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BACKGROUND: NF2-related schwannomatosis (NF2-SWN, formerly called neurofibromatosis type 2) is a tumor predisposition syndrome that is manifested by multiple vestibular schwannomas, nonvestibular schwannomas, meningiomas, and ependymomas. The condition is relentlessly progressive with no approved therapies. On the basis of preclinical activity of brigatinib (an inhibitor of multiple tyrosine kinases) in NF2-driven nonvestibular schwannoma and meningioma, data were needed on the use of brigatinib in patients with multiple types of progressive NF2-SWN tumors. METHODS: In this phase 2 platform trial with a basket design, patients who were 12 years of age or older with NF2-SWN and progressive tumors were treated with oral brigatinib at a dose of 180 mg daily. A central review committee evaluated one target tumor and up to five nontarget tumors in each patient. The primary outcome was radiographic response in target tumors. Key secondary outcomes were safety, response rate in all tumors, hearing response, and patient-reported outcomes. RESULTS: A total of 40 patients (median age, 26 years) with progressive target tumors (10 vestibular schwannomas, 8 nonvestibular schwannomas, 20 meningiomas, and 2 ependymomas) received treatment with brigatinib. After a median follow-up of 10.4 months, the percentage of tumors with a radiographic response was 10% (95% confidence interval [CI], 3 to 24) for target tumors and 23% (95% CI, 16 to 30) for all tumors; meningiomas and nonvestibular schwannomas had the greatest benefit. Annualized growth rates decreased for all tumor types during treatment. Hearing improvement occurred in 35% (95% CI, 20 to 53) of eligible ears. Exploratory analyses suggested a decrease in self-reported pain severity during treatment (-0.013 units per month; 95% CI, -0.002 to -0.029) on a scale from 0 (no pain) to 3 (severe pain). No grade 4 or 5 treatment-related adverse events were reported. CONCLUSIONS: Brigatinib treatment resulted in radiographic responses in multiple tumor types and clinical benefit in a heavily pretreated cohort of patients with NF2-SWN. (Funded by the Children's Tumor Foundation and others; INTUITT-NF2 ClinicalTrials.gov number, NCT04374305.).
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Antineoplásicos , Neurofibromatose 2 , Compostos Organofosforados , Pirimidinas , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neurilemoma/tratamento farmacológico , Neurilemoma/diagnóstico por imagem , Neurofibromatose 2/diagnóstico por imagem , Neurofibromatose 2/tratamento farmacológico , Neurofibromatose 2/terapia , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Administração Oral , Progressão da Doença , Imageamento por Ressonância Magnética , Carga Tumoral/efeitos dos fármacos , Transtornos da Audição/tratamento farmacológico , Transtornos da Audição/etiologia , Qualidade de VidaRESUMO
Cholesterol granulomas (CGs) are the most common benign lesions of the petrous apex (PA) and have distinct computed tomography (CT) and magnetic resonance imaging (MRI) characteristics. On CT, CGs of the PA (PACG) present as expansile lesions with erosion of bony trabeculae. MRI shows a hyperintense lesion on T1-and T2-weighted images and do not enhance with gadolinium. The objective is to describe the radiographic features of CGs of the skull base that do not arise from the PA. This study is a retrospective review. Three patients were operated on for suspected recurrent endolymphatic sac tumor, intracranial cholesteatoma, and recurrent sphenoid wing meningioma based on CT and MRI findings. Pathology results were consistent with CG in all three cases. All patients had bone erosion on CT. These skull base CGs did not demonstrate similar MRI features. These lesions were hyperintense, iso-to-hyperintense, and hypointense on T1-weighted MRI, respectively. These CGs were hyperintense in two cases and iso-to-hyperintense in one case on T2-weighted MRI. These lesions either demonstrated central or rim enhancement after gadolinium administration. Skull base CGs that do not arise from the PA demonstrate a broad spectrum of radiographic characteristics on MRI that are not typical of PACG.
