Perioperative management of pediatric patients undergoing juvenile angiofibroma resection. A case series and educational review highlighting patient blood management.

BACKGROUND: Juvenile nasopharyngeal angiofibromas are one of the most enigmatic, bloody tumors encountered by otorhinolarygnologists, head and neck surgeons, neurosurgeons, and anesthesiologists. Juvenile nasopharyngeal angiofibromas are rare, benign, highly vascular tumors with a propensity towards aggressive local invasion. Surgery, open or endoscopic, to remove the growth is the primary treatment of choice for Juvenile nasopharyngeal angiofibromas. Historically, surgical resection was associated with massive, rapid blood loss, traditionally managed by blood product transfusion and deliberate hypotension. Preventative management employing multimodal blood conservation strategies should be an essential standard of perioperative care for patients with Juvenile nasopharyngeal angiofibromas. METHODS: We describe a contemporary and comprehensive approach in the management of patients with high grade Juvenile nasopharyngeal angiofibromas. This includes surgical strategies such as preemptive external carotid artery embolization, endoscopic surgical approach, and staged operations, as well as anesthetic strategies including antifibrinolytic therapy and acute normovolemic hemodilution. These surgeries, once synonymous with massive transfusion, may potentially be performed without allogeneic blood transfusion, or deliberate hypotension. AIMS: Using a case series, the authors introduce a contemporary approach to multimodal, multidisciplinary blood conservation strategies for Juvenile nasopharyngeal angiofibromas surgery. RESULTS: Here in the authors report on an updated contemporary perioperative clinical approach to patients with Juvenile nasopharyngeal angiofibromas. From an anesthetic perspective, we describe the successful use of normal hemodynamic goals, restrictive transfusion strategy, antifibrinolytic therapy, autologous normovolemic hemodilution, and early extubation in the care of three adolescent males with highly invasive tumors. We demonstrate that new surgical and anesthetic strategies have yielded a significant decrease in intraoperative blood loss and eliminated the need for transfusion of autologous red blood cells, which enable improved outcomes. CONCLUSIONS: The perioperative approach to elective surgery for Juvenile nasopharyngeal angiofibromas management is presented from a multidisciplinary patient blood management perspective.

Nuclear exosome HMGB3 secreted by nasopharyngeal carcinoma cells promotes tumour metastasis by inducing angiogenesis.

Distant metastasis accompanied by angiogenesis is the main cause of nasopharyngeal carcinoma (NPC)-related death. Nuclear exosomes (nEXOs) are potential tumour biomarkers. High mobility group box 3 (HMGB3), a nuclear protein, is known to be overexpressed in cancers. However, its role in NPC has not been elucidated. Here, we explore for the first time the function of nEXO HMGB3 in tumour angiogenesis involved in NPC metastasis using a series of in vitro experiments with NPC cell lines and clinical specimens and in vivo experiments with tumour xenograft zebrafish angiogenesis model. We found a high expression of HMGB3 in NPC, accompanied by the formation of micronuclei, to be associated with metastasis. Furthermore, the NPC-secreted HMGB3 expression was associated with tumour angiogenesis. Moreover, HMGB3-containing nEXOs, derived from the micronuclei of NPC cells, were ingested by the human umbilical vein endothelial cells (HUVECs), and accelerated angiogenesis in vitro and in vivo. Importantly, western blotting and flow cytometry analysis showed that circulating nEXO HMGB3 positively correlated with NPC metastasis. In summary, nEXO HMGB3 can be a significant biomarker of NPC metastasis and provide a novel basis for anti-angiogenesis therapy in clinical metastasis.

CircRNA ZNF609 promotes angiogenesis in nasopharyngeal carcinoma by regulating miR-145/STMN1 axis.

