Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 25
Filter
2.
Facial Plast Surg ; 2024 Apr 08.
Article in English | MEDLINE | ID: mdl-38471659

ABSTRACT

OBJECTIVE: Evidence on facial rehabilitation therapy (FRT) for acute facial paralysis (FP) remains limited. We present a retrospective review of patients with acute FP who have received FRT with physical therapists within 1 year of FP onset as determined by Sunnybrook Facial Grading Scale (SFGS) composite scores. METHODS: A total of 702 patients with a clinical diagnosis of FP were referred to a university rehabilitation program between January 1, 2015 and January 1, 2022. Seventy-six patients met the criteria, defined as FP diagnosis <12 months before FRT initiation, ≥3 therapy sessions, and sufficient follow-up data. RESULTS: Average number of treatment sessions between SFGS scores was 7.7. History of cancer, sex, number of treatment sessions, and initial SFGS score were correlated with change in SFGS. Time to treatment was not correlated with change in SFGS score. SFGS improved with each additional treatment session (p < 0.01). Each additional point in the initial SFGS was correlated with less change in the final SFGS score (p < 0.01). CONCLUSIONS AND RELEVANCE: FRT can provide meaningful improvement in functionality for patients with acute FP, regardless of time to treatment. Furthermore, patients who present with poorer functionality at baseline and those who undergo more treatment are most likely to see SFGS improvement. Research comparing the effect of facial rehabilitation with other treatment modalities and to a control cohort is warranted.

3.
Article in English | MEDLINE | ID: mdl-38350142

ABSTRACT

Background: Dynamic reanimation of the lower lip is a challenging issue for patients, with depressor asymmetry commonly addressed with chemodenervation, selective neurectomy, or myectomy. Objective: To determine whether the anterior belly of digastric transfer is an effective method of lower-lip reanimation for patients with either isolated marginal mandibular branch weakness or inadequate depressor function after hemifacial reanimation, as measured by patient satisfaction and objective symmetry evaluation. Method: Systematic review of the literature was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Abstracts and full texts were reviewed. A Risk of Bias assessment was performed. Results: Nine studies with 164 patients were included. Anterior belly of digastric transfer was successfully performed in 162 patients. Most patients (52%) underwent one-staged reanimation innervated by the native nerve to the mylohyoid. A two-staged approach after placement of a cross face nerve graft was performed in 46%. Patient satisfaction was excellent (90.6%), with minimal complications including revision (4/162), infection (4/162), and lipofilling (8/162). Conclusion: In patients seeking a permanent outcome, use of an anterior belly of digastric transfer in either a one-stage or two-stage approach appears to be a safe and effective method to restore symmetry and dynamic function.

4.
Facial Plast Surg Aesthet Med ; 26(3): 355-361, 2024.
Article in English | MEDLINE | ID: mdl-38150513

ABSTRACT

Objective: To systematically analyze the outcomes of reanimation techniques that have been described for patients undergoing non-fascicle sparing resection of intratemporal facial schwannomas. Methods: A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines of the PubMed, MEDLINE, and Cochrane Central Register of Controlled Trials databases. Results: Eight hundred forty studies were screened with 22 meeting inclusion criteria comprising 266 patients. Most facial nerve reanimations (81.2%) were performed using an interposition nerve graft. The remaining patients underwent hypoglossal-facial nerve transposition (13.9%), primary anastomosis (3.4%), and free muscle transfer (0.1%). Of the reported interposition grafts, the two most utilized were the great auricular (113/199) and sural (86/199) nerves. Interposition nerve grafts resulted in significantly better outcomes in facial nerve function postoperatively than hypoglossal-facial transposition (3.48 vs. 3.92; p < 0.01). There was no difference between interposition grafts. Conclusion: This study systematically reports that interposition nerve grafts, after resection of intratemporal facial schwannoma, result in superior outcomes than hypoglossal-facial nerve transposition in these patients.