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Colesterol , Granuloma de Corpo Estranho/diagnóstico por imagem , Base do Crânio/diagnóstico por imagem , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: Compare cochlear implant (CI) outcomes in English speakers, Spanish speakers, and bilingual Hispanics. STUDY DESIGN: Retrospective review. SETTING: Academic tertiary care center. METHODS: Eighty-five postlingually deafened adults unilaterally implanted between January 2014 and December 2018 were stratified by primary language. Primary outcomes were: (1) English consonant-nucleus-consonant and Spanish bisyllables word tests in quiet, and (2) English AzBio and Latin American Hearing In Noise Test (LA-HINT) sentence tests in quiet and in noise at multiple time-intervals postactivation. RESULTS: In the respective languages, primary Spanish speakers (n = 24), and English speakers (n = 61) experienced the greatest increases in average scores for word and sentence tests in quiet during the first 6 months postactivation, with gradual increases in average scores over time. English speakers performed significantly worse on AzBio tests in noise, compared to quiet, while the addition of noise did not significantly affect average LA-HINT scores in Spanish speakers across multiple time intervals. An early ceiling effect was also demonstrated for LA-HINT. Although not significant, bilingual Hispanics (n = 12) had lower average AzBio in quiet scores than English speakers and higher average LA-HINT in quiet scores than the Spanish speakers across multiple time intervals. CONCLUSION: English and Spanish CI users experienced the greatest increases in speech understanding in quiet the first few months after implant activation. An early ceiling effect is demonstrated with LA-HINT, indicating LA-HINT is not appropriate for evaluating longitudinal CI outcomes in Spanish speakers. Bilingual Hispanics represent a unique group, and further investigations are necessary to understand speech perception patterns in both languages and develop the best CI test strategies for these individuals.
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Implante Coclear , Implantes Cocleares , Percepção da Fala , Adulto , Humanos , Percepção da Fala/fisiologia , Idioma , RuídoRESUMO
Vestibular schwannomas (VSs) are benign tumors that develop after biallelic inactivation of the neurofibromatosis type 2 (NF2) gene that encodes the tumor suppressor merlin. Merlin inactivation leads to cell proliferation by dysregulation of receptor tyrosine kinase signaling and other intracellular pathways. In VS without NF2 mutations, dysregulation of non-NF2 genes can promote pathways favoring cell proliferation and tumorigenesis. The tumor microenvironment of VS consists of multiple cell types that influence VS tumor biology through complex intercellular networking and communications.
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Neurofibromatose 2 , Neuroma Acústico , Humanos , Neuroma Acústico/genética , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Neurofibromatose 2/genética , Transdução de Sinais/genética , Biologia , Genes da Neurofibromatose 2 , Microambiente TumoralRESUMO
BACKGROUND: Vestibular schwannomas (VS) are benign intracranial tumors caused by loss of function of the merlin tumor suppressor. We tested three hypotheses related to radiation, hearing loss (HL), and VS cell survival: (1) radiation causes HL by injuring auditory hair cells (AHC), (2) fractionation reduces radiation-induced HL, and (3) single fraction and equivalent appropriately dosed multi-fractions are equally effective at controlling VS growth. We investigated the effects of single fraction and hypofractionated radiation on hearing thresholds in rats, cell death pathways in rat cochleae, and viability of human merlin-deficient Schwann cells (MD-SC). METHODS: Adult rats received cochlear irradiation with single fraction (0 to 18 Gray [Gy]) or hypofractionated radiation. Auditory brainstem response (ABR) testing was performed for 24 weeks. AHC viabilities were determined using immunohistochemistry. Neonatal rat cochleae were harvested after irradiation, and gene- and cell-based assays were conducted. MD-SCs were irradiated, and viability assays and immunofluorescence for DNA damage and cell cycle markers were performed. RESULTS: Radiation caused dose-dependent and progressive HL in rats and AHC losses by promoting expression of apoptosis-associated genes and proteins. When compared to 12 Gy single fraction, hypofractionation caused smaller ABR threshold and pure tone average shifts and was more effective at reducing MD-SC viability. CONCLUSIONS: Investigations into the mechanisms of radiation ototoxicity and VS radiobiology will help determine optimal radiation regimens and identify potential therapies to mitigate radiation-induced HL and improve VS tumor control.