Nasopharyngeal carcinoma (NPC) is the most common type of human malignant tumor in the head and neck, and tumor angiogenesis is essential for its development. Here, we showed that the circRNA ZNF609/microRNA (miR)-145/Stathmin 1 (STMN1) axis regulated angiogenesis in NPC.Circ-ZNF609, miR-145, and STMN1 expression in NPC cells and NPC samples were examined using qRT-PCR. The protein levels of STMN1, VEGFR1, and VEGFR2 were evaluated using western blotting. VEGF level was determined by ELISA. The proliferation of NPC cells and HUVECs was examined using a CCK-8 assay. Transwell assays and wound-healing assays were applied to assess the migration of NPC cells and HUVECs, respectively. Angiogenesis of HUVECs was evaluated by an angiogenesis assay. In addition, a dual-luciferase reporter assay and RNA pull-down assays were employed to verify the binding relationship between circ-ZNF609 and miR-145 as well as between miR-145 and STMN1. Here, we showed that circ-ZNF609 and STMN1 expression was increased, while miR-145 expression was decreased in NPC cells and NPC samples. Circ-ZNF609 may negatively regulate miR-145 expression by acting as a ceRNA. Silencing circ-ZNF609 suppressed cell proliferation, migration, and angiogenesis in NPC, while knockdown of miR-145 reversed these effects. In addition, we found that STMN1 was the downstream target of miR-145. MiR-145 overexpression suppressed cell proliferation, migration, and angiogenesis in NPC, which was abolished by STMN1 overexpression. Our data suggested that circ-ZNF609 promotes cell proliferation, migration, and angiogenesis in NPC by upregulating the expression of STMN1 by sponging miR-145 in NPC.

Foxq1 promotes metastasis of nasopharyngeal carcinoma by inducing vasculogenic mimicry via the EGFR signaling pathway.

In nasopharyngeal carcinoma (NPC), the treatment of tumor metastasis and recurrence is challenging and is associated with poor clinical efficacy. Vasculogenic mimicry (VM) is a new blood-supply model of malignant tumor that is closely related to tumors' distant metastasis. Our previous study demonstrated that miR-124 could target Foxq1 to inhibit NPC metastasis. Whether Foxq1 affects metastasis through vasculogenic mimicry is worth consideration. In this study, we show that VM formation positively correlates with the expression of Foxq1, and EGFR, and the TNM stage in 114 NPC patient samples. Meanwhile, we show that VM-positive NPC patients have a poor prognosis. Furthermore, using in vitro and vivo approaches, we confirm that Foxq1 has a significant effect on NPC metastasis through promoting VM formation, which could be effectively inhibited by EGFR inhibitors (Nimotuzumab or Erlotinib). Also a synergistic efficacy of anti-EGFR and anti-VEGF drugs has been found in NPC inhibition. Mechanistically, the luciferase reporter gene and CHIP assays show that Foxq1 directly binds to the EGFR promoter region and regulates EGFR transcription. In conclusion, our results show that Foxq1 is regulated by miR-124 and that it promotes NPC metastasis by inducing VM via the EGFR signaling pathway. Overall, these results provide a new theoretical support and a novel target selection for anti-VM therapy in the treatment of nasopharyngeal carcinoma.

Direct Tumoral Puncture Onyx Embolization for a Juvenile Nasopharyngeal Angiofibroma in a Hybrid Neurointerventional Suite.

This case video demonstrates a multidisciplinary approach to resection of a juvenile nasopharyngeal angiofibroma highlighting direct intratumoral onyx embolization. The patient is a 14-year-old boy who presented with a 1-month history of worsening epistaxis and nasal congestion. Preoperative magnetic resonance imaging demonstrated a 4.5 x 3 x 3 cm lobulated mass in the right pterygomaxillary space, sphenoid, and the nasopharynx adjacent to the cavernous carotid. Given the high vascularity of the lesion, intratumoral onyx embolization was undertaken, which significantly reduced intraoperative blood loss in this case. The present video demonstrates the technique for safe direct intratumoral onyx embolization and its role in significantly reducing intraoperative blood loss (Video 1). Postoperatively, the patient made an uncomplicated recovery. The patient consented to the procedure.

Efficacy and safety of preoperative internal maxillary arterial embolization with gelfoam for nasopharyngeal angiofibroma.

