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BACKGROUND: Long-segment, grade IV suprastomal tracheal stenosis is rare and difficult to treat (Carpenter et al., 2022 [1]). Patients with grade IV stenosis have significant quality of life impairments since they are tracheostomy dependent and aphonic. Open airway surgery is often needed to improve tracheal patency, restore the patient's voice, and progress towards decannulation (Abouyared et al., 2017 [2]). However, not all patients are candidates for upfront open surgery (Abouyared et al., 2017; Shamji, 2018 [2,3]). Therefore, it is important to develop and refine endoscopic interventions to improve quality of life for these patients. METHODS: We describe a step-by-step endoscopic approach to the recannulation of long-segment, grade IV suprastomal tracheal stenosis. Briefly, our approach utilizes dual (proximal & distal) visualization of the stenosis prior to passing a 25 gauge needle through the stenosis to identify the proper trajectory for recannulation. Then a 16 gauge needle is passed in the same manner, and a wire is placed through the needle and into the distal airway. Once the airway is recannulated, the initial pinpoint opening is gradually widened in Seldinger fashion over the wire with Savary dilators followed by balloon dilation. Finally, a suprastomal L-stent (modified Montgomery T-Tube) is placed to reduce the risk of restenosis (Edwards et al., 2023 [4]). CASE DISCUSSION: A 39-year-old woman with a past medical history significant for poorly controlled type I diabetes mellitus and polysubstance abuse presented with tracheostomy dependence and aphonia. She was diagnosed with a long-segment, grade IV suprastomal tracheal stenosis and initially underwent endoscopic recannulation. This intervention restored her voice and allowed for optimization of her medical conditions before open airway surgery. CONCLUSION: Most patients experience a significant improvement in their quality of life as their voice is typically restored following this procedure. Additionally, individuals who eventually require open airway surgery gain additional time for medical optimization. In our experience, this procedure represents a safe and effective means of extending the utility of traditional endoscopic airway interventions for the management of patients with grade IV stenosis.
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OBJECTIVES: To develop and implement a novel, comprehensive tool, the Digital Inequity Index (DII), that quantifiably measures modern-technology access in the US to assess the impact of digital inequity on laryngeal cancer (LC) care nationwide. METHODS: DII was calculated based on 17 census-tract level variables derived from the American Community Survey and Federal Communications Commission. Variables were categorized as infrastructure-access (i.e., electronic device ownership, type of broadband, internet provider availability, income-broadband subscription ratio) or sociodemographic (i.e., education, income, disability status), ranked and then averaged into a composite score. 22,850 patients from 2008 to 2017 in SEER were assessed for regression trends in long-term follow-up, survival, prognosis, and treatment across increasing overall digital inequity, as measured by the DII. This methodology allows for us to assess the independent contribution of digital inequity adjusted for socioeconomic confounders. RESULTS: With increasing overall digital inequity, length of long-term follow-up (p < 0.001) and survival (p = 0.025) decreased. Compared to LC patients with low DII, high DII was associated with increased odds of advanced preliminary staging (OR 1.06; 95 % CI 1.03-1.08), treatment with chemotherapy (OR 1.06; 95 % CI 1.04-1.08), and radiation therapy (OR 1.02; 95 % CI 1.00-1.04), as well as decreased odds of surgical resection (OR 0.96; 95 % CI 0.94-97). CONCLUSIONS: Digital inequities are associated with detrimental trends in LC patient outcomes in the US, allowing discourse for targeted means of alleviating disparities while contextualizing national sociodemographic trends of the impact of online access on informed care.
