection of the iliac artery has been rarely reported. Relationship between inactivation of polycystin/PKD genes and elastic fibers degradation through elevated TGFß signaling and matrix metalloproteinase 2 (MMP2) elastolytic activity, as recently reported in ADPKD, would be worth investigating.