Novel insights into the classification of Shamblin III carotid body tumors from a neurosurgical perspective.

BACKGROUND AND PURPOSE: The classic Shamblin system fails to provide valuable guidance in many Shamblin's III carotid body tumors (III-CBTs) due to the variable forms of carotid arteries and the complex anatomic relationships in parapharyngeal space. We proposed a modified classification to separately divide III-CBTs into different subgroups on the basis of arterial relevant features and anatomical relevant features. MATERIALS AND METHODS: From 2020 to 2023, a total of 129 III-CBTs at a single institution were retrospectively analyzed. All cases were independently classified as arterial-relevant and anatomical-relevant subgroups. The pre-, peri- and postoperative data were summarized and compared accordingly. RESULTS: Among the 129 cases, 69 cases were identified as "Classical type", 23 cases as "Medial type", 27 cases as "Lateral type" and 10 cases as "Enveloped type" according to arterial morphologies. Besides, 76 cases were identified as "Common type", 15 cases as "Pharynx- invasion type", 18 cases as "Skull base-invasion type" and 20 cases as "Mixed type" according to anatomical relationships. "Enveloped type" of tumors in arterial-relevant classification and "Mixed type" of tumors in anatomical-relevant classification are the most challenging cases for surgeons with the lowest resection rate, highest incidence of carotid arteries injury and postoperative stroke. CONCLUSION: The modified classifications provide comprehensive understanding of different III-CBTs which are applicable for individualized treatment in clinical practice.

H-ferritin-nanocaged gadolinium nanoparticles for ultra-sensitive MR molecular imaging.

Rationale: Magnetic resonance imaging (MRI) is a powerful diagnostic technology by providing high-resolution imaging. Although MRI is sufficiently valued in its resolving morphology, it has poor sensitivity for tracking biomarkers. Therefore, contrast agents are often used to improve MRI diagnostic sensitivity. However, the clinically used Gd chelates are limited in improving MRI sensitivity owing to their low relaxivity. The objective of this study is to develop a novel contrast agent to achieve a highly sensitive tracking of biomarkers in vivo. Methods: A Gd-based nanoprobe composed of a gadolinium nanoparticle encapsulated within a human H-ferritin nanocage (Gd-HFn) has been developed. The specificity and sensitivity of Gd-HFn were evaluated in vivo in tumor-bearing mice and apolipoprotein E-deficient mice (Apoe-/-) by MRI. Results: The Gd-HFn probe shows extremely high relaxivity values (r1 = 549 s-1mM-1, r2 = 1555 s-1mM-1 under a 1.5-T magnetic field; and r1 = 428 s-1mM-1 and r2 = 1286 s-1mM-1 under a 3.0-T magnetic field), which is 175-fold higher than that of the clinically standard Dotarem (Gd-DOTA, r1 =3.13 s-1mM-1) under a 1.5-T magnetic field, and 150-fold higher under a 3.0-T magnetic field. Owing to the substantially enhanced relaxivity values, Gd-HFn achieved a highly sensitive tracking for the tumor targeting receptor of TfR1 and enabled the in vivo MRI visualization of tumors approaching the angiogenic switch. Conclusions: The developed Gd-HFn contrast agent makes MRI a more powerful tool by simultaneously providing functional and morphological imaging information, which paves the way for a new perspective in molecular imaging.

Hypoxic Signaling Pathways in Carotid Body Tumors.

Carotid body tumors (CBTs) are rare tumors with a 1-2 incidence per 100,000 individuals. CBTs may initially present without apparent symptoms, and symptoms begin to arise since tumors grow bigger to compress surrounding tissue, such as recurrent laryngeal nerve and esophagus. Also, the etiology of CBTs remains unclear since it is more likely to occur in those who live in high-altitude areas or suffer from chronic hypoxic diseases such as COPD. SDH mutations and familial inheritance have been reported to be related to CBTs. SDH complexes play crucial roles in aerobic respiration, and SDH mutations in CBTs have been reported to be associated with hypoxia. Hypoxic signaling pathways, specifically hypoxic markers, have attracted more research attention in tumor exploration. However, the existing literature on these signaling and markers lacks a systematic review. Also, therapeutic approaches in CBTs based on hypoxic signaling are rarely used in clinics. In this review, we concluded the role of hypoxic signaling and markers and their potential implications in the initiation and progression of CBTs. Our findings underscore the involvement of the SDH family, the HIF family, VEGFs, and inflammatory cytokines (ICs) in tumorigenesis and treatment. Of particular interest is the role played by SDHx, which has recently been linked to oxygen sensing through mutations leading to hereditary CBTs. Among the SDH family, SDHB and SDHD exhibit remarkable characteristics associated with metastasis and multiple tumors. Besides SDH mutations in CBTs, the HIF family also plays crucial roles in CBTs via hypoxic signaling pathways. The HIF family regulates angiogenesis during mammalian development and tumor growth by gene expression in CBTs. HIF1α could induce the transcription of pyruvate dehydrogenase kinase 1 (PDK1) to inhibit pyruvate dehydrogenase kinase (PDH) by inhibiting the TCA cycle. Then, carotid body cells begin to hyperplasia and hypertrophy. At the same time, EPAS1 mutation, an activating mutation, could decrease the degradation of HIF2α and result in Pacak-Zhuang syndrome, which could result in paraganglioma. HIFs can also activate VEGF expression, and VEGFs act on Flk-1 to control the hyperplasia of type I cells and promote neovascularization. ICs also play a pivotal signaling role within the CB, as their expression is induced under hypoxic conditions to stimulate CB hyperplasia, ultimately leading to CBTs detecting hypoxic areas in tumors, and improving the hypoxic condition could enhance photon radiotherapy efficacy. Moreover, this review offers valuable insights for future research directions on understanding the relationship between hypoxic signaling pathways and CBTs.