Subject(s)
Facial Nerve , Facial Paralysis , Nerve Transfer , Neurilemmoma , Humans , Neurilemmoma/surgery , Facial Nerve/surgery , Facial Paralysis/surgery , Facial Paralysis/etiology , Nerve Transfer/methods , Cranial Nerve Neoplasms/surgery , Hypoglossal Nerve/surgery
5.
Article in English | MEDLINE | ID: mdl-37780671

ABSTRACT

Office-based procedures can be a fulfilling part of the facial plastic practice with the right tools, personnel, and preparation. Equipping the clinic for office-based procedures has several unique considerations that ultimately impact its success. It is important to strategize preemptively regarding what treatments will be offered and the respective equipment that will allow the safe, cost-effective, and high-quality delivery of those treatments. Most procedures in the office-based setting are cosmetic in nature and there are often overlapping treatment modalities that target similar outcomes. Patient selection and counseling is a crucial step in preparing for office-based procedures in the effort to maximize patient satisfaction. Nearly all the most common facial plastic procedures can be delivered in the office-based based setting under local anesthesia and moderate sedation, depending on the expertise of the surgeon. To enable these and other categories of treatments, there are certain expensive pieces of technology that one might consider for their office-based practice and other fundamental supplies that are necessary for almost all practices. Though the initial investment in equipment can be costly, this article also discusses more affordable alternatives or third-party sales of devices and equipment. The field of facial plastic surgery is very dynamic and having both peer and mentorship networks is invaluable in navigating some of the financial decisions discussed herein. This article also briefly covers personnel, training, and accreditation considerations.

6.
Otolaryngol Head Neck Surg ; 169(5): 1114-1121, 2023 11.
Article in English | MEDLINE | ID: mdl-37272720

ABSTRACT

OBJECTIVE: This systematic review and meta-analysis aimed to identify studies reporting the incidence of Bell's Palsy after vaccination against coronavirus disease 2019 (Covid-19) and assess whether this incidence is greater than among the general population. DATA SOURCES: PubMed, Embase, CINAHL, and Web of Science. REVIEW METHODS: A systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Databases were searched from inception to May 9, 2022, for studies reporting the incidence of Bell's Palsy among individuals vaccinated against Covid-19 and control populations. Meta-analyses of odds ratios (ORs) were performed to compare the incidence of Bell's Palsy in these groups. RESULTS: We identified 7 studies reporting the incidence of Bell's Palsy after vaccination and among the general population, including 20,234,931 total vaccinated patients. The length of postvaccination follow-up ranged from 7 to 43 days in these studies. The incidence of Bell's Palsy was not significantly greater among vaccinated individuals (OR: 1.06; 95% confidence interval [CI]: 0.65-1.71; p = .82). Stratifying by dose, the incidence of Bell's Palsy was not significantly greater after receiving either the first dose (OR: 0.84; 95% CI: 0.47-1.49; p = .54) or second dose (OR: 1.02; 95% CI: 0.58-1.79; p = .96). CONCLUSION: Among the available evidence, the incidence of Bell's Palsy after vaccination against Covid-19 is comparable to that of the general unvaccinated population. Patient counseling should provide reassurance that there is no known association between Bell's Palsy and Covid-19 vaccination.


Subject(s)
Bell Palsy , COVID-19 , Facial Paralysis , Humans , Bell Palsy/epidemiology , Bell Palsy/etiology , COVID-19 Vaccines/adverse effects , COVID-19/epidemiology , COVID-19/prevention & control , Incidence
7.
JAMA Otolaryngol Head Neck Surg ; 149(4): 374-375, 2023 04 01.
Article in English | MEDLINE | ID: mdl-36757719

ABSTRACT

This case report describes a case of a man in his 30s who presented with episodic right lower facial paresis for 10 days and was diagnosede with an episodic, transient pattern of unilateral facial palsy associated with relapsing remitting multiple sclerosis.