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BACKGROUND: The vestibular schwannoma (VS) secretome can initiate monocyte recruitment and macrophage polarization to M1 (proinflammatory) and/or M2 (protumorigenic) phenotypes, which in turn secrete additional cytokines that contribute to the tumor microenvironment. Profiling cyst fluid and cerebrospinal fluid (CSF) in cystic VS provides a unique opportunity to understand mechanisms that may contribute to tumor progression and cyst formation. HYPOTHESIS: Cystic VSs secrete high levels of cytokines into cyst fluid and express abundant M1 and M2 macrophages. METHODS: Tumor, CSF, and cyst fluid were prospectively collected from 10 cystic VS patients. Eighty cytokines were measured in fluid samples using cytokine arrays and compared with normal CSF from normal donors. Immunofluorescence was performed for CD80 + M1 and CD163 + M2 macrophage markers. Demographic, audiometric, and radiographic information was obtained through retrospective chart review. RESULTS: Cyst fluid expressed more osteopontin and monocyte chemotactic protein-1 (MCP-1; p < 0.0001), when compared with normal CSF. Cyst fluid also expressed more protein ( p = 0.0020), particularly MCP-1 ( p < 0.0001), than paired CSF from the same subjects. MCP-1 expression in cyst fluid correlated with CD80 + staining in VS tissue ( r = 0.8852; p = 0.0015) but not CD163 + staining. CONCLUSION: Cyst fluid from cystic VS harbored high levels of osteopontin and MCP-1, which are cytokines important in monocyte recruitment and macrophage polarization. MCP-1 may have a significant role in molding the tumor microenvironment, by polarizing monocytes to CD80 + M1 macrophages in cystic VS. Further investigations into the role of cytokines and macrophages in VS may lead to new avenues for therapeutic intervention.
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Neuroma Acústico , Osteopontina , Humanos , Macrófagos Associados a Tumor/metabolismo , Líquido Cístico/metabolismo , Estudos Retrospectivos , Citocinas/metabolismo , Microambiente TumoralRESUMO
Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas (VS). Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function, and other complications. Kinase inhibitor monotherapies have been evaluated clinically for NF2 patients with limited success, and more effective nonsurgical therapies are urgently needed. Schwannoma model cells treated with PI3K inhibitors upregulate activity of the focal adhesion kinase (FAK) family as a compensatory survival pathway. We screened combinations of 13 clinically relevant PI3K and FAK inhibitors using human isogenic normal and merlin-deficient Schwann cell lines. The most efficacious combination was PI3K/mTOR inhibitor omipalisib with SRC/FAK inhibitor dasatinib. Sub-GI50 doses of the single drugs blocked phosphorylation of their major target proteins. The combination was superior to either single agent in promoting a G1 cell-cycle arrest and produced a 44% decrease in tumor growth over a 2-week period in a pilot orthotopic allograft model. Evaluation of single and combination drugs in six human primary VS cell models revealed the combination was superior to the monotherapies in 3 of 6 VS samples, highlighting inter-tumor variability between patients consistent with observations from clinical trials with other molecular targeted agents. Dasatinib alone performed as well as the combination in the remaining three samples. Preclinically validated combination therapies hold promise for NF2 patients and warrants further study in clinical trials.
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Antineoplásicos , Neurilemoma , Neurofibromatose 2 , Humanos , Neurofibromatose 2/tratamento farmacológico , Neurofibromatose 2/genética , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Fosfatidilinositol 3-Quinases/farmacologia , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Dasatinibe/farmacologia , Fosfatidilinositol 3-Quinase/farmacologia , Fosfatidilinositol 3-Quinase/uso terapêutico , Neurilemoma/tratamento farmacológico , Neurilemoma/genética , Antineoplásicos/farmacologia , Proliferação de CélulasRESUMO
A direct communication between the glossopharyngeal and facial nerves known as Haller's ansa exists in a minority of patients. Clinical manifestations of this anastomosis are not commonly observed. We describe post-operative facial movement with swallowing after facial nerve sacrifice in two patients who underwent surgery for skull base tumors. Patient 1, a 49-year-old male, received a transcochlear approach for resection of endolymphatic sac tumor and intratemporal facial nerve sacrifice without nerve reconstruction. Patient 2, a 23-year-old female, underwent surgery for left jugular paraganglioma, requiring facial nerve sacrifice and cable graft. Both patients had preoperative facial weakness and intraoperative preservation of the glossopharyngeal nerve. A literature review related to Haller's ansa was performed using PubMed, EMBASE, and Scopus from 1920-2021. Post-operatively, both patients demonstrated oral commissure movement with swallowing, suggesting a communication between the glossopharyngeal nerve and the facial nerve (Haller's ansa). Although anatomical references to Haller's ansa exist, there are no reported clinical manifestations of this neural anastomosis. Glossopharyngeal-facial nerve communications may contribute to facial tone and movement. Pre- and post-operative assessment of facial nerve movement with swallowing may help assess for the presence of Haller's ansa. Better understanding of this neural anastomosis may have implications for facial reanimation surgery. Laryngoscope, 132:1750-1752, 2022.