Investigating the Association of Carotid Atherosclerotic Plaque MRI Features and Silent Stroke After Carotid Endarterectomy.

BACKGROUND: The predictive value of carotid plaque characteristics for silent stroke (SS) after carotid endarterectomy (CEA) is unclear. OBJECTIVE: To investigate the associations between carotid plaque characteristics and postoperative SS in patients undergoing CEA. STUDY TYPE: Prospective. POPULATION: One hundred fifty-three patients (mean age: 65.4 ± 7.9 years; 126 males) with unilateral moderate-to-severe carotid stenosis (evaluated by CT angiography) referred for CEA. FIELD STRENGTH/SEQUENCE: 3 T, brain-MRI:T2-PROPELLER, T1-/T2-FLAIR, diffusion weighted imaging (DWI) and T2*, carotid-MRI:black-blood T1-/T2W, 3D TOF, Simultaneous Non-contrast Angiography intraplaque hemorrhage. ASSESSMENT: Patients underwent carotid-MRI within 1-week before CEA, and brain-MRI within 48-hours pre-/post-CEA. The presence and size (volume, maximum-area-percentage) of carotid lipid-rich necrotic core (LRNC), intraplaque hemorrhage (Type-I/Type-II IPH) and calcification were evaluated on carotid-MR images. Postoperative SS was assessed from pre-/post-CEA brain DWI. Patients were divided into moderate-carotid-stenosis (50%-69%) and severe-carotid-stenosis (70%-99%) groups and the associations between carotid plaque characteristics and SS were analyzed. STATISTICAL TESTS: Independent t test, Mann-Whitney U-test, chi-square test and logistic regressions (OR: odds ratio, CI: confidence interval). P value <0.05 was considered statistically significant. RESULTS: SS was found in 8 (16.3%) of the 49 patients with moderate-carotid-stenosis and 21 (20.2%) of the 104 patients with severe-carotid-stenosis. In patients with severe-carotid-stenosis, those with SS had significantly higher IPH (66.7% vs. 39.8%) and Type-I IPH (66.7% vs. 38.6%) than those without. The presence of IPH (OR 3.030, 95% CI 1.106-8.305) and Type-I IPH (OR 3.187, 95% CI 1.162-8.745) was significantly associated with SS. After adjustment, the associations of SS with presence of IPH (OR 3.294, 95% CI 1.122-9.669) and Type-I IPH (OR 3.633, 95% CI 1.216-10.859) remained significant. Moreover, the volume of Type-II IPH (OR 1.014, 95% CI 1.001-1.028), and maximum-area-percentage of Type-II IPH (OR 1.070, 95% CI 1.002-1.142) and LRNC (OR 1.030, 95% CI 1.000-1.061) were significantly associated with SS after adjustment. No significant (P range: 0.203-0.980) associations were found between carotid plaque characteristics and SS in patients with moderate-carotid-stenosis. DATA CONCLUSIONS: In patients with unilateral severe-carotid-stenosis, carotid vulnerable plaque MR features, particularly presence and size of IPH, might be effective predictors for SS after CEA. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

The Relation of the Iron Metabolism Index to the Vulnerability Index of Carotid Plaque with Different Degrees of Stenosis.