Subject(s)
Facial Paralysis , Multiple Sclerosis , Humans , Facial Paralysis/diagnosis , Facial Paralysis/etiology , Multiple Sclerosis/complications , Multiple Sclerosis/diagnosis
8.
Laryngoscope ; 132(3): 550-553, 2022 03.
Article in English | MEDLINE | ID: mdl-34355794

ABSTRACT

Successful tracheal reconstruction remains a challenging task for the reconstructive surgeon. A variety of techniques have been previously employed, using both autografts and allografts. The authors present a novel method for tracheal reconstruction utilizing a prelaminated fascial flap in conjunction with a bioabsorbable scaffold. Laryngoscope, 132:550-553, 2022.


Subject(s)
Absorbable Implants , Plastic Surgery Procedures/methods , Tissue Scaffolds , Trachea/surgery , Cartilage/transplantation , Free Tissue Flaps , Humans , Male , Middle Aged , Plastic Surgery Procedures/instrumentation , Ribs/transplantation
9.
Clin Plast Surg ; 49(1): 179-189, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34782135

ABSTRACT

Rhinoplasty is widely regarded as one of the more technically challenging surgeries, owing in part to the many possible short- and long-term complications that can arise. Although severe complications are uncommon, unforeseen complications can lead to esthetic and functional compromise, patient dissatisfaction, and need for revision surgery. The rhinoplasty surgeon must be prepared to counsel patients and identify and manage the range of complications that may result from this procedure. This article reviews some of the most frequently encountered complications related to rhinoplasty and their management approaches.


Subject(s)
Rhinoplasty , Esthetics , Humans , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Reoperation , Rhinoplasty/adverse effects
10.
Clin Case Rep ; 9(1): 522-525, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33489207

ABSTRACT

Metastatic melanoma may be included in the differential diagnosis of hyoid masses in patients with a history of melanoma. Hyoid resection is well tolerated and of diagnostic and therapeutic benefit in patients with tumors metastatic to the hyoid bone.

12.
OTO Open ; 4(2): 2473974X20924332, 2020.
Article in English | MEDLINE | ID: mdl-32500113

ABSTRACT

Nasal septal perforations can cause issues of epistaxis, whistling, crusting, saddle deformity, and obstruction, which motivate patients to seek surgical repair. Numerous methods of septal perforation repair have been described, with surgical success rates ranging from 52% to 100%, but few studies address situations with concomitant septal deviation. In treating patients with septal perforation and deviation, both issues should be addressed for optimal outcomes. While routine septoplasty involves the removal of septal cartilage, septal perforation repair involves the addition of interposition grafts. The composite chondromucosal septal rotation flap harmoniously combines these seemingly conflicting goals as an effective and efficient technique for septal perforation repair. We present 3 patients successfully treated for their septal perforation and septal deviation concurrently with this technique.

14.
Cancer ; 126(8): 1793-1803, 2020 04 15.
Article in English | MEDLINE | ID: mdl-31943172

ABSTRACT

BACKGROUND: The prevalence of survivors of oropharyngeal cancer (OPC) is increasing due to improved survival for individuals with human papillomavirus (HPV)-related disease. Although elderly survivors of OPC are known to have a high burden of comorbidities, to the authors' knowledge it is unknown how this compares with a similar cohort without a history of cancer. METHODS: The current retrospective, cross-sectional study included individuals with a first incident primary diagnosis of OPC from 2004 through 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked databases and matched controls. The baseline prevalence and subsequent incidence of comorbid conditions were identified. The association between comorbidity and overall survival was evaluated. RESULTS: A total of 2497 eligible patients with OPC were matched to 4994 noncancer controls. Baseline comorbidity was higher in cases (Charlson Comorbidity Index >0 for 48.5% of cases vs 35.8% of controls). At 5 years, cases were more likely than controls to develop comorbidities. Survivors of OPC were at high risk (≥20% cumulative prevalence by 5 years) of developing several comorbidities, including cardiovascular diseases, cerebrovascular disease, chronic obstructive pulmonary disease, and tobacco abuse, and were at moderately high risk (10%-19% cumulative prevalence) of developing other conditions including carotid artery occlusive stroke, alcohol abuse, depression, and anxiety. In both cases and controls, the presence of the majority of comorbidities either at the time of diagnosis or during the follow-up period was associated with worse survival. CONCLUSIONS: Patients with OPC have a higher comorbidity burden compared with matched controls, both at baseline and during survivorship, the majority of which are associated with decreased survival. Oncologic surveillance of survivors of OPC should include screening for highly prevalent conditions.


