Proteomics analysis of carotid body tumor revealed potential mechanisms and molecular differences among Shamblin classifications.

Carotid body tumors (CBTs) are a rare type of paraganglioma, and surgical resection is the only effective treatment. Because of the proximity of CBTs to the carotid artery, jugular vein, and cranial nerve, surgery is extremely difficult, with high risks of hemorrhage and neurovascular injury. The Shamblin classification is used for CBT clinical evaluation; however, molecular mechanisms underlying classification differences remain unclear. This study aimed to investigate pathogenic mechanisms and molecular differences between CBT types. In Shamblin I, II, and III tumors, differentially expressed proteins (DEPs) were identified using direct data-independent acquisition (DIA). DEPs were validated using immunohistochemistry. Proteomics profiling of three Shamblin subtypes differed significantly. Bioinformatics analysis showed that adrenomedullin signaling, protein kinase A signaling, vascular endothelial growth factor (VEGF) signaling, ephrin receptor signaling, gap junction signaling, interleukin (IL)-1 signaling, actin cytoskeleton signaling, endothelin-1 signaling, angiopoietin signaling, peroxisome proliferator-activated receptor (PPAR) signaling, bone morphogenetic protein (BMP) signaling, hypoxia-inducible factor 1-alpha (HIF-1α) signaling, and IL-6 signaling pathways were significantly enriched. Furthermore, 60 DEPs changed significantly with tumor progression. Immunohistochemistry validated several important DEPs, including aldehyde oxidase 1 (AOX1), mediator complex subunit 22 (MED22), carnitine palmitoyltransferase 1A (CPT1A), and heat shock transcription factor 1 (HSF1). To our knowledge, this is the first application of proteomics quantification in CBT. Our results will deepen the understanding of CBT-related pathogenesis and aid in identifying therapeutic targets for CBT treatment.

Perioperative blood pressure and heart rate alterations after carotid body tumor excision: a retrospective study of 108 cases.

BACKGROUND: Arising from chemoreceptor cells, carotid body tumors (CBTs) are rare neoplasms associated with hemodynamics. Perioperative changes in blood pressure (BP) and heart rate (HR) are not completely understood. METHODS: This retrospective, observational, controlled study included all CBT patients from 2013 to 2018 in Peking Union Medical College Hospital. Perioperative changes in BP/HR within or between unilateral/bilateral/control groups were investigated. Perioperative details across Shamblin types were also assessed. RESULTS: This study included 108 patients (116 excised CBTs). The postoperative systolic BP and HR increased in both unilateral (mean difference of systolic BP = 5.9mmHg, 95% CI 3.1 ~ 8.6; mean difference of HR = 3.7 bpm, 95% CI 2.6 ~ 4.9) and bilateral (mean difference of systolic BP = 10.3mmHg, 95% CI 0.6 ~ 19.9; mean difference of HR = 8.4 bpm, 95% CI 0.5 ~ 16.2) CBT patients compared with the preoperative measures. Compared with control group, the postoperative systolic BP increased (difference in the alteration = 6.3mmHg, 95% CI 3.5 ~ 9.0) in unilateral CBT patients; both systolic BP (difference in the alteration = 9.2mmHg, 95% CI 1.1 ~ 17.3) and HR (difference in the alteration = 5.3 bpm, 95% CI 1.0 ~ 9.6) increased in bilateral CBT patients. More CBT patients required extra antihypertensive therapy after surgery than controls (OR = 2.5, 95% CI 1.14 ~ 5.5). Maximum tumor diameter, intraoperative vascular injury, continuous vasoactive agent requirement, total fluid volume, transfusion, estimated blood loss, operation duration, postoperative pathology, overall complications, and intensive care unit/hospital lengths of stay significantly varied among Shamblin types. CONCLUSION: CBT excision may be associated with subtle perioperative hemodynamic changes. Perioperative management of CBT patients necessitates careful assessment, full preparation and close postoperative monitoring.

[Effects of Leptin and Leptin-associated Signaling Pathways on the Occurrence and Progression of Abdominal Aortic Aneurysms].