OBJECTIVE: To investigate the differences in serum iron index and iron metabolizing protein expression in plaques in patients with different degrees of carotid artery stenosis and the relationship with plaque traits. METHODS: A total of 100 patients eligible for carotid endarterectomy (CEA) from August 2021 to February 2022 were included. Patients completed a computed tomography (CTA) scan for patient grouping and a magnetic resonance imaging (MRI) for precise quantification of carotid plaque traits within 1 week prior to surgery. Clinical indicators associated with the progression of carotid stenosis to occlusion were analyzed using ordered logistic regression. Twenty carotid plaques were analyzed immunohistochemically to investigate the relationship between plaque traits and the iron metabolism indexes. RESULTS: No significant correlation between high serum ferritin (SF), unsaturated iron binding capacity (UIBC) and progression of carotid stenosis (OR 1.100, 95% CI 0.004-0.165, p = 0.039; OR 1.050, 95% CI 0.005-0.094, p = 0.031). SF and serum transferrin receptor (sTfR) were correlated with normalized wall index (NWI) (R = 0.470, p = 0.036; R = 0.449, p = 0.046), and the results of multiple linear regression suggested that SF and sTfR remained associated with NWI (R = 0.630, R2 = 0.397, Adjusted R2 = 0.326, p = 0.014). In plaques, H-type ferritin (H-FT) was correlated with NWI and lipid-rich necrotic core (LRNC) volume (R = 0.502, p = 0.028; R = 0.468, p = 0.043). Transferrin receptor 1 (TfR1) was correlated with LRNC volume and intraplaque hemorrhage (IPH) volume (R = 0.538, p = 0.017; R = 0.707, p = 0.001). CONCLUSIONS: There were statistical differences in the expression of iron metabolism proteins in carotid plaques with different degrees of stenosis. Serum iron metabolism index (SF and sTfR) and expression of iron metabolizing proteins (H-FT and TfR1) in plaques were positively correlated with carotid plaque vulnerability index (NWI, LRNC volume).

Intraperitoneal Injection of Human Ferritin Heavy Chain Attenuates the Atherosclerotic Process in APOE-Knockout Mice.

Background: Iron overload can accelerate the accumulation of lipid oxides and contribute to the progression of atherosclerosis. Ferritin heavy chain (FT-H) exhibits oxidase activity, which inhibits the toxicity of ferrous ions and reduces oxidative damage. We investigated the effect of the intraperitoneal injection of FT-H on the progression of atherosclerosis in APOE-knockout mice (Apo-E(-/-) mice). Methods: All mice were fed on a high-fat diet. After 10 weeks, the mice were divided into an injection group (n = 4) and a control group (n = 4). The injection group was injected intraperitoneally with FT-H (50 mg/kg, once a week), and the control group was treated with PBS buffer (at an equal volume to the injection group, once a week). After 10 weeks of intervention, MRI of the aortas was performed. Then, the animals were sacrificed, and tissues were taken. Hematoxylin-eosin (HE) staining was used for histomorphometry, Masson staining was used to quantify the collagen content in the arteries, Prussian blue staining was used to visualize iron deposition in the arteries, and MRI was used to analyze the structure of the aorta in vivo. Immunohistochemistry was performed to detect the expression of MCP-1, MMP-2, MMP-9, FT-H, FT-L, TfR1, NRF-2 and GPX-4. Results: The serological results showed that the injection group had lower levels of glucose (Glu), triacylglycerol (TG), cholesterol (CHO), low-density lipoprotein-C (LDL-C) and malondialdehyde (MDA) (p = 0.0058, p = 0.0098, p = 0.0019, p = 0.0368 and p = 0.0025, respectively), and their serum ferritin (SF) and superoxide dismutase (SOD) levels were higher (p = 0.0004 and p < 0.0001). The Masson staining and MRI results showed that the injection group had less collagen deposition (p = 0.0226), a larger arterial lumen area and arterial volume (p = 0.0006 and p = 0.0005), thinner arterial wall thickness (p = 0.0013) and a more stable arterial plaque structure (p < 0.0001). The immunohistochemical results showed reduced expression of FT-H, FT-L, TfR1, MMP-2, MMP-9, MCP-1 and NRF-2 in the injection group (p = 0.0054, p = 0.0242, p = 0.0221, p = 0.0477, p = 0.0131, p = 0.0435 and p = 0.0179). Prussian blue staining showed that the area of iron-positive areas in the aortic plaques of the control group was larger than that of injected group. The expression of GPX-4 was lower in the control group than in the injection group (p = 0.016). Conclusions: The intraperitoneal administration of FT-H to Apo-E(-/-) mice resulted in lower blood glucose and lipid levels; reduced iron and iron metabolism protein deposition in the aorta; reduced indices of their ferroptosis, oxidation and inflammatory aggregation; and reduced collagen deposition in the aorta, which delayed the process of aortic atherosclerosis in mice.

Study on the Influencing Factors of Short-Term Recovery of Neurological Symptoms after Carotid Body Tumor Resection.