PURPOSE: To investigate the efficacy and safety of preoperative internal maxillary arterial embolization with gelfoam particles in patients with nasopharyngeal angiofibroma. MATERIALS AND METHODS: We retrospectively reviewed a total of 27 consecutive patients with pathologically confirmed nasopharyngeal angiofibroma from August 2006 to September 2018. Of the 27 enrolled patients, 10 patients received surgical excision alone; 17 patients received preoperative internal maxillary arterial embolization followed by surgical excision. Embolic agents were gelfoam particles. RESULTS: The mean volume of intro-operative blood loss was 385.3 ml in patients with preoperative arterial embolization, which was significantly lower than 1215.0 ml in the patients without preoperative arterial embolization (P < 0.001). The mean surgical time was shorter in patients with preoperative arterial embolization than in the patient without preoperative arterial embolization, but the difference had no statistical significance (205.0 vs 264.5 min, P = 0.064). Neurological complications such as facial palsy or vision loss or hemiplegia were not observed in patients with preoperative arterial embolization. CONCLUSION: Internal maxillary artery embolization with gelfoam particles suffices to provide an effective and safe adjuvant procedure for surgical excision of nasopharyngeal angiofibroma.

Endoscopic endonasal transmaxillary ligation of a feeding artery and coblation plasma technology enables en bloc resection of advanced juvenile nasopharyngeal angiofibroma without preoperative embolization.

Juvenile nasopharyngeal angiofibroma (JNA) is a hypervascular tumor and uncontrolled hemorrhage makes its removal very difficult. Although preoperative intravascular embolization of a feeding artery is recommended, serious complications such as iatrogenic thrombosis in the brain and insufficient decrease in blood flow to the tumor are concerns. Recently, coblation plasma technology has been reported to be useful for tumor removal with minimum hemorrhage under a clear surgical field. Here we report successful removal of advanced JNA without preoperative embolization, using intraoperative ligation of the maxillary artery and coblation plasma technology. The left nasal cavity of a 23-years-old man was closed by a JNA tumor at Radkowski stage IIC, which was 65mm in size and extended from the nasal cavity to the infratemporal fossa. MRA imaging showed the maxillary artery running along the posterior wall of the maxillary sinus. Therefore, the maxillary artery was first clipped using an endoscopic modified medial maxillectomy (EMMM) approach and endoscopic endonasal en bloc resection of the tumor was then completed using coblation technology with no need for blood transfusion. This case illustrates that preoperative embolization is dispensable in JNA surgery even at Stage IIC if the maxillary artery can be ligated during surgery and a coblation device can be utilized.

Investigating the correlation of arterial spin labeling and dynamic contrast enhanced perfusion in primary tumor of nasopharyngeal carcinoma.

PURPOSE: This prospective study aimed to investigate the correlation between two perfusion methods: arterial spin labeling (ASL) and dynamic contrast enhanced (DCE) technique in patients with nasopharyngeal carcinoma (NPC) and to optimize ASL protocol. MATERIALS AND METHODS: Forty-five newly diagnosed NPC patients underwent MR examinations with both 3D pseudo-continuous ASL (pCASL) and DCE-MRI sequences. Tumor blood flow (TBF) derived in pCASL with three post-labeling delay (PLD) times (i.e. 1.0 s, 1.5 s, and 2.0 s) and DCE derived parameters including MaxSlop, contrast enhancement ratio (CER), Initial area under the gadolinium curve (IAUGC), Ktrans, Kep and Ve were measured by two independent observers, and their correlation coefficients were investigated using Spearman test. RESULTS: Inter-observer reproducibility (ICC = 0.931-0.998) was observed to be excellent. Positive correlations between mean, maximum and minimum value of TBFs with different PLDs and DCE-MRI parameters (except Ve) were respectively observed (r = 0.308-0.688, P = 0.000-0.040). CONCLUSION: pCASL may be an alternative method for DCE-MRI in assessing the perfusion level in NPC in the future.

Vasculogenic mimicry formation in EBV-associated epithelial malignancies.