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Neoplasias Laríngeas , Humanos , Neoplasias Laríngeas/epidemiologia , Neoplasias Laríngeas/terapia , Atenção à Saúde , Comunicação , Prognóstico , RendaRESUMO
PURPOSE: To identify patient and tumor characteristics predictive of primary parotid malignancy. MATERIALS AND METHODS: Records were reviewed for patients who underwent parotidectomy at the University of Wisconsin from 1994 to 2013. Patients with primary parotid neoplasms were separated into benign or malignant subgroups. A multivariate logistic regression model was employed to compare categorical (gender, lesion side, nature of presentation, recurrence) and numerical variables (age, tumor size) between the benign and malignant groups. Mean BMI was compared between the groups by univariate analysis. RESULTS: 771 patients underwent parotidectomy from 1994 to 2013, and 474 had a primary parotid neoplasm. No relationship existed between malignancy and gender (p=0.610), lesion side (p=0.110), or BMI (p=0.196). Mean age (p=0.015) and tumor size (p=0.011) were significantly different between the benign and malignant groups. Patient presentation was classified into three categories: symptomatic (n=109), palpable and asymptomatic (n=303), and incidentally noted on imaging (n=57). From all patients with symptomatic, asymptomatic or incidentally noted masses, 41.3%, 10.6% and 5.3%, respectively, were diagnosed with malignant disease. There was a significant relationship between the patient's initial presentation and malignancy (p<0.001), and patients with facial nerve dysfunction or skin involvement had the greatest likelihood of malignancy. Finally, there was a significant association between malignancy and recurrence (p=0.001). CONCLUSIONS: In this study, age, tumor size, and nature of presentation were all associated with primary parotid malignancy. Understanding the impact of these features on the probability of malignancy is valuable in decision making and counseling of patients presenting with a newly diagnosed parotid neoplasm.
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Recidiva Local de Neoplasia/epidemiologia , Neoplasias Parotídeas/complicações , Neoplasias Parotídeas/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Neoplasias Parotídeas/cirurgia , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Carga Tumoral , WisconsinRESUMO
Human papillomaviruses (HPVs) are involved in approximately 5% of all human cancer. Although initially recognized for causing nearly all cases of cervical carcinoma, much data has now emerged implicating HPVs as a causal factor in other anogenital cancers as well as a subset of head and neck squamous cell carcinomas (HNSCCs), most commonly oropharyngeal cancers. Numerous clinical trials have demonstrated that patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) have improved survival compared to patients with HPV- cancers. Furthermore, epidemiological evidence shows the incidence of OPSCC has been steadily rising over time in the United States. It has been proposed that an increase in HPV-related OPSCCs is the driving force behind the increasing rate of OPSCC. Although some studies have revealed an increase in HPV+ head and neck malignancies over time in specific regions of the United States, there has not been a comprehensive study validating this trend across the entire country. Therefore, we undertook this meta-analysis to assess all literature through August 2013 that reported on the prevalence of HPV in OPSCC for patient populations within the United States. The results show an increase in the prevalence of HPV+ OPSCC from 20.9% in the pre-1990 time period to 51.4% in 1990-1999 and finally to 65.4% for 2000-present. In this manner, our study provides further evidence to support the hypothesis that HPV-associated OPSCCs are driving the increasing incidence of OPSCC over time in the United States.
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Alphapapillomavirus/isolamento & purificação , Carcinoma de Células Escamosas/virologia , Neoplasias Orofaríngeas/virologia , Alphapapillomavirus/genética , DNA Viral/isolamento & purificação , Humanos , Hibridização In Situ , Reação em Cadeia da Polimerase , Estados UnidosRESUMO
Coronary microvascular dysfunction is an underdiagnosed pathologic process that is associated with adverse clinical outcomes. There are data to suggest that coronary microvascular dysfunction, in some cases, may be genetically determined. We present an updated review of single nucleotide polymorphisms in coronary microvascular dysfunction.
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Doença da Artéria Coronariana , Isquemia Miocárdica , Humanos , Circulação Coronária , Polimorfismo de Nucleotídeo Único , Vasos Coronários/diagnóstico por imagem , Microcirculação , Doença da Artéria Coronariana/genéticaRESUMO
We describe 2 challenging cases of cardiac transthyretin amyloidosis initially treated as cardiac amyloidosis light chain in the setting of active myeloma. Endomyocardial biopsy with mass spectrometry was essential to confirm the appropriate diagnosis to direct the treatment.