OBJECTIVE: To compare the differences in the short-term recovery from neurological symptoms (SRN) (≤ 6 months) and clinical characteristics of patients with different Shamblin classifications carotid body tumor (CBT) resection and to analyze the risk factors affecting SRN after surgery. METHODS: Patients who underwent CBT resection between June 2018 and September 2022 were recruited. Perioperative factors and indicators of the nature of the tumor were recorded. The risk factors affecting SRN after CBT resection were analyzed using logistic regression analysis. RESULTS: Eighty-five patients (43.86 ± 12.7 years, 46 females) were included, 40 (47.06%) of whom exhibited SRN. Univariate logistic regression showed that preoperative symptoms, surgical side, bilateral posterior communicating artery (PcoA) opening, some indicators of tumor size, operative/anesthesia time, and Shamblin III classification were correlated with postoperative neurological prognosis (all p < 0.05). After adjusting for confounders, preoperative symptoms (OR, 5.072; 95% CI 1.027-25.052; p = 0.046), surgical side (OR, 0.025; 95% CI 0.003-0234; p = 0.001), bilateral PcoA opening (OR, 22.671; 95% CI 2.549-201.666; p = 0.005), distance from the tip of the C2 dens to the superior aspect (dens-CBT) (OR, 0.918; 95% CI 0.858-0.982; p = 0.013) and Shamblin III classification (OR, 28.488; 95% CI 1.986-408.580; p = 0.014) were correlated with postoperative neurological symptom recovery. CONCLUSION: Preoperative symptoms, surgical side (right), bilateral PcoA opening, a short dens-CBT and Shamblin III classification are risk factors affecting SRN after CBT resection. Early resection is recommended for small-volume CBTs without neurovascular compression or invasion to obtain SRN.

Utility of sample entropy from intraoperative cerebral NIRS oximetry data in the diagnosis of postoperative cognitive improvement.

Background: Appropriate monitoring and early recognition of postoperative cognitive improvement (POCI) are essential. Near-infrared spectroscopy (NIRS) showed the predictive potential of POCI. Non-linear dynamical analysis is a powerful approach for understanding intraoperative regional cerebral oxygen saturation (rSO2). Objective: We hypothesized that the sample entropy (SampEn) value of intraoperative rSO2 has the potential to predict POCI. Methods: This retrospective cohort study was conducted from June 2019 and December 2020 in a tertiary hospital in Beijing, China. A total of 126 consecutive patients who underwent carotid endarterectomy (CEA) were screened. 57 patients were included in this analysis. The primary outcome was the diagnostic accuracy of rSO2 for the prediction of POCI. Results: 33 patients (57.9%) developed POCI on postoperative day. The SampEn values of rSO2 were significantly higher in the POCI group (p < 0.05). SampEn remained an independent predictor of POCI in multivariate analysis. The area under the ROC curve (AUC) value of SampEn of rSO2 for POCI were 0.706 (95% CI, 0.569-0.843; p = 0.008). Addition of preoperative MoCA assessment and blood pressure-lowering treatment increased the AUC to 0.808 (95% CI, 0.697-0.919; p < 0.001). Conclusions: The SampEn value of rSO2 showed promise as a predictor of POCI. Non-linear analysis could be used as a supplementary method for intraoperative physiological signals.

A single-center retrospective study with 1-year follow-up after CEA in patients with severe carotid stenosis with contralateral carotid artery occlusion.

Objective: To analyze the risk factors associated with adverse events after carotid endarterectomy (CEA) in patients with unilateral severe carotid stenosis and contralateral occlusion. Methods: Patients were recruited for CEA between August 2014 and February 2020. CEA was performed under general anesthesia. The carotid clamp time (CCT; long CCT: >20 min) is defined as the period between clamp-on and clamp-off for the stenotic carotid artery. The perioperative factors and postoperative adverse events were recorded. All patients were followed up for 1 year after CEA. Results: Sixty subjects (65.8 ± 7.2 years; 54 males) were included. Patients with adverse events had significantly longer CCT than those without adverse events (60% vs. 40%, P = 0.013). Univariate logistic regression analysis showed that a history of diabetes was significantly associated with adverse events (OR, 0.190; 95% CI, 0.045-0.814; P = 0.025); long CCT was significantly associated with adverse events (OR, 8.500; 95% CI, 1.617-44.682; P = 0.011). After adjusting for confounding factors, including age, sex, BMI, diabetes, PSV, long CCT, non-use of shunt, and history of stroke or TIA, the associations between diabetes and adverse events (OR, 0.113; 95% CI, 0.013-0.959; P = 0.046) were statistically significant; the associations between long CCT and adverse events (OR, 1.301; 95% CI, 1.049-1.613; P = 0.017) were statistically significant. Conclusions: A longer carotid clamp time (>20 min) and a history of diabetes may increase the risk of adverse events in patients with unilateral severe carotid stenosis and contralateral occlusion after CEA. With good preoperative evaluation and intraoperative monitoring, the use of shunts may not be needed intraoperatively in patients with unilateral severe carotid stenosis and contralateral occlusion.