Abdominal aortic aneurysm(AAA) is a chronic dilated artery disease induced by atherosclerosis,infection,trauma and other related causes.The available studies about AAA mainly focus on the inflammatory response,senility,and microenvironmental changes,while the research on the metabolic changes such as glucose metabolism and lipid metabolism remains to be conducted.As a critical regulatory factor in endocrine,glucose,and lipid metabolisms,leptin is associated with a variety of signaling pathways such as adenosine monophosphate-activated protein kinase,Janus kinase/signal transducer and activator of transcription,and cytokine-cytokine receptor,as demonstrated by the KEGG pathway enrichment analysis.Moreover,these signaling pathways are generally involved in regulating the occurrence of AAA.In addition,leptin affects the occurrence of a variety of diseases such as obesity,diabetes,and hyperlipidemia,which contribute to the formation of AAA.Diabetes might be a protective factor for the formation of AAA,while the relationship of hyperlipidemia and obesity with the formation of AAA remains unclear.Therefore,leptin might play an essential role in the formation of AAA.Further studies about the effect of leptin on AAA may provide the potential research direction and facilitate the discovery of therapeutic targets.

Clinical Features and Endovascular Management of Iliac Arteriovenous Fistulas: A 10-Year Single Center Experience.

Objective: Iliac arteriovenous fistulas (IAVFs) are rare abnormalities with limited reported cases. This study aimed to summarize the clinical features and experiences on the diagnosis and endovascular treatment of IAVFs. Methods: A single-center retrospective study of IAVFs from 2010 to 2019 was performed. Data including demographics, clinical characteristics, radiological images, surgical details, and follow-up were collected. Results: A total of 16 patients diagnosed with IAVFs were identified. The female to male ratio was 3:1. The mean age was 47.7 ± 10.4 years (range: 35-73 years). Leg swelling and cardiac insufficiency, especially heart failure, were the most common primary symptoms in this series, which were revealed in 68.8 and 37.5% of patients, respectively. Iatrogenic, traumatic, and congenital IAVFs were diagnosed in 62.5, 12.5, and 25.0% of patients, respectively, among which hysterectomy was thought to be the main cause for female iatrogenic IAVFs (31.3%). Anatomic analysis found that internal iliac vessels were the predilected sites of IAVFs. All the patients were treated by endovascular procedures composed of transarterial embolization (50.0%), transarterial and stage II transvenous embolization (31.3%), stage I transarterial and transvenous embolization (12.5%), and transarterial embolization plus stent implantation (6.3%). The clinical success rate was 93.8%. Minor complications including fever (18.8%) and exudation at the puncture point (6.25%) were noted and well-treated. During a follow-up period of 51.3 ± 41.9 months after operations, only one patient experienced re-emergence of heart failure because of recurrence of leiomyosarcoma; other patients recovered uneventfully with symptoms relief and no severe embolization-related complications was encountered. Conclusion: IAVFs are rare disorders and correct diagnosis requires careful history taking and physical examination, combined with proper imaging investigation. The primary goal for treatment of IAVFs was to relieve associated symptoms. Based on the results of this study, endovascular approach is safe and effective for treatment of IAVFs.

Comparison of Contrast-Enhanced Ultrasonography to Color Doppler Ultrasound in Evaluation of Carotid Body Tumors.

Objective: The objectives of this study were to prospectively 1) explore the characteristics and enhanced patterns of carotid body tumors (CBTs) at color Doppler ultrasound (CDU) and contrast-enhanced ultrasonography (CEUS) qualitatively and quantitatively and 2) compare CDU and CEUS for their morphology and vascularity signature. Methods: CDU and CEUS with Sonovue® were used to evaluate 25 CBT lesions. The comparison between these ultrasonic modalities included the size, Shamblin type, vascularity, and feeding vessels of the lesion areas. The time-intensity curve (TIC) analysis was used to obtain the dynamics of the contrast-enhancement features of CBTs. Results: The TIC analysis presented a fast wash-in [wash-in time: 3.00 ± 1.10 s, mean ± SD] and slow wash-out [wash-out time: 58.79 ± 24.21 s, mean ± SD] pattern in the CBT lesions, with a high area under the curve (AUC) of 669.68 ± 143.46 mm2 (mean ± SD). In comparison with CDU, CEUS was superior in identifying Shamblin type I or III CBT lesions (χ2 = 17.389, p=0.002). It detected a significant difference in the AUC between moderate and marked vascularity groups (563.33 ± 102.63 vs. 707.22 ± 138.81, t=-2.311, p=0.031.), while CDU observed no significant difference between these two groups. Although CDU was more sensitive than CEUS in detecting feeding vessels (100% vs. 88%), CEUS better visualized the origins of feeding vessels (χ2 = 9.162, p=0.010). Conclusion: CEUS can better investigate the Shamblin type and vascularity of CBT lesions than CDU. CBTs displayed a fast wash-in, slow wash-out pattern with high AUC in the TIC analysis in the CEUS mode. CDU is more sensitive in detecting feeding vessels than CEUS, while CEUS can better visualize the origins of feeding vessels.