Subject(s)
Comorbidity , Oropharyngeal Neoplasms/epidemiology , Oropharyngeal Neoplasms/mortality , Aged , Cancer Survivors , Cardiovascular Diseases/epidemiology , Cerebrovascular Disorders/epidemiology , Cross-Sectional Studies , Female , Humans , Male , Oropharyngeal Neoplasms/etiology , Papillomaviridae/pathogenicity , Papillomavirus Infections/complications , Papillomavirus Infections/mortality , Prevalence , Pulmonary Disease, Chronic Obstructive/epidemiology , Retrospective Studies , SEER Program , Survivorship
15.
Otolaryngol Head Neck Surg ; 160(1): 85-92, 2019 01.
Article in English | MEDLINE | ID: mdl-30252608

ABSTRACT

OBJECTIVE: The aim of this study was to evaluate the prevalence of comorbidities among patients with head and neck squamous cell carcinoma (HNSCC) at the time of their cancer diagnosis and during their survivorship trajectory. The second aim was to evaluate the differences in comorbidities developed according to treatment type received. STUDY DESIGN: Retrospective cross-sectional. SETTING: SEER (Surveillance, Epidemiology, and End Results)-Medicare linked database. SUBJECTS AND METHODS: Individuals with a first-incident primary diagnosis of HNSCC from 2004 to 2011 per the SEER-Medicare database were included in analysis. The presence or absence of 30 comorbid conditions of interest was identified during distinct periods and analyzed according to treatment with surgery alone, primary (chemo)radiation, or surgery with (chemo)radiation. RESULTS: The study population consisted of 10,524 individuals diagnosed with HNSCC, with a mean age of 74.8 years. At diagnosis, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and diabetes were the most prevalent comorbidities, and they increased over time. The probability of developing treatment-related comorbidities such as pneumonia, dysphagia, weight loss, malnutrition, and dental issues rose significantly in the short and long term following treatment ( P < .05). By 5 years from cancer diagnosis, patients were most likely to have newly diagnosed hypertension, dysphagia, anemia, and weight loss. Primary surgery alone was associated with a lower risk of diagnosis with these treatment-related comorbidities, as compared with treatments involving radiation therapy and/or chemotherapy in the primary or adjuvant settings ( P < .05). CONCLUSIONS: There is a large burden of comorbidities among patients following HNSCC treatment, which warrant clinical attention during surveillance.


Subject(s)
Cause of Death , Comorbidity , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/therapy , Squamous Cell Carcinoma of Head and Neck/mortality , Squamous Cell Carcinoma of Head and Neck/therapy , Aged , Aged, 80 and over , Cross-Sectional Studies , Diabetes Mellitus/epidemiology , Disease-Free Survival , Female , Geriatric Assessment , Head and Neck Neoplasms/pathology , Humans , Hyperlipidemias/epidemiology , Hypertension/epidemiology , Male , Medicare/economics , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Prevalence , Prognosis , Pulmonary Disease, Chronic Obstructive/epidemiology , Retrospective Studies , SEER Program , Squamous Cell Carcinoma of Head and Neck/pathology , Survival Analysis , United States
16.
Cancer ; 125(2): 249-260, 2019 01 15.
Article in English | MEDLINE | ID: mdl-30444527