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Nervo Facial , Paralisia Facial , Adulto , Face , Nervo Facial/cirurgia , Paralisia Facial/etiologia , Paralisia Facial/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Base do Crânio/cirurgia , Adulto JovemRESUMO
Schwannomatosis is a rare genetic disorder that predisposes individuals to development of multiple schwannomas mainly in spinal and peripheral nerves and to debilitating chronic pain often unrelated to any schwannoma. Pathogenic variants of two genes, SMARCB1 and LZTR1, are causal in familial cases. However, many schwannomatosis patients lack mutations in these genes. Surgery is the standard treatment for schwannomas but leaves patients with increasing neurological deficits. Pain management is a daily struggle controlled by the use of multiple analgesic and anti-inflammatory drugs. There is a need for both nonsurgical treatment to manage tumor growth and nonaddictive, nonsedative pain control. Because standard clinical trials are exceedingly difficult for patients with rare disorders, precision medicine approaches offer the possibility of bespoke therapeutic regimens to control tumor growth. As a proof of principle, we obtained a bio-specimen of paraspinal schwannoma from a schwannomatosis patient with a germline point mutation in the SMARCB1/INI gene. We created an hTERT immortalized cell line and tested the ability of targeted small molecules with efficacy in neurofibromatosis type 2-related schwannomas to reduce cell viability and induce cell death. We identified WP1066, a STAT3 inhibitor, currently in phase 2 clinical trials for pediatric and adult brain tumors as a lead compound. It reduced cell viability and STAT-3 phosphorylation and induced expression of markers for both necroptosis and caspase-dependent cell death. The results demonstrate feasibility in creating patient-derived cell lines for use in precision medicine studies.
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Neurilemoma , Neurofibromatoses , Piridinas , Neoplasias Cutâneas , Tirfostinas , Adulto , Morte Celular , Linhagem Celular Tumoral , Criança , Humanos , Neurilemoma/genética , Neurilemoma/patologia , Neurofibromatoses/genética , Neurofibromatoses/patologia , Piridinas/farmacologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fatores de Transcrição/genética , Tirfostinas/farmacologiaRESUMO
OBJECTIVES: Determine whether asymmetric hearing loss (AHL) affects postoperative speech outcomes in cochlear implant (CI) patients. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary care hospital. PATIENTS: Adult English-speaking patients with unilateral CIs implanted between 2014 and 2018 were stratified into NonAHL and AHL groups based on preoperative AzBio scores in quiet from the nonimplanted ear (0-50% vs. 51-100%, respectively). INTERVENTIONS: CI surgery in the poorer performing ear. MAIN OUTCOME MEASURES: Postoperative consonant-nucleusconsonant (CNC) word and AzBio sentence test scores in quiet and/or noise at +5âdB signal-to-noise ratio (SNR). RESULTS: Of 512 patients, 33 non-AHL and 27 AHL patients were included. Average ages were 65.6 and 63.6âyears, respectively. As expected, preoperative AzBio scores in quiet from the nonimplanted ear were higher in the AHL group (95% confidence interval [95%CI]: 66.4-76.4%) than the non-AHL group at baseline (95%CI: 12.3-23.6%). In both cohorts, AzBio scores in quiet from the implanted ear improved from baseline, with 24-month scores (95%CI: 73.8 - 84.9%) being higher than preoperative scores (95%CI: 13.2-23.1%). There were also significant differences in AzBio scores in quiet between cohorts overall (pâ =â0.0120) on mixed model analysis, with the AHL group performing â¼6.4% better than the non-AHL group; however, differences were not significant when scores were stratified by time. In addition, there were no significant differences in CNC in quiet and AzBio scores in noise at +5âdB SNR between cohorts (pâ =â0.1786 and pâ =â0.6215, respectively). CONCLUSIONS: After CI, patients with AHL can achieve scores on word and sentence tests at least comparable to traditional CI candidates, supporting the expansion of CI candidacy to include patients with AHL.