[Differences of Gut Microbiota Diversity between Patients with Abdominal Aortic Aneurysm and Atherosclerosis].

Objective To investigate the differences of gut microbiota between patients with abdominal aortic aneurysm and atherosclerosis.Methods From December 2018 to June 2019,20 fresh stool samples were collected respectively from the patients with abdominal aortic aneurysm and atherosclerosis treated at the Department of Vascular Surgery,Peking Union Medical College Hospital.The 16S rDNA high-throughput sequencing was employed to compare the composition,abundance,and α and ß diversities of gut microbiota between the two disease groups,and further determine the significantly differential genera.Results The two groups had great similarities in the composition of gut microbiota.There was no statistical difference in α diversity.Although ß diversity did not have statistically significant difference,certain microbial taxa showed differences between the two groups.The LEfSe demonstrated that the abdominal aortic aneurysm group had higher relative abundance of Leuconostocaceae,Ruminococcaceae,Weissella,and Faecalibacterium while lower relative abundance of Firmicuteria,Selenomonadales,and Veillonellaceae.Conclusion The structure of gut microbiota has differences between patients with abdominal aortic aneurysm and atherosclerosis,and sample size should be enlarged to validate the results.

Discovery of potential biomarkers for human atherosclerotic abdominal aortic aneurysm through untargeted metabolomics and transcriptomics.

Abdominal aortic aneurysm (AAA) and atherosclerosis (AS) have considerable similarities in clinical risk factors and molecular pathogenesis. The aim of our study was to investigate the differences between AAA and AS from the perspective of metabolomics, and to explore the potential mechanisms of differential metabolites via integration analysis with transcriptomics. Plasma samples from 32 AAA and 32 AS patients were applied to characterize the metabolite profiles using untargeted liquid chromatography-mass spectrometry (LC-MS). A total of 18 remarkably different metabolites were identified, and a combination of seven metabolites could potentially serve as a biomarker to distinguish AAA and AS, with an area under the curve (AUC) of 0.93. Subsequently, we analyzed both the metabolomics and transcriptomics data and found that seven metabolites, especially 2'-deoxy-D-ribose (2dDR), were significantly correlated with differentially expressed genes. In conclusion, our study presents a comprehensive landscape of plasma metabolites in AAA and AS patients, and provides a research direction for pathogenetic mechanisms in atherosclerotic AAA.

Exploration of Crucial Mediators for Carotid Atherosclerosis Pathogenesis Through Integration of Microbiome, Metabolome, and Transcriptome.

BACKGROUND: Carotid atherosclerosis (CAS) is an important cause of stroke. Although interactions between the gut microbiome and metabolome have been widely investigated with respect to the pathogenesis of cardiovascular diseases, information regarding CAS remains limited. MATERIALS AND METHODS: We utilized 16S ribosomal DNA sequencing and untargeted metabolomics to investigate the alterations in the gut microbiota and plasma metabolites of 32 CAS patients and 32 healthy controls. The compositions of the gut microbiota differed significantly between the two groups, and a total of 11 differentially enriched genera were identified. In the metabolomic analysis, 11 and 12 significantly changed metabolites were screened in positive (POS) and negative (NEG) modes, respectively. α-N-Phenylacetyl-L-glutamine was an upregulated metabolite in CAS patients detected in both POS and NEG modes and had the highest | log2(fold change)| in POS mode. In addition, transcriptomic analysis was performed using the GSE43292 dataset. RESULTS: A total of 132 differentially expressed genes (DEGs) were screened. Among the upregulated DEGs in CAS patients, FABP4 exhibited the highest | log2(fold change)|. Furthermore, FABP4 was positively associated with Acidaminococcus and had the highest Spearman's correlation coefficient and the most significant p-value among the microbiota-DEG pairs. CONCLUSION: In this study, we investigated the potential "microbiota-metabolite-gene" regulatory axis that may act on CAS, and our results may help to establish a theoretical basis for further specialized study of this disease.