Epstein-Barr virus (EBV)-associated epithelial cancers, including nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancers, termed EBVaGC, represent 80% of all EBV-related malignancies. However, the exact role of EBV in epithelial cancers remains elusive. Here, we report that EBV functions in vasculogenic mimicry (VM). Epithelial cancer cells infected with EBV develop tumor vascular networks that correlate with tumor growth, which is different from endothelial-derived angiogenic vessels and is VEGF-independent. Mechanistically, activation of the PI3K/AKT/mTOR/HIF-1α signaling cascade, which is partly mediated by LMP2A, is responsible for EBV-induced VM formation. Both xenografts and clinical samples of NPC and EBVaGC exhibit VM histologically, which are correlated with AKT and HIF-1α activation. Furthermore, although anti-VEGF monotherapy shows limited effects, potent synergistic antitumor activities are achieved by combination therapy with VEGF and HIF-1α-targeted agents. Our findings suggest that EBV creates plasticity in epithelial cells to express endothelial phenotype and provides a novel EBV-targeted antitumor strategy.

Induction of chemokine (C-C motif) ligand 5 by Epstein-Barr virus infection enhances tumor angiogenesis in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is etiologically associated with Epstein-Barr virus (EBV) infection and is known to be highly vascularized. Previous studies have suggested that EBV oncoproteins contribute to NPC angiogenesis. However, the regulatory network of EBV in angiogenesis still remains elusive. Herein, we reveal a novel mechanism of EBV-induced angiogenesis in NPC. First, we showed that EBV-infected NPC cell lines generated larger tumors with more microvessels in mouse xenograft models. Subsequent proteomic analysis revealed that EBV infection increased the expression of a series of angiogenic factors, including chemokine (C-C motif) ligand 5 (CCL5). We then proved that CCL5 was a target of EBV in inducing tumor angiogenesis and growth. Further investigation through transcriptome analysis indicated that the pro-angiogenic function of CCL5 might be mediated by the PI3K/AKT pathway. Furthermore, we confirmed that activation of the PI3K/AKT and hypoxia-inducible factor-1α pathways was essential for CCL5-promoted angiogenesis. Finally, the immunohistochemical analysis of human NPC specimens also showed that CCL5 was correlated with angiogenesis. Taken together, our study identifies CCL5 as a key EBV-regulated molecular driver that promotes NPC angiogenesis, suggesting it as a potential therapeutic target.

Nasopharyngeal angiofibroma in a 32-year-old man.

Nasopharyngeal angiofibroma (NA) is a benign, highly vascularised tumour of the nasopharynx, which typically occurs in young males aged 14-25 years. We report an interesting case of an NA arising de novo in a 32-year-old male. He was referred to our facility for severe nasal haemorrhage after biopsy of a left nasopharyngeal mass. In the operating room, extensive bleeding was noted, and an endoscopic medial maxillectomy was performed, and the left internal maxillary artery was ligated allowing for near total resection of the lesion. The pathological specimen confirmed the diagnosis of NA. To our knowledge, this is one of the oldest patients presenting with a de novo NA, in his fourth decade of life, confirming that this diagnosis must be considered in all those with large nasopharyngeal masses.

Patterns of vascularization and surgical morbidity in juvenile nasopharyngeal angiofibroma: A case series, systematic review, and meta-analysis.

BACKGROUND: Vascular patterns of juvenile nasopharyngeal angiofibroma (JNA) are poorly defined. We performed both institutional and systematic literature reviews to characterize the relationship between arterial supply patterns of JNA with intraoperative blood loss and tumor recurrence. METHODS: A retrospective review of 26 patients with JNA treated at our institution from 1995 to 2015 with available angiograms, and systematic reviews and meta-analyses of 828 JNA cases undergoing angiographic embolization published between 1995 and 2015 were completed per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: The systematic review (828 cases) found internal carotid artery (ICA) supply in 35.6% of tumors, and 30.8% of tumors received bilateral vascular supply. Our institutional data (n = 26) indicated 69% had bilateral supply. Meta-analysis of data from 5 studies demonstrated ICA/bilateral arterial supply is predictive of increased operative blood loss (P < .01). CONCLUSION: Complex vascular contributions to JNA are frequent, underreported, and portends increased blood loss. This information can justifiably be included in staging systems to enhance prognostic counseling of patients.