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Neuropatias Amiloides Familiares , Cardiomiopatias , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Cardiomiopatias/diagnóstico , Pré-Albumina , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico , CoraçãoRESUMO
Cardiovascular risk stratification is a frequent evaluation performed by health professionals. Not uncommonly, requests for risk stratification involve activities or procedures that fall outside of the scope of current evidence-based guidelines. Estimating risk and providing guidance for these requests can be challenging due to limited available evidence. This review focuses on some of these unique requests, each of which are real examples encountered in our practice. We offer guidance by synthesizing the available medical literature and formulating recommendations on topics such as the initiation of testosterone and erectile dysfunction therapy, SCUBA and skydiving, polygraphy, and electroconvulsive therapy.
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Doenças Cardiovasculares , Disfunção Erétil , Masculino , Humanos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Fatores de Risco , Testosterona/uso terapêutico , Fatores de Risco de Doenças Cardíacas , Medição de RiscoRESUMO
Recurrence of cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) after heart transplant is rare, with rates of 5% in CS and 8% in GCM. We aim to identify all reported cases of recurrence in the literature and to assess clinical course, treatments, and outcomes to improve understanding of the conditions. A systematic review, utilizing Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, was conducted by searching MEDLINE/PubMed and Embase of all available literature describing post-transplant recurrent granulomatous myocarditis, CS, or GCM. Data on demographics, transplant, recurrence, management, and outcomes data were collected from each publication. Comparison between the 2 groups were made using standard statistical approaches. Post-transplant GM recurrence was identified in 39 patients in 33 total publications. Reported cases included 24 GCM, 12 CS, and 3 suspected cases. Case reports were the most frequent form of publication. Mean age of patients experiencing recurrence was 42 years for GCM and 48 years for CS and favored males (62%). Time to recurrence ranged from 2 weeks to 9 years post-transplant, occurring earlier in GCM (mean 1.8 vs 3.0 years). Endomyocardial biopsies (89%) were the most utilized diagnostic method over cardiac magnetic resonance and positron emission tomography. Recurrence treatment regimens involved only steroids in 40% of CS, whereas other immunomodulatory regimens were utilized in 70% of GCM. In conclusion, GCM and CS recurrence after cardiac transplantation holds associated risks including concurrent acute cellular rejection, a higher therapeutic demand for GCM recurrence compared with CS, and mortality. New noninvasive screening techniques may help modify post-transplant monitoring regimens to increase both early detection and treatment of recurrence.
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Cardiomiopatias , Transplante de Coração , Miocardite , Sarcoidose , Adulto , Humanos , Masculino , Biópsia , Cardiomiopatias/diagnóstico , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Células Gigantes/patologia , Transplante de Coração/efeitos adversos , Miocardite/diagnóstico , Miocardite/etiologia , Miocardite/terapia , Sarcoidose/diagnóstico , Sarcoidose/patologiaRESUMO
BACKGROUND AIMS: Mesenchymal stromal cells (MSC) have now been shown to reside in numerous tissues throughout the body, including the pancreas. Ex vivo culture-expanded MSC derived from many tissues display important interactions with different types of immune cells in vitro and potentially play a significant role in tissue homeostasis in vivo. In this study, we investigated the biologic and immunomodulatory properties of human pancreatic islet-derived MSC. METHODS: We culture-expanded MSC from cadaveric human pancreatic islets and characterized them using flow cytometry, differentiation assays and nuclear magnetic resonance-based metabolomics. We also investigated the immunologic properties of pancreatic islet-derived MSC compared with bone marrow (BM) MSC. RESULTS: Pancreatic islet and BM-derived MSC expressed the same cell-surface markers by flow cytometry, and both could differentiate into bone, fat and cartilage. Metabolomics analysis of MSC from BM and pancreatic islets also showed a similar set of metabolic markers but quantitative polymerase chain reactions showed that pancreatic islet MSC expressed more interleukin(IL)-1b, IL-6, STAT3 and FGF9 compared with BM MSC, and less IL-10. However, similar to BM MSC, pancreatic islet MSC were able to suppress proliferation of allogeneic T lymphocytes stimulated with anti-CD3 and anti-CD28 antibodies. CONCLUSIONS: Our in vitro analysis shows pancreatic islet-derived MSC have phenotypic, biologic and immunomodulatory characteristics similar, but not identical, to BM-derived MSC. We propose that pancreatic islet-derived MSC could potentially play an important role in improving the outcome of pancreatic islet transplantation by promoting engraftment and creating a favorable immune environment for long-term survival of islet allografts.