Surgical Excision of a Functional Carotid Body Tumor Presenting Intraoperative Hypertensive Crisis: A Case Report and Literature Review.

Carotid body tumor (CBT) is a rare neoplasm arising from the carotid bifurcation. Functional CBTs are extremely rare and are usually associated with elevated serum catecholamine and catecholamine-induced symptoms such as paroxysmal hypertension, palpitations, dizziness, flushing and tachycardia. We reported a 47-year-old female with a functional CBT that was biochemically silent and had no catecholamine-induced symptoms preoperatively, but experienced hypertensive crisis during surgical excision of the lesion. Postoperative pathology confirmed the diagnosis of CBT, and a functional tumor was considered due to the hypertensive crisis during surgical manipulation of the lesion. Under careful management of intraoperative blood pressure and close monitoring of vital sign along with adequate crystalloid infusion after surgery, the tumor was successfully excised and the patient recovered uneventfully during a follow-up period of 12 months. To the best of our knowledge, this is an unusual report of functional CBT presenting merely hypertensive crisis during surgery, with no elevated serum catecholamine or catecholamine-induced symptoms preoperatively. Clinicians should be aware of such lesions so that appropriate medication and gentle manipulation are given when encountering hypertensive crisis during surgical excision of CBTs, to prevent life-threatening cardiovascular complications. The appropriate management and recognition of functional CBTs were also discussed by means of a review of the literature.

Proposed modification to the Shamblin's classification of carotid body tumors: A single-center retrospective experience of 116 tumors.

OBJECTIVES: Carotid body tumors (CBTs) are rare head and neck neoplasms, we aimed to propose a modification to the Shamblin's classification of CBTs. MATERIALS AND METHODS: This retrospective study included 105 patients (116 CBTs) operated at our institution from March 2013 to July 2020. CBTs were divided by a modified Shamblin's classification into five subtypes (type I-V) based on the radiographic features. Correlations between modified classification and intraoperative bleeding, internal carotid artery (ICA) bypass and postoperative neural complications, as main outcomes, as well as other outcomes were analyzed. RESULTS: Surgeries for type V and type I CBTs had the most (median: 700 ml, IQR: 375-1575 ml) and least (median: 20 ml, IQR: 20-50 ml) bleeding, respectively. Intraoperatively, ICA bypass was needed in 41.7% (10/24) type V, 18.2% (8/44) type IV and 5.9% (1/17) type III lesions, but not in other subtypes (p = .001). Postoperatively, overall cranial nerve deficits (CND) were found most frequently in type V tumors (17/24, 70.8%) (p = .016). Permanent CND were found in 33.3% (8/24) type V and 4.5% (2/44) type IV lesions, but not in other subtypes (p = .001). Other outcomes including external carotid artery ligation, operation time, blood transfusion, postoperative intensive unit care and postoperative hospitalization also showed significant difference among different subtypes. Patients recovered uneventfully during a follow-up of 23.5 ± 16.2 months except for one ipsilateral recurrence at 42 months after surgery. CONCLUSIONS: The modified classification was correlated with surgical outcomes of CBTs and will be helpful for making surgical plans.

[Value of Head and Neck CT Angiography in the Clinical Evaluation of Intraoperative Bleeding Volume of Carotid Body Tumours].