Ophthalmic artery occlusion following neuro-embolization of the external carotid artery, a case report.

BACKGROUND: Embozene® is a new neuroembolizing microsphere used to reduce intraoperative bleeding for head and neck tumours. We report a case of iatrogenic ophthalmic artery occlusion after Embozene® embolization of the external carotid artery (ECA). CASE PRESENTATION: A 22-year-old African gentleman presented with left nasal obstruction and epistaxis for 2 years and was diagnosed with nasopharyngeal carcinoma. He subsequently underwent embolization of the maxillary branch of the left ECA using Embozene® Microspheres - 250 µm in size before endoscopic tumour excision to reduce intra-operative bleeding. He complained of sudden painless profound visual loss in the left eye (LE) two hours after embolization. Visual acuity in LE was no light perception. Fundus examination showed pale retina with no cherry red spot. Arterial narrowing and segmentation were seen in all quadrants. A diagnosis of left ophthalmic artery occlusion was made. Despite immediate management including ocular massage and lowering of intraocular pressure, the visual loss remained. Retrospective review of digital subtraction angiogram showed an anastomosis between the left ophthalmic artery and anterior deep temporal artery as a potential route for microspheres migration. CONCLUSION: Pre-operative angio-architecture understanding and diligent selection of embolic material are helpful in preventing this adverse event. The use of newer agents for embolotherapy may cause migration of embolic material from the external to the internal carotid system leading to ophthalmic artery occlusion and blindness.

Efficacy of Preoperative Transcatheter Arterial Embolization for Nasopharyngeal Angiofibroma: A Comparative Study.

OBJECTIVE: This study aimed to retrospectively evaluate the efficacy and safety of preoperative transcatheter arterial embolization (pTAE) for treating nasopharyngeal angiofibroma (NPAF). METHODS: Seventy-four NPAF patients were hospitalized for elective surgical treatment with pTAE (pTAE group, n = 32) or surgical treatment alone (non-pTAE group, n = 42) between January 1990 and December 2013. The following outcome measures were retrospectively analyzed and compared: intraoperative bleeding volume, surgery time (ST), duration of postoperative hospital stay (PHS), and disease recurrence. RESULTS: Among Radkowski stage I patients, those in pTAE group had a slightly higher but not significant bleeding volume than patients in non-pTAE group (344 ± 407 vs. 248 ± 219 mL, P = 0.899); among stage II/III patients, however, patients in pTAE group showed a significantly lower bleeding volume than patients in non-pTAE group (stage II, 829 ± 519 vs. 1339 ± 767 mL, P = 0.035; stage III, 1267 ± 592 vs. 2125  ± 479 mL, P = 0.024). The two groups presented comparable OTs, PHSs, and rates of frontal recurrence (all P>0.05). CONCLUSIONS: pTAE significantly reduces intraoperative bleeding in NPAF patients with Radkowski stage II/III disease, but offers no additional benefits regarding ST, PHS, or recurrence.

Noninvasive monitoring of early antiangiogenic therapy response in human nasopharyngeal carcinoma xenograft model using MRI with RGD-conjugated ultrasmall superparamagnetic iron oxide nanoparticles.