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Células da Medula Óssea , Ilhotas Pancreáticas , Células-Tronco Mesenquimais , Antígenos de Superfície/análise , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Cadáver , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Citometria de Fluxo , Expressão Gênica , Humanos , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismoRESUMO
CASE PRESENTATION: A 43-year-old woman with a medical history of hypothyroidism, psoriasis, and tobacco abuse (30-pack year history) who had quit smoking several months prior to presentation presented with pleuritic chest pain. She also noted a 2-year history of progressive numbness and weakness in her bilateral upper and lower extremities that now prevented her from completing her activities of daily living. She had worsening exertional dyspnea and a subjective 50-lb weight loss over the past year.
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Atividades Cotidianas , Dor no Peito , Adulto , Dor no Peito/diagnóstico , Dor no Peito/etiologia , Dispneia/diagnóstico , Dispneia/etiologia , Extremidades , Feminino , Humanos , FumarRESUMO
OBJECTIVES/HYPOTHESIS: Patients with tracheostomies have an anatomically altered connection between their upper and lower airways that could impact SARS-CoV-2 testing. Our goal was to evaluate for discordance in SARS-CoV-2 detection in hospitalized patients with COVID-19 and tracheostomies based on the site analyzed. STUDY DESIGN: Retrospective chart review. METHODS: This single-institution study evaluated hospitalized patients with COVID-19 who had tracheostomies placed during their treatment. We analyzed SARS-CoV-2 RNA nucleic acid amplification test (NAAT) results after tracheostomy. All included patients had nasopharyngeal (NP) and tracheal (TR) samples taken within a 48-hour period, allowing us to characterize rate of test concordance. RESULTS: Forty-five patients met our inclusion criteria. Thirty-two (71.1%) patients had entirely concordant results after tracheostomy. However, 13 (28.9%) patients had at least one set of discordant results, the majority of which were NP negative and TR positive. There were no statistically significant differences in demographic or clinical variables, including time to tracheostomy and time to testing, among patients with concordant versus discordant SARS-CoV-2 results. CONCLUSION: This represents the first study to examine SARS-CoV-2 RNA NAAT concordance between NP and TR sites in hospitalized patients with COVID-19 and tracheostomies. One-third of patients demonstrated discordant testing when NP and TR specimens were collected within a 48-hour time period. Thus, patients with tracheostomies may have a higher false-negative rate if only one site is assessed for SARS-CoV-2. We recommend analyzing samples from both the nasopharynx and trachea for these patients until more prospective data exist. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E2634-E2638, 2021.
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Teste de Ácido Nucleico para COVID-19/estatística & dados numéricos , COVID-19/diagnóstico , RNA Viral/análise , SARS-CoV-2/genética , Traqueostomia , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/virologia , Teste de Ácido Nucleico para COVID-19/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nasofaringe/virologia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Traqueia/virologia , Adulto JovemRESUMO
OBJECTIVE: Patients with COVID-19 are at risk for laryngeal injury and dysfunction secondary to respiratory failure, prolonged intubation, and other unique facets of this illness. Our goal is to report clinical features and treatment for patients presenting with voice, airway, and/or swallowing concerns postacute COVID-19. STUDY DESIGN: Case series. SETTING: Academic tertiary care center. METHODS: Patients presenting with laryngeal issues following recovery from COVID-19 were included after evaluation by our laryngology team. Data were collected via retrospective chart review from March 1, 2020, to April 1, 2021. This included details of the patient's COVID-19 course, initial presentation to laryngology, and subsequent treatment. RESULTS: Twenty-four patients met inclusion criteria. Twenty (83%) patients were hospitalized, and 18 required endotracheal intubation for a median (range) duration of 14 days (6-31). Ten patients underwent tracheostomy. Patients were evaluated at a median 107 days (32-215) after their positive SARS-CoV-2 test result. The most common presenting concerns were dysphonia (n = 19, 79%), dyspnea (n = 17, 71%), and dysphagia (n = 6, 25%). Vocal fold motion impairment (50%), early glottic injury (39%), subglottic/tracheal stenosis (22%), and posterior glottic stenosis (17%) were identified in patients who required endotracheal intubation. Patients who did not need intubation were most frequently treated for muscle tension dysphonia (67%). CONCLUSION: Patients may develop significant voice, airway, and/or swallowing issues postacute COVID-19. These complications are not limited to patients requiring intubation or tracheostomy. Multidisciplinary laryngology clinics will continue to play an integral role in diagnosing and treating patients with COVID-19-related laryngeal sequelae.
