Matrix metalloproteinase 9: An emerging biomarker for classification of adherent vestibular schwannoma.

Background: The progression of vestibular schwannoma (VS) is intricately linked with interactions between schwannoma cells and the extracellular matrix. Surgical resection of VS is associated with substantial risks as tumors are adherent to the brainstem and cranial nerves. We evaluate the role of matrix metalloproteinase 9 (MMP9) in VS and explore its potential as a biomarker to classify adherent VS. Methods: Transcriptomic analysis of a murine schwannoma allograft model and immunohistochemical analysis of 17 human VS were performed. MMP9 abundance was assessed in mouse and human schwannoma cell lines. Transwell studies were performed to evaluate the effect of MMP9 on schwannoma invasion in vitro. Plasma biomarkers were identified from a multiplexed proteomic analysis in 45 prospective VS patients and validated in primary culture. The therapeutic efficacy of MMP9 inhibition was evaluated in a mouse schwannoma model. Results: MMP9 was the most highly upregulated protease in mouse schwannomas and was significantly enriched in adherent VS, particularly around tumor vasculature. High levels of MMP9 were found in plasma of patients with adherent VS. MMP9 outperformed clinical and radiographic variables to classify adherent VS with outstanding discriminatory ability. Human schwannoma cells secreted MMP9 in response to TNF-α which promoted cellular invasion and adhesion protein expression in vitro. Lastly, MMP9 inhibition decreased mouse schwannoma growth in vivo. Conclusions: We identify MMP9 as a preoperative biomarker to classify adherent VS. MMP9 may represent a new therapeutic target in adherent VS associated with poor surgical outcomes that lack other viable treatment options.

Tumor biomechanical stiffness by magnetic resonance elastography predicts surgical outcomes and identifies biomarkers in vestibular schwannoma and meningioma.

Variations in the biomechanical stiffness of brain tumors can not only influence the difficulty of surgical resection but also impact postoperative outcomes. In a prospective, single-blinded study, we utilize pre-operative magnetic resonance elastography (MRE) to predict the stiffness of intracranial tumors intraoperatively and assess the impact of increased tumor stiffness on clinical outcomes following microsurgical resection of vestibular schwannomas (VS) and meningiomas. MRE measurements significantly correlated with intraoperative tumor stiffness and baseline hearing status of VS patients. Additionally, MRE stiffness was elevated in patients that underwent sub-total tumor resection compared to gross total resection and those with worse postoperative facial nerve function. Furthermore, we identify tumor microenvironment biomarkers of increased stiffness, including αSMA + myogenic fibroblasts, CD163 + macrophages, and HABP (hyaluronic acid binding protein). In a human VS cell line, a dose-dependent upregulation of HAS1-3, enzymes responsible for hyaluronan synthesis, was observed following stimulation with TNFα, a proinflammatory cytokine present in VS. Taken together, MRE is an accurate, non-invasive predictor of tumor stiffness in VS and meningiomas. VS with increased stiffness portends worse preoperative hearing and poorer postoperative outcomes. Moreover, inflammation-mediated hyaluronan deposition may lead to increased stiffness.

Identifying Tumor Microenvironment Biomarkers in Adherent and Cystic Vestibular Schwannomas.

OBJECTIVE: A subset of vestibular schwannomas (VSs), including cystic tumors, have higher postoperative morbidity because of the presence of adhesions between the tumor, facial nerve (FN), and brainstem. We identify tumor microenvironment (TME) biomarkers to better classify these tumors and predict the degree of tumor adherence. STUDY DESIGN: Retrospective case series. SETTING: Tertiary skull base referral center. METHODS: Adult patients with cystic and solid VS matched in tumor size who underwent surgical resection were included. Expressions of seven biomarkers of extracellular matrix remodeling and tumor immune response were quantified via immunohistochemistry. The distribution of CD45+ immune cells was evaluated in intratumoral and perivascular compartments. The degree of tumor adherence was categorized as none, adherent to FN, or adherent to both FN and brainstem. RESULTS: Twenty-eight patients were included. Cystic VSs were significantly more adherent than solid VSs ( p = 0.02). Patients with adherent VS had shorter duration of symptoms and were more likely to undergo subtotal resection. In solid tumors, matrix metalloproteinase (MMP)-2 expression ( p = 0.02) and CD163+ macrophage infiltration ( p = 0.007) were correlated with tumor size. Linear discriminant analyses (LDAs) demonstrated MMP-2, MMP-14, CD80, CD163, and perivascular CD45 to be individually predictive of the degree of tumor adherence (all p < 0.05), with perivascular CD45 being the best independent predictor ( p = 0.005). An LDA model including these biomarkers demonstrated 100% accurate discrimination of all three levels of tumor adherence ( p = 0.04). CONCLUSIONS: Adherent VS have a distinct proinflammatory TME characterized by elevated MMP expression, enrichment of tumor-associated macrophages, and perivascular immune cell infiltration.