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Implante Coclear , Implantes Cocleares , Perda Auditiva , Percepção da Fala , Adulto , Humanos , Estudos Retrospectivos , Fala , Resultado do TratamentoRESUMO
Objectives Vestibular schwannomas (VS) are intracranial tumors, which are caused by NF2 gene mutations that lead to loss of merlin protein. A treatment for VS is stereotactic radiosurgery, a form of radiation. To better understand the radiobiology of VS and radiation toxicity to adjacent structures, our main objectives were (1) investigate effects of single fraction (SF) radiation on viability, cytotoxicity, and apoptosis in normal Schwann cells (SCs) and merlin-deficient Schwann cells (MD-SCs) in vitro, and (2) analyze expression of double strand DNA breaks (γ-H2AX) and DNA repair protein Rad51 following irradiation. Study Design This is a basic science study. Setting This study is conducted in a research laboratory. Participants Patients did not participate in this study. Main Outcome Measures In irradiated normal SCs and MD-SCs (0-18 Gy), we measured (1) viability, cytotoxicity, and apoptosis using cell-based assays, and (2) percentage of cells with γ-H2AX and Rad51 on immunofluorescence. Results A high percentage of irradiated MD-SCs expressed γ-H2AX, which may explain the dose-dependent losses in viability in rodent and human cell lines. In comparison, the viabilities of normal SCs were only compromised at higher doses of radiation (>12 Gy, human SCs), which may be related to less Rad51 repair. There were no further reductions in viability in human MD-SCs beyond 9 Gy, suggesting that <9 Gy may be insufficient to initiate maximal tumor control. Conclusion The MD-SCs are more susceptible to radiation than normal SCs, in part through differential expression of γ-H2AX and Rad51. Understanding the radiobiology of MD-SCs and normal SCs is important for optimizing radiation protocols to maximize tumor control while limiting radiation toxicity in VS patients.
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Neurofibromatosis Type 2 (NF2) is a rare tumor disorder caused by pathogenic variants of the merlin tumor suppressor encoded by NF2. Patients develop vestibular schwannomas (VS), peripheral schwannomas, meningiomas, and ependymomas. There are no approved drug therapies for NF2. Previous work identified phosphoinositide-3 kinase (PI3K) as a druggable target. Here we screened PI3K pathway inhibitors for efficacy in reducing viability of human schwannoma cells. The lead compound, CUDC907, a dual histone deacetylase (HDAC)/PI3K inhibitor, was further evaluated for its effects on isolated and nerve-grafted schwannoma model cells, and primary VS cells. CUDC907 (3 nM IG50) reduced human merlin deficient Schwann cell (MD-SC) viability and was 5-100 fold selective for MD over WT-SCs. CUDC907 (10 nM) promoted cell cycle arrest and caspase-3/7 activation within 24 h in human MD-SCs. Western blots confirmed a dose-dependent increase in acetylated lysine and decreases in pAKT and YAP. CUDC907 decreased tumor growth rate by 44% in a 14-day treatment regimen, modulated phospho-target levels, and decreased YAP levels. In five primary VS, CUDC907 decreased viability, induced caspase-3/7 cleavage, and reduced YAP levels. Its efficacy correlated with basal phospho-HDAC2 levels. CUDC907 has cytotoxic activity in NF2 schwannoma models and primary VS cells and is a candidate for clinical trials.
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Neurilemoma , Neurofibromatose 2 , Humanos , Apoptose , Caspase 3 , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases , Lisina , Neurilemoma/patologia , Neurofibromatose 2/tratamento farmacológico , Neurofibromatose 2/metabolismo , Neurofibromatose 2/patologia , Neurofibromina 2 , Fosfatidilinositol 3-Quinases , Fosfatidilinositóis/farmacologia , Fosfatidilinositóis/uso terapêutico , Inibidores de Fosfoinositídeo-3 QuinaseRESUMO
HYPOTHESIS: AR42, a histone deacetylase (HDAC) inhibitor, reduces viability of primary vestibular schwannoma (VS) cells and delays tumor progression and hearing loss (HL) in a xenograft model of VS. BACKGROUND: The impact of HDAC expression on AR42 response in primary VS cells is unknown, as well as the effects of AR42 on VS-associated HL and imbalance. METHODS: Primary human VS cells (n = 7) were treated with AR42 (0-3.0 µM), and viability assays were conducted. Immunohistochemistry and western blotting for phosphorylated-HDAC2 (pHDAC2) were performed on tumor chunks. Pharmacokinetic studies were conducted in Fischer rats using mass spectrometry. Merlin-deficient Schwann cells were grafted onto cochleovestibular nerves of immunodeficient rats and treated with vehicle (n=7) or AR42 (25 mg/kg/day for 4weeks; n=12). Tumor bioluminescence imaging, auditory brainstem response (ABR), and rotarod tests were conducted to 6weeks. Final tumor weight and toxicities were measured. RESULTS: AR42 caused dose-dependent reductions in viability of VS cells. Tumors with higher pHDAC2:HDAC2 ratios had greater reductions in viability with AR42. On pharmacokinetic studies, AR42 reached peak levels in nerve ~24 hours after oral administration. Although AR42-treated rats demonstrated mean ABR threshold shifts ~10 to 20 dB lower than controls, this did not persist nor reach significance. When compared to controls, AR42 did not affect tumor bioluminescence, tumor weight, and rotarod measurements. CONCLUSIONS: Response of primary VS cells to AR42 may be influenced by pHDAC2 expression in tumor. Although AR42 may delay HL in our xenograft model, it did not halt tumor growth or vestibular dysfunction. Further investigations are warranted to evaluate the AR42 effectiveness in NF2-associated VS.