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BACKGROUND: Implantable medical devices and hardware are prolific in medicine, but hardware associated infections remain a major issue. OBJECTIVE: To develop and evaluate a novel, biologic antimicrobial coating for medical implants. METHODS: Electrochemically compacted collagen sheets with and without crosslinked heparin were synthesized per a protocol developed by our group. Sheets were incubated in antibiotic solution (gentamicin or moxifloxacin) overnight, and in vitro activity was assessed with five-day diffusion assays against Pseudomonas aeruginosa. Antibiotic release over time from gentamicin-infused sheets was determined using in vitro elution and high performance liquid chromatography (HPLC). RESULTS: Collagen-heparin-antibiotic sheets demonstrated larger growth inhibition zones against P. aeruginosa compared to collagen-antibiotic alone sheets. This activity persisted for five days and was not impacted by rinsing sheets prior to evaluation. Rinsed collagen-antibiotic sheets did not produce any inhibition zones. Elution of gentamicin from collagen-heparin-gentamicin sheets was gradual and remained above the minimal inhibitory concentration for gentamicin-sensitive organisms for 29 days. Conversely, collagen-gentamicin sheets eluted their antibiotic load within 24 hours. Overall, heparin-associated sheets demonstrated larger inhibition zones against P. aeruginosa and prolonged elution profile via HPLC. CONCLUSION: We developed a novel, local antibiotic delivery system that could be used to coat medical implants/hardware in the future and reduce post-operative infections.
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Heparina , Antibacterianos , Colágeno , Gentamicinas , Pseudomonas aeruginosaRESUMO
ErbB3 has been widely implicated in treatment resistance, but its role as a primary treatment target is less clear. Canonically ErbB3 requires EGFR or ErbB2 for activation, whereas these two established treatment targets are thought to signal independently of ErbB3. In this study, we show that ErbB3 is essential for tumor growth of treatment-naive HNSCC patient-derived xenografts. This ErbB3 dependency occurs via ErbB3-mediated control of EGFR activation and HIF1α stabilization, which require ErbB3 and its ligand neuregulin-1. Here, we show that ErbB3 antibody treatment selects for a population of ErbB3-persister cells that express high levels of the transmembrane protein Trop2 that we previously identified as an inhibitor of ErbB3. Co-treatment with anti-ErbB3 and anti-Trop2 antibodies is synergistic and produces a greater anti-tumor response than either antibody alone. Collectively, these data both compel a revision of ErbB-family signaling and delineate a strategy for its effective inhibition in HNSCC.
