Publications by authors named "Daniel L Faden"

30 Publications

  • Page 1 of 1

Prolapsed Nasal Polyp Causing Acute Airway Obstruction: An Exceptional Presentation.

ORL J Otorhinolaryngol Relat Spec 2021 Mar 3:1-3. Epub 2021 Mar 3.

Department of Otolaryngology-Head & Neck Surgery, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA.

Although nasal polyposis is a common clinical entity, there is limited literature describing the rare presentation of sudden prolapse of a massive nasal polyp resulting in an airway emergency in an adult. We present the first case report to our knowledge of a patient without any preceding sinonasal symptoms or history of anticoagulation who experienced acute upper airway obstruction due to sudden hemorrhage and prolapse of a large nasal polyp. Based on our experience treating this patient, we discuss special considerations in all phases of care to ensure safe and effective management of such an exceptional clinical scenario.
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http://dx.doi.org/10.1159/000513564DOI Listing
March 2021

Prospective assessment of multiple HPV-positive oropharyngeal squamous cell carcinomas.

Oral Oncol 2021 Feb 15:105212. Epub 2021 Feb 15.

Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1016/j.oraloncology.2021.105212DOI Listing
February 2021

Human Papillomavirus in Sinonasal Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis.

Cancers (Basel) 2020 Dec 25;13(1). Epub 2020 Dec 25.

Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA 02114, USA.

Human papillomavirus (HPV) drives tumorigenesis in a subset of oropharyngeal squamous cell carcinomas (OPSCC) and is increasing in prevalence across the world. Mounting evidence suggests HPV is also involved in a subset of sinonasal squamous cell carcinomas (SNSCC), yet small sample sizes and variability of HPV detection techniques in existing literature hinder definitive conclusions. A systematic review was performed by searching literature through March 29th 2020 using PubMed, Embase, and Web of Science Core Collection databases. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed by two authors independently. A meta-analysis was performed using the random-effects model. Sixty studies ( = 1449) were eligible for statistical analysis estimating an overall HPV prevalence of 25.5% (95% CI 20.7-31.0). When stratified by HPV detection method, prevalence with multiple substrate testing (20.5%, 95% CI 14.5-28.2) was lower than with single substrate testing (31.7%, 95% CI 23.6-41.1), highest in high-exposure anatomic subsites (nasal cavity and ethmoids) (37.6%, 95% CI 26.5-50.2) vs. low-exposure (15.1%, 95% CI 7.3-28.6) and highest in high HPV+ OPSCC prevalence geographic regions (North America) (30.9%, 95% CI 21.9-41.5) vs. low (Africa) (13.1, 95% CI 6.5-24.5)). While small sample sizes and variability in data cloud firm conclusions, here, we provide a new reference point prevalence for HPV in SNSCC along with orthogonal data supporting a causative role for virally driven tumorigenesis, including that HPV is more commonly found in sinonasal subsites with increased exposure to refluxed oropharyngeal secretions and in geographic regions where HPV+ OPSCC is more prevalent.
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http://dx.doi.org/10.3390/cancers13010045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796014PMC
December 2020

A national cancer database analysis on stereotactic body radiation therapy of head and neck cancers.

Am J Otolaryngol 2021 Jan 12;42(3):102913. Epub 2021 Jan 12.

Department of Radiation Oncology, Boston Medical Center, Boston University School of Medicine, Boston, MA, United States of America. Electronic address:

Background: To evaluate demographic, clinicopathological, treatment factors including biological effective radiation dose (BED) that influence overall survival in head and neck cancer (HNC) patients treated with stereotactic body radiation therapy (SBRT).

Methods: Between 2004 and 2015, 591 SBRT-treated HNC patients were identified from the National Cancer Data Base. A BED using an alpha/beta ratio of 10 (BED), was used to compare dose fractionation of different SBRT regimens. Overall survival was estimated using the Kaplan Meier method, and log-rank tests were used to determine statistical significance. Cox regression modeling was used to compute crude and adjusted hazard ratios (HR) with 95% confidence intervals (CI).

Results: Median follow-up was 11.9 (interquartile range, 5.5 to 26.7) months. The 5-year overall survival rate was 15.5%. On multivariate analysis, older age, Charlson-Deyo comorbidity score ≥ 1, history of cancer, tumor, nodal and metastatic stage, and receiving treatment at academic/research program were associated with poor survival. Compared to SBRT alone, superior survival was observed with SBRT with chemotherapy, surgery with SBRT, but not surgery with SBRT and chemotherapy. Improved survival was observed with aa BED of ≥59.5 Gy (adjusted HR 0.57, 95% CI 0.46-0.70, P < 0.0001).