Objective To investigate the value of head and neck CT angiography(CTA)in the evaluation of intraoperative hemorrhage of carotid body tumours. Methods Head and neck CTA images of 36 patients with carotid body tumours confirmed by pathology were retrospectively analyzed.Patients were divided into two groups based on the intraoperative bleeding volume:<500 ml and≥500 ml groups.The patient's age,sex,Shamblin classification,size of the lesion,number of blood supply arteries,course of the disease,plain scan,and enhanced CT value between two groups were compared and analyzed.Logistics regression equation was established based on the CTA parameters with significant differences between the two intraoperative bleeding volume groups,and combined parameter was acquired.The receiver operating characteristic curve was established based on CTA single and combined parameters. Results The bleeding volume during the operation of carotid body tumors was significantly correlated with the age of patients(P=0.019),the maximum diameter of tumours on axial images(P=0.003),the maximum upper and lower diameters(P=0.004),Shamblin classification(P=0.012),and number of blood supply arteries(P<0.001).The area under the receiver operating characteristic curve of the number of feeding arteries,the maximum diameter of axial images,maximum upper and lower diameters,Shamblin classification,and combined parameters were 0.865,0.781,0.806,0.766,and 0.927,respectively.When the optimal critical value was 0.408,the Youden index was 0.794,and the corresponding accuracy,sensitivity,and specificity were 0.919,0.909,and 0.923,respectively. Conclusions Preoperative head and neck CTA can be used to evaluate the intraoperative blood loss.Combined parameters has the best diagnostic performance compared with single parameters.

Costoclavicular ligament as a novel cause of venous thoracic outlet syndrome: from anatomic study to clinical application.

PURPOSE: Venous thoracic outlet syndrome (VTOS) is a compressive disorder of subclavian vein (SCV); we aimed to investigate the role of costoclavicular ligament (CCL) in the pathogenesis of VTOS. METHODS: A cadaver study was carried out to investigate the presence and morphology of CCL in thoracic outlet regions, as well as its relationship with the SCV. Six formalin-fixed adult cadavers were included, generating 12 dissections of costoclavicular regions (two sides per cadaver). Once CCL was identified, observation and measurement were made of its morphology and dimensions, and its relationship with SCV was studied. To take a step further, a clinical VTOS case was reported to prove the anatomical findings. RESULTS: Two out of twelve costoclavicular regions (2/12, 16.7%) were found to possess CCLs. Both ligaments were located in the left side of two male cadavers and were closely attached to the lateral aspect of sternoclavicular joint capsules. The lateral fibers of the ligament proceed in a superolateral-to-inferomedial manner, while the medial fibers proceed more vertically. Both ligaments were tightly adherent to the SCV, causing significant compression on the vein. In the clinical case, multiple bunches of CCLs were found to compress the SCV tightly intraoperatively. After removing the ligaments, the patient's symptom kept relief during a follow-up period of 2 years. CONCLUSION: Our study demonstrated that CCL could be a novel cause of VTOS by severe compression of SCV. Patients diagnosed with this etiology could get less invasive surgical treatment by simply removing the ligament.

Distinct features of malignant carotid body tumors and surgical techniques for challengeable lesions: a case series of 11 patients.

PURPOSE: Malignant carotid body tumor (CBT) is a rare disorder with poor prognosis. In this article, we presented the clinical features and surgical management of malignant CBTs at our department, aiming to improve the outcome for treating such lesions. METHODS: A retrospective analysis (2005-2018) of CBT excisions at our institution was performed. About 195 patients with CBTs were identified, among which 11 patients with eleven malignant CBTs were identified and carefully reviewed. Data obtained included demographics, radiological details, intra-operative details, post-operative morbidity, and long-term outcomes. RESULTS: Compared with benign CBTs, malignant CBTs have more advanced Shamblin classification (p < 0.001) and larger tumor size (4.5 ± 2.1 cm vs. 6.7 ± 2.6 cm, p = 0.003). Among the 11 malignant cases, 9 patients underwent surgical resection and 8 cases (8/9, 89%) underwent internal carotid artery (ICA) reconstruction. Intra-operative findings showed that malignant CBTs revealed more severe arterial and nerve adhesions. With the use of specific techniques including pre-reconstruction technique and carotid shunt, all surgeries were successful and no deaths or major complications including stroke or hemiplegia occurred perioperatively and during the follow-up. During the follow-up period (41.6 ± 44.5 months), two patients developed distant metastasis at 7 and 11 years post-operatively. The 5-year and 10-year distant metastasis-free survival rates were 72.7% and 36.4%, respectively. CONCLUSIONS: With more advanced Shamblin classification and larger tumor size, malignant CBTs remain challengeable for surgery due to severe intra-operative hemorrhage, need of vascular reconstruction and cervical nerve injury. Specific surgical techniques including pre-reconstruction technique and carotid shunt are safe and effective to improve the outcome.