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Neuroma Acústico , Animais , Modelos Animais de Doenças , Xenoenxertos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Neuroma Acústico/patologia , Ratos , Células de Schwann/metabolismoRESUMO
OBJECTIVE: Perineural invasion (PNI) negatively affects disease-specific survival in patients with head and neck cutaneous squamous cell carcinoma (HNcSCC). We aim to analyze the prognostic implications of PNI-related features. STUDY DESIGN: Retrospective cohort study. SETTING: Academic tertiary care hospital. METHODS: Retrospective chart review was performed on 104 patients diagnosed with HNcSCC between January 2011 and October 2019 who underwent resection, parotidectomy, and neck dissection with more than 1 year of follow-up. PNI was classified as incidental (identified on histopathology alone) or clinical (present on radiography and/or physical exam). Primary outcome measures were overall survival and disease-free survival (DFS). Kaplan-Meier analysis, logistic regression, and Cox regression were performed. RESULTS: The overall 5-year DFS was 57.9%. Sixty-one patients had PNI. On histopathology, 28 lesions showed complete nerve encirclement, 10 involved >5 nerves, and 12 involved named nerves. Patients with facial weakness (P = .026) and positive margins (P = .0029) had a higher likelihood of histopathologic PNI, and positive margins retained significance on multivariable analysis (P = .0079). Worse DFS was seen in patients with PNI (P = .004), advanced tumor stage (P = .049), positive margins (P = .014), and >5 nerves involved (P = .0061). Furthermore, histopathologic PNI was a predictor of DFS (hazard ratio [HR], 3.07; 95% CI, 0.33-1.38; P = .0061) overall and in the clinical PNI cohort (HR, 3.43; 95% CI, 1.65-7.10; P = .00091). CONCLUSION: DFS was significantly worse in patients with PNI, facial nerve weakness, advanced T stage, positive margins, and multiple nerve involvement. Further characterization of PNI features may help improve prognostic predictions and identify patients who may benefit from more aggressive treatment.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Cutâneas , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Margens de Excisão , Invasividade Neoplásica/patologia , Nervos Periféricos/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
OBJECTIVE: To describe the RAD51 response (DNA repair) to radiation-induced DNA damage in patient-derived vestibular schwannoma (VS) cells and investigate the utility of RAD51 inhibitor (RI-1) in enhancing radiation toxicity. STUDY DESIGN: Basic and translational science. SETTING: Tertiary academic facility. METHODS: VS tumors (n = 10) were cultured on 96-well plates and 16-well slides, exposed to radiation (0, 6, 12, or 18 Gy), and treated with RI-1 (0, 5, or 10 µM). Immunofluorescence was performed at 6 hours for γ-H2AX (DNA damage marker), RAD51 (DNA repair protein), and p21 (cell cycle arrest protein). Viability assays were performed at 96 hours, and capillary Western blotting was utilized to determine RAD51 expression in naïve VS tumors (n = 5). RESULTS: VS tumors expressed RAD51. In cultured VS cells, radiation initiated dose-dependent increases in γ-H2AX and p21 expression. VS cells upregulated RAD51 to repair DNA damage following radiation. Addition of RI-1 reduced RAD51 expression in a dose-dependent manner and was associated with increased γ-H2AX levels and decreased viability in a majority of cultured VS tumors. CONCLUSION: VS may evade radiation injury by entering cell cycle arrest and upregulating RAD51-dependent repair of radiation-induced double-stranded breaks in DNA. Although there was variability in responses among individual primary VS cells, RAD51 inhibition with RI-1 reduced RAD51-dependent DNA repair to enhance radiation toxicity in VS cells. Further investigations are warranted to understand the mechanisms of radiation resistance in VS and determine whether RI-1 is an effective radiosensitizer in patients with VS.