Conclusions: Factors affecting associated with worse survival in HNC patients treated with SBRT included older age, patient comorbidities, advanced tumor stage, cancer history, and lower biological effective SBRT dose.

Level Of Evidence: 2b (individual cohort study).
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http://dx.doi.org/10.1016/j.amjoto.2021.102913DOI Listing
January 2021

Opioid Usage and Prescribing Predictors Following Transoral Robotic Surgery for Oropharyngeal Cancer.

Laryngoscope 2020 Nov 19. Epub 2020 Nov 19.

Department of Otolaryngology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, U.S.A.

Objective/hypothesis: Pain management following transoral robotic surgery (TORS) varies widely. We aim to quantify opioid usage following TORS for oropharyngeal squamous cell carcinoma (OPSCC) and identify prescribing predictors.

Study Design: Retrospective cohort study.

Methods: A consecutive series of 138 patients undergoing TORS for OPSCC were reviewed from 2016 to 2019. Opioid usage (standardized to morphine milligram equivalents [MME]) was gathered for 12 months post-surgery via prescribing record cross-check with the Massachusetts Prescription Awareness Tool.

Results: Of 138 OPSCC TORS patients, 92.8% were human papillomavirus (HPV) positive. Adjuvant therapy included radiation (XRT;67.4%) and chemoradiation (cXRT;6.5%). Total MME usage from start of treatment averaged 1395.7 MMEs with 76.4% receiving three prescriptions or less. Categorical analysis showed age <65, male sex, overweight BMI, lower frailty, former smokers, HPV+, higher T stage, and BOT subsite to be associated with increased MMEs. Adjuvant therapy significantly increased MMEs (TORS+XRT:1646.2; TORS+cXRT:2385.0; TORS alone:554.7 [P < .001]) and 12-month opioid prescription totals (TORS+XRT:3.2; TORS+cXRT:5.5; TORS alone:1.6 [P < .001]). Adjuvant therapy increased time to taper (total MME in TORS alone versus TORS+XRT/cXRT: 0 to 3 months:428.2 versus 845.5, 4 to 6 months:46.8 versus 541.8, 7 to 9 months:12.4 versus 178.6, 10 to 12 months:11.0 versus 4.4,[P < .001]). Positive predictors of opioid prescribing at the 4- to 6-month and 4- to 12-month intervals included adjuvant therapy (odds ratio [OR]:5.56 and 4.51) and mFI-5 score ≥3 (OR:36.67 and 31.94). Following TORS at 6-, 9-, and 12-month, 15.7%, 6.6%, and 4.1% were still using opioids.

Conclusions: In OPSCC treated with TORS, opioid use tapers faster for surgery alone versus with adjuvant therapy. Opioid prescribing risks include adjuvant therapy and higher frailty index.

Level Of Evidence: 4 Laryngoscope, 2020.
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http://dx.doi.org/10.1002/lary.29276DOI Listing
November 2020

The mutational landscape of early- and typical-onset oral tongue squamous cell carcinoma.

Cancer 2021 Feb 4;127(4):544-553. Epub 2020 Nov 4.

Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: The incidence of oral tongue squamous cell carcinoma (OTSCC) is increasing among younger birth cohorts. The etiology of early-onset OTSCC (diagnosed before the age of 50 years) and cancer driver genes remain largely unknown.

Methods: The Sequencing Consortium of Oral Tongue Cancer was established through the pooling of somatic mutation data of oral tongue cancer specimens (n = 227 [107 early-onset cases]) from 7 studies and The Cancer Genome Atlas. Somatic mutations at microsatellite loci and Catalog of Somatic Mutations in Cancer mutation signatures were identified. Cancer driver genes were identified with the MutSigCV and WITER algorithms. Mutation comparisons between early- and typical-onset OTSCC were evaluated via linear regression with adjustments for patient-related factors.

Results: Two novel driver genes (ATXN1 and CDC42EP1) and 5 previously reported driver genes (TP53, CDKN2A, CASP8, NOTCH1, and FAT1) were identified. Six recurrent mutations were identified, with 4 occurring in TP53. Early-onset OTSCC had significantly fewer nonsilent mutations even after adjustments for tobacco use. No associations of microsatellite locus mutations and mutation signatures with the age of OTSCC onset were observed.