PURPOSE: Arginine-glycine-aspartic acid (RGD)-based nanoprobes allow specific imaging of integrin αvß3, a protein overexpressed during angiogenesis. Therefore, this study applied a novel RGD-coupled, polyacrylic acid (PAA)-coated ultrasmall superparamagnetic iron oxide (USPIO) (referred to as RGD-PAA-USPIO) in order to detect tumor angiogenesis and assess the early response to antiangiogenic treatment in human nasopharyngeal carcinoma (NPC) xenograft model by magnetic resonance imaging (MRI). MATERIALS AND METHODS: The binding specificity of RGD-PAA-USPIO with human umbilical vein endothelial cells (HUVECs) was confirmed by Prussian blue staining and transmission electron microscopy in vitro. The tumor targeting of RGD-PAA-USPIO was evaluated in the NPC xenograft model. Later, mice bearing NPC underwent MRI at baseline and after 4 and 14 days of consecutive treatment with Endostar or phosphate-buffered saline (n=10 per group). RESULTS: The specific uptake of the RGD-PAA-USPIO nanoparticles was mainly dependent on the interaction between RGD and integrin αvß3 of HUVECs. The tumor targeting of RGD-PAA-USPIO was observed in the NPC xenograft model. Moreover, the T2 relaxation time of mice in the Endostar-treated group decreased significantly compared with those in the control group both on days 4 and 14, consistent with the immunofluorescence results of CD31 and CD61 (P<0.05). CONCLUSION: This study demonstrated that the magnetic resonance molecular nanoprobes, RGD-PAA-USPIOs, allow noninvasive in vivo imaging of tumor angiogenesis and assessment of the early response to antiangiogenic treatment in NPC xenograft model, favoring its potential clinical translation.

Elevated expression of CD93 promotes angiogenesis and tumor growth in nasopharyngeal carcinoma.

CD93, also known as the complement component C1q receptor (C1qRp), has been reported to promote the progression of some cancer types. However, the expression and physiological significance of CD93 in nasopharyngeal carcinoma (NPC) remain largely elusive. In this study, we first examined the expression of CD93 in NPC and experimentally manipulated its expression. We observed that vascular CD93 expression is elevated in NPC and is correlated with T classification, N classification, distant metastasis, clinical stage and poor prognosis (all P < 0.05). In addition, overexpression of CD93 promoted angiogenesis in vitro. What's more, we found that CD93 was highly expressed in NPC tissues and cells, and the regulation of CD93 on cell proliferation was determined by cell counting kit (CCK)-8 assay and cell cycle analyses. Our findings provide unique insight into the pathogenesis of NPC and underscore the need to explore novel therapeutic targets such as CD93 to improve NPC treatment.

Endoscopic Management of Vascular Sinonasal Tumors, Including Angiofibroma.

The greatest challenge in the surgical treatment of angiofibromas is dealing with the hypervascularity of these tumors. Staging systems that take into account the vascularity of the tumor may be more prognostic. A variety of treatment strategies are used to deal with the vascularity of angiofibromas, including preoperative embolization, segmentation of the tumor into vascular territories, use of hemostatic tools, and staging of surgery. Even large angiofibromas with intracranial extension and residual vascularity can be successfully managed by a skull base team using endoscopic techniques.

Association between vascular supply, stage and tumour size of juvenile nasopharyngeal angiofibroma.

Juvenile nasopharyngeal angiofibroma (JNA) is a highly vascular tumour seen in adolescent males. To study the vascular pattern of these tumours, we retrospectively reviewed the records of patients with JNA who underwent preoperative angiography. Most (82.2 %) of the 45 patients assessed were Radkowski stage III with a mean size of 5.29 cm. There was a significant association between tumour stage and size (p = 0.029). Ten different vessels were seen to supply these tumours. All tumours had primary supply from the distal third of the ipsilateral internal maxillary artery (IMA). Accessory vessel supply was chiefly from the Vidian branch of internal carotid artery (ICA) (55.6 %). Stage III tumours were supplied by a greater number of feeding vessels than earlier stage tumours (p < 0.01). Larger tumours were more likely to have ICA supply (p = 0.04). Bilateral supply was seen in 48.7 %. However, there was no predominance of bilateral over ipsilateral IMA supply even in advanced stage tumours. One patient in our series was found to have a caroticocavernous fistula. Residual or recurrent tumours were characterized by new vasculature (100 %) and greater accessory supply from the ipsilateral ICA (85.7 %). Our study highlights the fact that surgical planning cannot be dependent on staging alone and should include preoperative assessment of tumour vasculature by angiography.