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Neuroma Acústico , Rad51 Recombinase , Lesões por Radiação , Humanos , Linhagem Celular Tumoral , Dano ao DNA , Reparo do DNA , Rad51 Recombinase/antagonistas & inibidores , Células Tumorais Cultivadas/efeitos da radiaçãoRESUMO
BACKGROUND: Papaverine, a vasodilator approved for use by the U.S. Food and Drug Administration, has shown efficacy in treating vasospasm in cardiology, urology, and nephrology. The vasodilatory effect of papaverine is also hoped to protect the facial nerve from ischemic damage and nerve manipulation during vestibular schwannoma surgery. Our institution uses intracisternal papaverine irrigation during vestibular schwannoma resection to protect the facial nerve in patients with neuromonitoring changes. Our objective was to investigate the safety and facial nerve outcomes of intracisternal papaverine irrigation during vestibular schwannoma resection. METHODS: We retrospectively reviewed patients who underwent resection of vestibular schwannoma at our institution between 2008 and 2021. Patients received papaverine if the intraoperative facial nerve stimulation threshold increased above 0.05 mA. Postoperative outcomes were compared with control patients who did not receive papaverine. RESULTS: A total of 283 cases were included in our analysis. Patients who received papaverine (n = 60) had lower immediate postoperative House-Brackmann (HB) grades than did control individuals (mean, 1.54 vs. 1.95; P = 0.029) and a lower likelihood of immediate postoperative HB grade >1 (odds ratio, 0.514; P = 0.039). At long-term follow-up, there was no significant difference in HB grade. Papaverine use was not associated with increased rates of perioperative complications (P = 0.24). CONCLUSIONS: The off-label use of intracisternal papaverine irrigation during vestibular schwannoma resection can certainly be used safely for select cases. It is associated with improved immediate postoperative facial nerve outcomes, similar long-term facial nerve outcomes, and no significant increase in complications.
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Traumatismos do Nervo Facial , Neuroma Acústico , Humanos , Nervo Facial/cirurgia , Neuroma Acústico/cirurgia , Neuroma Acústico/complicações , Papaverina , Estudos Retrospectivos , Traumatismos do Nervo Facial/etiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
OBJECTIVE: The purpose of this study is to retrospectively evaluate the clinical and surgical outcomes of a large surgical series of vestibular schwannoma from North America over 20 years. METHODS: After institutional review board approval a retrospective review of the senior author's personal case logs to identify patients who had operations for vestibular schwannoma was performed. The clinical notes, operative record, preoperative and postoperative imagings, and long-term clinical follow-up notes were evaluated. RESULTS: A total of 415 patients who underwent 420 surgeries were identified from the years 1998-2021. The average length of follow-up was 3 years and 9 months. Overall, at last follow-up the rate of "good" facial nerve outcomes (House-Brackmann [HB] score I and II) was 86% and "poor" facial nerve outcomes (HB III-VI) was 14%. The amount of cerebellopontine angle extension (P = 0.023), tumor volume (P = 0.015), facial nerve consistency (P < 0.001), preoperative HB score (P < 0.001), and FN stimulation threshold at the end of the procedure (P < 0.001) were correlated to facial nerve function at the last follow-up. CONCLUSIONS: This study represents one of the largest recently reported surgical series of vestibular schwannoma in North American literature with available long term follow-up. Facial nerve outcomes correlated with cerebellopontine angle extension, tumor volume, facial nerve stimulation threshold, facial nerve consistency, preoperative facial nerve function, and history of a prior resection. Tumor recurrence remains significantly higher after subtotal resection. We believe the data supports a continuation of a strategy of general intent of gross total resection, greatly modifiable by intraoperative findings and judgment.