Comparison of Postoperative Outcomes in Cystic Versus Solid Vestibular Schwannoma in a Multi-institutional Cohort.

OBJECTIVE: Cystic vestibular schwannomas (cVSs) have more variable and less favorable clinical outcomes after microsurgical resection compared with solid VS (sVS). This study compares the preoperative presentation and postoperative outcomes between cVS and sVS. STUDY DESIGN: Retrospective cohort study. SETTING: Two tertiary skull base referral centers. METHODS: Consecutive adult patients who underwent VS resection from 2016 to 2021 were included. Univariate and multivariate analyses compared differences in baseline symptoms and postoperative outcomes between cVS and sVS. RESULTS: There were a total of 315 patients (64% female; mean age, 54 yrs) and 46 (15%) were cystic. cVS were significantly larger than sVS (maximum diameter, 28 vs. 18 mm, p < 0.001) and had higher rates of dysphagia and dysphonia preoperatively (p < 0.02). cVSs were more likely to undergo translabyrinthine resection (76 vs. 50%, p = 0.001) and have a higher rate of subtotal resection (STR) compared with sVS (30 vs. 13%, p = 0.003). At latest follow-up, fewer cVS achieved good facial nerve (FN) outcome (House-Brackmann [HB] I/II) (80 vs. 90%, p = 0.048). Subanalysis of cVS and sVS matched in tumor size, and surgical approach did not show differences in the rate of STR or FN outcomes (HB I/II, 82 vs. 78%, p = 0.79). CONCLUSION: In this large multi-institutional series, cVSs represent a distinct entity and are characterized by larger tumor size and higher incidence of atypical symptoms. Although cVSs were more likely to undergo STR and portend worse FN outcomes than sVSs, this may be due to their larger tumor size rather than the presence of the cystic component.

Current Mechanistic Understandings of Lymphedema and Lipedema: Tales of Fluid, Fat, and Fibrosis.

Lymphedema and lipedema are complex diseases. While the external presentation of swollen legs in lower-extremity lymphedema and lipedema appear similar, current mechanistic understandings of these diseases indicate unique aspects of their underlying pathophysiology. They share certain clinical features, such as fluid (edema), fat (adipose expansion), and fibrosis (extracellular matrix remodeling). Yet, these diverge on their time course and known molecular regulators of pathophysiology and genetics. This divergence likely indicates a unique route leading to interstitial fluid accumulation and subsequent inflammation in lymphedema versus lipedema. Identifying disease mechanisms that are causal and which are merely indicative of the condition is far more explored in lymphedema than in lipedema. In primary lymphedema, discoveries of genetic mutations link molecular markers to mechanisms of lymphatic disease. Much work remains in this area towards better risk assessment of secondary lymphedema and the hopeful discovery of validated genetic diagnostics for lipedema. The purpose of this review is to expose the distinct and shared (i) clinical criteria and symptomatology, (ii) molecular regulators and pathophysiology, and (iii) genetic markers of lymphedema and lipedema to help inform future research in this field.

Transtemporal Sigmoid Sinus Decompression: A Novel Surgical Procedure for the Treatment of Idiopathic Pulsatile Tinnitus.

OBJECTIVE: Idiopathic pulsatile tinnitus (IPT) is associated with high patient morbidity although treatment methods remain unsatisfactory. In the present study, the transtemporal sigmoid sinus decompression is used in the treatment of idiopathic pulsatile tinnitus. STUDY DESIGN: Retrospective case study. SETTING: Tertiary referral center. PATIENTS: From 2005 to 2020, 287 patients presented with a complaint of pulsatile tinnitus. After exclusion criteria, 25 patients were diagnosed with IPT. Those patients underwent treatment and were included in a retrospective study. INTERVENTIONS: Following failed conservative therapies, the primary author performed a transtemporal sigmoid sinus decompression surgery on the patients under general anesthesia. MAIN OUTCOME MEASURES: Long-term resolution of IPT was measured using the Tinnitus Handicap Inventory (THI). Outcome measurements were taken preoperatively, immediately postoperatively, three months postoperatively, and the status of all 25 patients is known at the time of this study. RESULTS: Transtemporal sigmoid sinus decompression was performed on 25 patients (mean age: 51.7 years, 80.0% female). Out of the 25 patients, 23 (92.0%) patients experienced complete resolution of their IPT. Statistically significant differences based on preoperative THI (mean THI: 4.19) were evident immediately after surgery (mean THI: 1.31; p < 0.001), at 3 months postoperatively (mean THI: 1.19; p < 0.001), and over a mean follow-up time of 68.7 months (range, 3-168 months) (mean THI: 1.38; p < 0.001). Out of the two patients considered unsuccessful, Case 21 experienced a partial resolution. No major postoperative complications occurred. CONCLUSIONS: Transtemporal sigmoid sinus decompression is a safe and effective surgical procedure demonstrated to give near total resolution in properly selected patients and provides long-term relief for patients with IPT.