ABSTRACT

BACKGROUND: The increasing incidence of human papillomavirus (HPV)-related head and neck cancer (HNC) has led to the increasing prevalence of survivors, yet to the best of the authors' knowledge the prevalence of comorbidities during the survivorship period and their effects on survival are relatively unknown. METHODS: In this retrospective cross-sectional study, individuals with a first incident primary diagnosis of HNC from 2004 through 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked databases were included in the analysis and classified as patients with HPV-related or HPV-unrelated HNC. The presence of 30 comorbid conditions of interest was identified. Associations between comorbidity and treatment group as well as overall survival were evaluated. RESULTS: The study population consisted of 8025 patients with HPV-unrelated HNC and 2499 patients with HPV-related HNC. Hypertension, congestive heart failure, cerebrovascular disease, and chronic obstructive pulmonary disease all were found to be highly prevalent at the time of the cancer diagnosis and increased over time for both groups. These comorbidities were found at significantly lower rates in the HPV-related HNC population, yet were associated with an increased risk of death in both groups. The probabilities of developing cancer-related comorbidities such as pneumonia, dysphagia, weight loss, malnutrition, and dental issues rose significantly in both groups after treatment but were more likely in patients with HPV-related HNC. In both groups of patients, the presence of each comorbidity either at the time of diagnosis or during survivorship was associated with a significantly increased risk of death. CONCLUSIONS: There is a large burden of comorbidities in both patients with HPV-related and HPV-unrelated HNC, both of which are associated with decreased survival. Oncologic surveillance should not be limited to the evaluation of disease status, but also should include screening for the highly prevalent conditions associated with the risk of death.


Subject(s)
Head and Neck Neoplasms/epidemiology , Head and Neck Neoplasms/therapy , Papillomavirus Infections/epidemiology , Aged , Cancer Survivors , Comorbidity , Cross-Sectional Studies , Female , Head and Neck Neoplasms/diagnosis , Head and Neck Neoplasms/virology , Humans , Hypertension/epidemiology , Incidence , Male , Papillomavirus Infections/pathology , Prevalence , Retrospective Studies , SEER Program , Survival Analysis , United States/epidemiology
17.
Laryngoscope ; 128(2): 398-402, 2018 02.
Article in English | MEDLINE | ID: mdl-28782105

ABSTRACT

OBJECTIVES: Preoperative fine needle aspiration (FNA) of parotid lesions often is used in the initial evaluation of parotid masses, but its role in guiding surgical decision making remains unclear, in part due to varying diagnostic accuracy reported. We sought to evaluate the role of preoperative FNA in detection of malignancy and impact on surgical management. STUDY DESIGN: Retrospective study. METHODS: The medical records of patients who underwent parotidectomy at a single tertiary medical center were reviewed from 2000 to 2015. Patients who had a preoperative FNA comprised the study cohort. RESULTS: A total of 1,074 consecutive patients underwent parotidectomy during the study period; of those, 477 had a preoperative FNA. FNA was nondiagnostic in 26 cases. There were 29 false positives (6.4%), 26 false negatives (5.8%), 122 true positives (27.1%), and 274 true negatives (60.8%). The sensitivity and specificity of FNA were 82.4% and 90.4%, respectively, with a positive predictive value of 80.8% and a negative predictive value of 91.3%. The overall accuracy of preoperative FNA was 87.8%. The preoperative FNA resulted in a change in the surgical plan in 85 (18.9%) cases. In 66 of these cases (78%), surgery was extended to include neck dissection at time of resection. In 10 cases, FNA led to surgical management over surveillance. In 11 cases, FNA downgraded the extent of surgery planned to an excisional biopsy. CONCLUSION: Preoperative FNA is a valuable adjunct in the surgical management of parotid lesions, with high specificity for the detection of malignant disease. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:398-402, 2018.