Endovascular Treatment of Multiple Bronchial Artery Aneurysms With Prominent Fistula to Pulmonary Artery in a Patient With Interstitial Lung Disease: A Case Report and Literature Review.

Bronchial artery aneurysm (BAA) is a rare entity. Ruptured BAA can cause life-threatening hemorrhage. It is recommended that treatment should be initiated immediately after diagnosis. We present the case of a 56-year-old female with multiple BAAs and interstitial lung disease. Aortic computed tomography angiography demonstrated that the largest aneurysm at the right hilum was fed by right subclavian artery and right bronchial artery. A fistula between the pulmonary trunk and the aneurysm was also revealed. The patient underwent transcatheter embolization. Coils were placed in the feeding vessels instead of the aneurysms to avoid nontarget embolization of the pulmonary arteries through the fistula. The procedure achieved reduction in aneurysmal blood flow. The patient's cough resolved at 6-month follow-up.

Vascular Ehlers-Danlos Syndrome With a Novel Missense COL3A1 Mutation Present With Pulmonary Complications and Iliac Arterial Dissection.

Vascular Ehlers-Danlos syndrome (vEDS) is a life-threatening connective tissue disorder due to its high tendency of arterial and organ rupture. Pulmonary complications in vEDS are rare. We present a young male patient with vEDS who developed severe pulmonary complications and severe rupture of the iliac artery at different stages of his life. Vascular Ehlers-Danlos syndrome was diagnosed based on clinical manifestations and confirmed by the identification of COL3A1 gene mutation. Due to high bleeding tendency and weak cardiopulmonary capacity, conservative treatment was taken for him. To our knowledge, this is the first report of vEDS case in which the patient developed both pulmonary complications and dissection of large arteries. Our report emphasizes the importance of considering vEDS when an adolescent develops unexplained pulmonary cysts with fragility of lung tissues. Genetic counseling and close monitoring should be performed for earlier diagnosis and prevention of severe complications of large arteries. The typical presentations of vEDS were also discussed by means of a review of case reports on vEDS with pulmonary complications.

An evaluation on novel application of cone-beam CT imaging with multi-volume technique in carotid body tumor.

Due to the high risk of vascular and nerve damage during surgery, precise pre-operative evaluation of carotid body tumor (CBT) is important. We aim to apply intra-operative contrast-enhanced cone-beam CT (CBCT) with multi-volume technique in CBT evaluation, where the tumor, patent carotid arteries, and skull are demonstrated in three different colors, and to compare this novel technique with traditional computed tomography angiography (CTA). Seven CBT patients scheduled for traditional surgical removal were enrolled in this study between October 2013 and March 2016. For each patient, two CBCT scans were performed on the carotid region both pre- and post-operatively, with contrast injected into the common carotid artery directly. CT-like cross-sectional slices were then reconstructed with a dedicated workstation, and a novel multi-volume technique was further applied for advanced image post-processing. For all seven patients, the anatomic relationship between tumor and surrounding vessels was clearly demonstrated by reconstructed CBCT images with multiple fused volumes. Carotid was either completely or partially incarcerated by tumors. Interestingly, two sets of draining vein systems of CBT were found feeding into the internal jugular vein and the anterior vertebral venous plexus, respectively, which have not been revealed in pre-operative CTA. Post-operative CBCT confirmed the thorough removal of the tumor with an intact preservation of the internal carotid artery. CBCT with multi-volume technique outperforms CTA in discovering fine structures and revealing tumor-vessel relationship for CBT. This emerging imaging technique would offer more accurate diagnosis of CBT and assist in the decision of surgical plan.