Conclusions: This international, multicenter consortium is the largest study to characterize the somatic mutational landscape of OTSCC and the first to suggest differences by age of onset. This study validates multiple previously identified OTSCC driver genes and proposes 2 novel cancer driver genes. In analyses by age, early-onset OTSCC had a significantly smaller somatic mutational burden that was not explained by differences in tobacco use.

Lay Summary: This study identifies 7 specific areas in the human genetic code that could be responsible for promoting the development of tongue cancer. Tongue cancer in young patients (under the age of 50 years) has fewer overall changes to the genetic code in comparison with tongue cancer in older patients, but the authors do not think that this is due to differences in smoking rates between the 2 groups. The cause of increasing cases of tongue cancer in young patients remains unclear.
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http://dx.doi.org/10.1002/cncr.33309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891879PMC
February 2021

HPV+ oropharyngeal squamous cell carcinomas from patients with two tumors display synchrony of viral genomes yet discordant mutational profiles and signatures.

Carcinogenesis 2021 Feb;42(1):14-20

Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.

Human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (HPV + OPSCC) is increasing in prevalence in the USA, as are cases of patients with multiple HPV + OPSCCs (mHPV + OPSCC). mHPV + OPSCCs present a unique opportunity to examine HPV + OPSCC mutation acquisition and evolution. We performed sequencing of the viral genome, somatic exome and somatic transcriptome from 8 patients each with 2 spatially distinct HPV + OPSCCs, and 37 'traditional' HPV + OPSCCs to first address if paired tumors are caused by the same viral isolate and next, if acquired alterations, and the underlying processes driving mutagenesis, are shared within pairs. All tumor pairs contained viral genomes from the same HPV type 16 sublineage and differed by 0-2 clonal single nucleotide polymorphisms (SNPs), suggesting infection with the same viral isolate. Despite this, there was significant discordance in expression profiles, mutational burden and mutational profiles between tumors in a pair, with only two pairs sharing any overlapping mutations (3/3343 variants). Within tumor pairs there was a striking discrepancy of mutational signatures, exemplified by no paired tumors sharing high APOBEC mutational burden. Here, leveraging mHPV + OPSCCs as a model system to study mutation acquisition in virally mediated tumors, in which the germline, environmental exposures, immune surveillance and tissue/organ type were internally controlled, we demonstrate that despite infection by the same viral isolate, paired mHPV + OPSCCs develop drastically different somatic alterations and even more strikingly, appear to be driven by disparate underlying mutational processes. Thus, despite a common starting point, HPV + OPSCCs evolve through variable mutational processes with resultant stochastic mutational profiles.
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http://dx.doi.org/10.1093/carcin/bgaa111DOI Listing
February 2021

Treatment sequence of cetuximab and immune checkpoint inhibitor in head and neck squamous cell carcinoma differentially affects outcomes.

Oral Oncol 2020 12 13;111:105024. Epub 2020 Oct 13.

Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, United States; Harvard Medical School, 25 Shattuck St, Boston, MA 02115, United States; Massachusetts Eye and Ear, 243 Charles St, Boston, MA 02114, United States; Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA 02142, United States. Electronic address:

Objectives: To examine the impact of treatment sequences of Immune checkpoint inhibitor (ICI) and cetuximab on clinical outcomes in patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

Materials And Methods: Clinicopathologic data were retrospectively collected on patients with R/M HNSCC who received ICI treatment. Association between treatment sequence and clinical outcomes were assessed.

Results: A total of 113 patients with R/M HNSCC were analyzed. Patients who had cetuximab prior to ICI had worse overall (HR, 1.83) and progression-free survival (HR, 1.76) compare to those without prior cetuximab. Among patients who had subsequent therapy after ICI, cetuximab-based therapy was associated with a trend toward higher response rate and longer survival than non-cetuximab regimen.

Conclusion: Our single institution analysis showed that treatment sequence of cetuximab and ICI in R/M HNSCC may affect clinical outcomes. Cetuximab prior to ICI was associated with worse outcomes while the efficacy of cetuximab may be enhanced after ICI therapy.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105024DOI Listing
December 2020

Systematic Review of Second Primary Oropharyngeal Cancers in Patients With p16+ Oropharyngeal Cancer.

Otolaryngol Head Neck Surg 2020 Sep 15:194599820951175. Epub 2020 Sep 15.

Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri, USA.