Subject(s)
Biopsy, Fine-Needle/statistics & numerical data , Clinical Decision-Making/methods , Parotid Gland/pathology , Parotid Neoplasms/pathology , Preoperative Care/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , Biopsy, Fine-Needle/methods , Child , False Negative Reactions , False Positive Reactions , Female , Humans , Male , Middle Aged , Parotid Gland/surgery , Parotid Neoplasms/diagnosis , Parotid Neoplasms/surgery , Predictive Value of Tests , Preoperative Care/methods , Retrospective Studies , Sensitivity and Specificity , Young Adult
18.
Otolaryngol Head Neck Surg ; 156(2): 329-333, 2017 02.
Article in English | MEDLINE | ID: mdl-27899468

ABSTRACT

Objective To determine the impact of unilateral vagal sacrifice for vagal schwannoma on postoperative swallowing function. Study Design Case series, chart review. Setting Academic medical institution. Subjects and Methods Ten patients underwent vagus nerve sacrifice for vagal schwannoma resection. Archived pathology records dating from 1985 through 2012 at our institution were retrospectively queried for cases of vagal schwannoma with vagus nerve sacrifice. Medical records were abstracted for demographic and disease information as well as cranial nerve and swallowing function. Preoperative and postoperative cranial nerve function, subjective and objective measures of swallowing function, Functional Oral Intake Scale (FOIS) level, and need for vocal fold medialization were variables collected. Data were analyzed with summary statistics. Results The patients who underwent vagal sacrifice for vagal schwannoma at our institution had a mean age of 42.3 years (median, 44 years; range, 15-63 years) and follow-up of 35.6 months (median, 9 months; range, 1-115 months). Most presented with no preoperative cranial nerve deficit or difficulty swallowing. Immediately postoperatively, 90% had a vagus nerve deficit, but 50% had no subjective difficulty swallowing, and 70% had a FOIS level of 7 at postoperative hospital discharge. Within 1 month after surgery, 70% had normal swallowing function according to a modified barium swallow study. A full diet was tolerated by mouth within an average of 2.7 days (median, 2 days; range, 1-6 days) after surgery in this cohort. Seventy percent required vocal fold medialization postoperatively for incomplete glottic closure. Conclusion Vagal nerve sacrifice during resection of vagal schwannoma can be performed with normal postoperative swallowing function.


Subject(s)
Cranial Nerve Neoplasms/surgery , Deglutition/physiology , Neurilemmoma/surgery , Vagus Nerve/surgery , Adolescent , Adult , Female , Humans , Male , Middle Aged , Treatment Outcome , Vocal Cords/surgery
19.
Cancer Res ; 76(18): 5442-5454, 2016 09 15.
Article in English | MEDLINE | ID: mdl-27469115

ABSTRACT

Comparison of tumors from The Cancer Genome Atlas (TCGA) reveals that head and neck squamous cell carcinomas (HNSCC) harbor the most frequent genomic amplifications of Fas-associated death domain (FADD), with or without Baculovirus inhibitor of apoptosis repeat containing BIRC2 (cIAP1), affecting about 30% of patients in association with worse prognosis. Here, we identified HNSCC cell lines harboring FADD/BIRC2 amplifications and overexpression by exome sequencing, RT-PCR, and Western blotting. In vitro, FADD or BIRC2 siRNA knockdown inhibited HNSCC displaying amplification and increased expression of these genes, supporting their functional importance in promoting proliferation. Birinapant, a novel SMAC mimetic, sensitized multiple HNSCC lines to cell death by agonists TNFα or TRAIL and inhibited cIAP1>XIAP>IAP2. Combination of birinapant and TNFα induced sub-G0 DNA fragmentation in sensitive lines and birinapant alone also induced significant G2-M cell-cycle arrest and cell death in UM-SCC-46 cells. Gene transfer and expression of FADD sensitized resistant UM-SCC-38 cells lacking FADD amplification to birinapant and TNFα, supporting a role for FADD in sensitization to IAP inhibitor and death ligands. HNSCC varied in mechanisms of cell death, as indicated by reversal by inhibitors or protein markers of caspase-dependent apoptosis and/or RIPK1/MLKL-mediated necroptosis. In vivo, birinapant inhibited tumor growth and enhanced radiation-induced TNFα, tumor responses, and host survival in UM-SCC-46 and -11B xenograft models displaying amplification and overexpression of FADD+/- BIRC2 These findings suggest that combination of SMAC mimetics such as birinapant plus radiation may be particularly active in HNSCC, which harbor frequent FADD/BIRC2 genomic alterations. Cancer Res; 76(18); 5442-54. ©2016 AACR.


Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Squamous Cell/genetics , Chemoradiotherapy/methods , Dipeptides/administration & dosage , Fas-Associated Death Domain Protein/genetics , Head and Neck Neoplasms/genetics , Indoles/administration & dosage , Inhibitor of Apoptosis Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Animals , Blotting, Western , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Female , Gene Amplification , Gene Knockdown Techniques , Head and Neck Neoplasms/pathology , Humans , Immunohistochemistry , Mice , Mice, Inbred BALB C , Mice, SCID , Real-Time Polymerase Chain Reaction , Squamous Cell Carcinoma of Head and Neck , TNF-Related Apoptosis-Inducing Ligand/administration & dosage , Tumor Necrosis Factor-alpha/administration & dosage , Xenograft Model Antitumor Assays
20.
Clin Cancer Res ; 21(17): 3946-56, 2015 Sep 01.
Article in English | MEDLINE | ID: mdl-25977343

ABSTRACT

PURPOSE: Head and neck squamous cell carcinomas exhibit variable sensitivity to inhibitors of the PI3K/mTOR pathway, an important target of genomic alterations in this cancer type. The mitogen-activated protein kinase kinase (MEK)/ERK/activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) pathways are also frequently co-activated, but their roles in resistance mechanisms to PI3K/mTOR inhibitors and as therapeutic targets in head and neck squamous cell carcinoma (HNSCC) are not well defined. EXPERIMENTAL DESIGN: We determined the IC50s of dual PI3K/mTOR inhibitor PF-05212384 (PF-384) by XTT assays in 14 HNSCC lines with PI3K/Akt/mTOR cascade alterations. In two resistant models, we further characterized the molecular, cellular, and in vivo attributes and effects of combining PF-384 with MEK inhibitor PD-0325901 (PD-901). RESULTS: PF-384 IC50s varied between 0.75 and 133 nmol/L in 14 HNSCC lines with overexpression or mutations of PIK3CA, and sensitivity correlated with increased phospho-AKT(T308/S473). In resistant UMSCC-1 and -46 models, PF-384 increased G0-/G1-phase accumulation but weakly induced sub-G0 cell death. PF-384 inhibited direct targets of PI3K/mTOR, but incompletely attenuated co-activated ERK and UMSCC-1 xenograft growth in vivo. PD-901 strongly inhibited MEK/ERK targets, and the combination of PF-384 and PD-901 inhibited downstream NF-κB and AP-1 transactivation, and IL8 and VEGF production in vitro. PD-901 potently inhibited tumor growth alone and with PF384, enhanced antiproliferative, apoptotic, and anti-angiogenesis activity in vivo. CONCLUSIONS: PI3K/mTOR inhibitor PF-384 exhibits variable activity in a panel of HNSCC cell lines with differing PIK3CA expression and mutation status. MEK inhibitor PD-901 overcomes resistance and enhances antitumor effects observed with PF-384 in vivo.


Subject(s)
Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Carcinoma, Squamous Cell/metabolism , Diphenylamine/analogs & derivatives , Drug Resistance, Neoplasm , Head and Neck Neoplasms/metabolism , Morpholines/pharmacology , Protein Kinase Inhibitors/pharmacology , Triazines/pharmacology , Animals , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cell Transformation, Neoplastic/drug effects , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cytokines/metabolism , Diphenylamine/pharmacology , Disease Models, Animal , Drug Synergism , Gene Expression , Genes, Reporter , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/pathology , Humans , Inflammation Mediators/metabolism , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinase Kinases/metabolism , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Phosphorylation , Signal Transduction/drug effects , Squamous Cell Carcinoma of Head and Neck , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Transcription Factor AP-1/metabolism , Transcriptional Activation , Xenograft Model Antitumor Assays
SELECTION OF CITATIONS
SEARCH DETAIL
...