Assuntos
Neuroma Acústico , Humanos , Neuroma Acústico/diagnóstico por imagem , Neuroma Acústico/cirurgia , Nervo Facial/diagnóstico por imagem , Nervo Facial/cirurgia , Seguimentos , Estudos Retrospectivos , Procedimentos Neurocirúrgicos/efeitos adversos , Procedimentos Neurocirúrgicos/métodos , Resultado do Tratamento , Recidiva Local de Neoplasia/cirurgia , Complicações Pós-Operatórias/cirurgiaRESUMO
OBJECTIVES: As specialists of the upper airway, otolaryngologists are at high risk for COVID-19 transmission. N95 and half-face respirator (HFR) masks are commonly worn, each with advantages in functionality and comfort. In this study, physiologic and psychological parameters of prolonged N95 vs HFR wear were compared. STUDY DESIGN: Prospective crossover cohort study. SETTING: Single academic tertiary care hospital. METHODS: A prospective crossover cohort study was performed. Healthy otolaryngology trainees and medical students (N = 23) participated and wore N95 and HFR masks continuously for 3 hours each on separate days. Various measures were analyzed: vitals, spirometry variables, scores on the State-Trait Anxiety Inventory and HIT-6 (Headache Impact Test-6), distress, and "difficulty being understood." RESULTS: The average age was 26.3 years (SD, 3.42). There were no significant differences in vital signs and spirometry variables between N95 and HFR wear. N95 wear was associated with decreases in oxygen saturation of approximately 1.09% more than with HFRs (95% CI, 0.105-2.077). State-Trait Anxiety Inventory scores increased more with HFR wear when compared with mean changes with N95 wear (95% CI, 1.350-8.741). There were no significant differences in HIT-6 scores or distress levels between masks. The proportions of participants reporting difficulty being understood was significantly higher with HFRs. CONCLUSIONS: Oxygen saturation decreases with prolonged N95 wear, but anxiety and difficulty being understood are greater with HFR wear. Although HFRs have less resistance to gas exchange, N95 respirators may produce less anxiety and distress in clinical situations. Further studies are warranted to evaluate the clinical significance of these differences. LEVEL OF EVIDENCE: 2.
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OBJECTIVE: (1) Characterize the distribution of M1 and M2 macrophages in vestibular schwannomas by hearing status. (2) Develop assays to assess monocyte migration and macrophage polarization in cocultures with vestibular schwannoma cells. STUDY DESIGN: Basic and translational science. SETTING: Tertiary care center. METHODS: A retrospective chart review of 30 patients with vestibular schwannoma (VS) was performed. Patients were stratified into serviceable and unserviceable hearing groups. Immunohistochemistry for CD80+ M1 and CD163+ M2 macrophages was conducted. Primary VS cultures (n = 4) were developed and cocultured with monocytes. Immunohistochemistry for macrophage markers was performed to assess monocyte migration and macrophage polarization. RESULTS: Although tumors associated with unserviceable hearing had higher levels of CD80 and CD163 than those with serviceable hearing, the relationship was only significant with CD163 (P = .0161). However, CD163 level did not remain a significant predictor variable associated with unserviceable hearing on multivariate analysis when adjusted for other variables. In vitro assays show that VS cells induced monocyte migration and polarization toward CD80+ M1 or CD163+ M2 macrophage phenotypes, with qualitative differences in CD163+ macrophage morphologies between serviceable and unserviceable hearing groups. CONCLUSION: Vestibular schwannomas express varying degrees of CD80+ M1 and CD163+ M2 macrophages. We present evidence that higher expression of CD163+ may contribute to poorer hearing outcomes in patients with VS. We also describe in vitro assays in a proof-of-concept investigation that VS cells can initiate monocyte migration and macrophage polarization. Future investigations are warranted to explore the relationships between tumor, macrophages, secreted cytokines, and hearing outcomes in patients with VS.
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The most common oral cavity cancer is squamous cell carcinoma (SCC), of which perineural invasion (PNI) is a significant prognostic factor associated with decreased survival and an increased rate of locoregional recurrence. In the classical theory of PNI, cancer was believed to invade nerves directly through the path of least resistance in the perineural space; however, more recent evidence suggests that PNI requires reciprocal signaling interactions between tumor cells and nerve components, particularly Schwann cells. Specifically, head and neck SCC can express neurotrophins and neurotrophin receptors that may contribute to cancer migration towards nerves, PNI, and neuritogenesis towards cancer. Through reciprocal signaling, recent studies also suggest that Schwann cells may play an important role in promoting PNI by migrating toward cancer cells, intercalating, and dispersing cancer, and facilitating cancer migration toward nerves. The interactions of neurotrophins with their high affinity receptors is a new area of interest in the development of pharmaceutical therapies for many types of cancer. In this comprehensive review, we discuss diagnosis and treatment of oral cavity SCC, how PNI affects locoregional recurrence and survival, and the impact of adjuvant therapies on tumors with PNI. We also describe the molecular and cellular mechanisms associated with PNI, including the expression of neurotrophins and their receptors, and highlight potential targets for therapeutic intervention for PNI in oral SCC.