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Antígenos de Neoplasias/metabolismo , Moléculas de Adesão Celular/metabolismo , Receptor ErbB-3/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Linhagem Celular Tumoral , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Cobalto/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Neuregulina-1/antagonistas & inibidores , Neuregulina-1/genética , Neuregulina-1/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor ErbB-3/antagonistas & inibidores , Receptor ErbB-3/imunologia , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Transplante HeterólogoAssuntos
Estenose da Valva Aórtica , Substituição da Valva Aórtica Transcateter , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Humanos , Fatores de Risco , Substituição da Valva Aórtica Transcateter/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Does the extent of parotidectomy or other patient or tumor characteristics influence the rate of sialocele/salivary fistula formation? METHODS: All patients who underwent parotidectomy at the University of Wisconsin from 1994 to 2013 were considered. Patients who developed a sialocele/salivary fistula were identified. Extent of dissection, age, sex, body mass index (BMI), volume of specimen, and rate of malignancy were examined. RESULTS: Seventy of 771 patients (9.1%) developed a sialocele/salivary fistula. Sixty-seven fistulae (96%) developed within 1 month and all resolved by 6 months. Age, sex, pathology, and BMI were not increased in the sialocele group. Inferior and middle superficial parotidectomy had a significantly higher rate of sialocele than other extents of dissection. Volume of tissue removed was not significantly different between dissection groups. CONCLUSION: Sialocele/salivary fistula is common postparotidectomy and is more likely with inferior and middle superficial parotidectomy. © 2016 Wiley Periodicals, Inc. Head Neck 39: 387-391, 2017.
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Glândula Parótida/cirurgia , Neoplasias Parotídeas/patologia , Neoplasias Parotídeas/cirurgia , Fístula das Glândulas Salivares/etiologia , Fístula das Glândulas Salivares/cirurgia , Adulto , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Reoperação/métodos , Estudos Retrospectivos , Fatores de Risco , Fístula das Glândulas Salivares/epidemiologia , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: Patient derived xenografts (PDXs) represent an essential tool in oncologic research, and we sought to further expand our repertoire of head and neck squamous cell carcinoma (HNSCC) while determining potential boundaries for this system. METHODS: We consented new patients for PDX development and determined if a 24-h time delay from tumor excision to xenograft implantation affected PDX establishment. We developed a tissue microarray (TMA) from formalin fixed, paraffin embedded PDXs and their subsequent passages and carried out quantitative immunohistochemistry for EGFR, pEGFR, pAkt, pERK and ERCC1. First and last passaged PDXs were compared via a paired t-test to examine for the stability of protein expression across passages. We performed a similar comparison of the mutational profile of the patient tumor and resulting xenografts using a targeted sequencing approach. RESULTS: No patient/tumor characteristics influenced PDX take rate and the 24-h time delay from tumor excision to xenograft implantation did not affect PDX establishment, growth or histology. There was no significant difference in biomarker expression between the first and last passaged PDXs for EGFR, pEGFR, pAkt, and ERCC1. For pERK there was a significant difference (p=0.002), but further analysis demonstrated this only arose in three of 15 PDXs. Targeted sequencing revealed striking stability of passenger and likely driver mutations from patient to xenograft. CONCLUSIONS: The stability of protein expression across PDX passages will hopefully allow greater investigation of predictive biomarkers in order to identify ones for further pre-clinical and clinical investigation.
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Neoplasias de Cabeça e Pescoço/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Feminino , Neoplasias de Cabeça e Pescoço/genética , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , MutaçãoRESUMO
The epidermal growth factor receptor (EGFR) is a therapeutic target in patients with various cancers. Unfortunately, resistance to EGFR-targeted therapeutics is common. Previous studies identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab, and the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. Thus, we hypothesized that AXL mediated the nuclear translocation of EGFR in the setting of cetuximab resistance. Cetuximab-resistant clones of non-small cell lung cancer in culture and patient-derived xenografts in mice had increased abundance of AXL and nuclear EGFR (nEGFR). Cellular fractionation analysis, super-resolution microscopy, and electron microscopy revealed that genetic loss of AXL reduced the accumulation of nEGFR. SRC family kinases (SFKs) and HER family ligands promote the nuclear translocation of EGFR. We found that AXL knockdown reduced the expression of the genes encoding the SFK family members YES and LYN and the ligand neuregulin-1 (NRG1). AXL knockdown also decreased the interaction between EGFR and the related receptor HER3 and accumulation of HER3 in the nucleus. Overexpression of LYN and NRG1 in cells depleted of AXL resulted in accumulation of nEGFR, rescuing the deficit induced by lack of AXL. Collectively, these data uncover a previously unrecognized role for AXL in regulating the nuclear translocation of EGFR and suggest that AXL-mediated SFK and NRG1 expression promote this process.