Objective: To systematically review the literature to determine the prevalence and clinical outcomes of second primary oropharyngeal squamous cell carcinoma (OPSCC).

Data Sources: Search strategies created with a medical librarian were implemented using multiple databases in October 2019.

Review Methods: The population of interest included adults age >18 years with a p16+ or human papillomavirus-positive OPSCC. The outcome was a synchronous or metachronous second primary OPSCC. Inclusion and exclusion criteria were designed to capture all study designs. In total, 685 records were identified by the search strategy. Two reviewers independently performed the review, extracted data, and performed a quality assessment. Primary Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. A random-effects model was used for the meta-analysis.

Results: A total of 2470 patients with 35 second primary OPSCCs from 15 studies were identified. The pooled prevalence of second primary OPSCC was 1.4% (range, 0%-14.3%). In the random-effects model, the prevalence was estimated at 1.3% (95% CI, 0.7%-2.3%; = .51, = 52%). Of the 30 patients with treatment information, 26 (86.7%) received surgical treatment, while 4 (13.3%) underwent nonsurgical therapy. Of the 29 patients with available survival information, 22 (75.9%) had no evidence of disease at last follow-up, 5 (17.2%) ultimately died of disease, and 2 (6.9%) were alive with disease.

Conclusion: Overall, the rate of second primary OPSCC in patients with an index p16+ OPSCC is low, and most patients are successfully treated. Insufficient evidence currently exists to recommend routine elective tonsillectomy during surgical treatment of p16+ OPSCC.
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http://dx.doi.org/10.1177/0194599820951175DOI Listing
September 2020

The age of telemedicine is upon us.

Laryngoscope Investig Otolaryngol 2020 Jun 29;5(3):584-585. Epub 2020 Apr 29.

Department of Otolaryngology-Head and Neck Surgery Yale University School of Medicine New Haven Connecticut USA.

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http://dx.doi.org/10.1002/lio2.391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267534PMC
June 2020

Sinonasal Squamous Cell Carcinoma: Etiology, Pathogenesis, and the Role of Human Papilloma Virus.

Curr Otorhinolaryngol Rep 2020 Jun;8(2):111-119

Massachusetts Eye and Ear, Boston, MA 02114, USA.

Purpose Of Review: Sinonasal squamous cell carcinoma (SNSCC) is a rare disease with considerable histologic diversity. Currently, there is a poor understanding of the etiology and pathogenesis of SNSCC. Here, we review recent literature to summarize what is known regarding (1) the etiology of SNSCC, (2) the role of Human Papilloma Virus (HPV) in SNSCC, and (2) the molecular underpinnings of SNSCC.

Recent Findings: 1. High risk HPVappears to play a role in the pathogenesis of a subset of SNSCCs. SNSCCs with high risk HPV have improved survival compared with those without HPV and occur in patients who are younger, similar to HPV mediated oropharyngeal cancer. 2. A subset of inverted papillomas have transcriptionally active low-risk HPV and have a higher risk of transformation, while low risk HPV negative inverted papillomas frequently have EGFR mutations.

Summary: SNSCC is a diverse disease with likely multiple etiologies including carcinogen, irritant exposure, and HPV. While not definitively proven, evidence supports a role for high-risk HPV in a subset of SNSCC, and low-risk HPV in a subset of inverted papillomas which transform to SNSCC. In-depth molecular and genomic studies are needed in SNSCC to better understand the genomic underpinnings and oncogenic drivers.
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http://dx.doi.org/10.1007/s40136-020-00279-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314379PMC
June 2020

Hypofractionated radiotherapy and surgery compared to standard radiotherapy in early glottic cancer.

Am J Otolaryngol 2020 Sep - Oct;41(5):102544. Epub 2020 May 15.

Boston University School of Medicine, Radiation Oncology, 830 Harrison Ave, Moakley Building LL 237, Boston, MA 02118, USA. Electronic address:

Purpose: Early-stage glottic laryngeal cancer is treated with surgery or radiotherapy (RT), but limited randomized data exists to support one modality over the other. This study evaluates survival differences in early glottic cancer patients treated with either surgery or RT.

Materials And Methods: 14,498 patients with early glottic cancer diagnosed from 2004 to 2015 and treated with surgery or RT were identified in the National Cancer Database. Kaplan-Meier method was used to analyze differences in overall survival (OS) by treatment (surgery vs. RT) and radiation dose fractionation. Cox regression modeling and propensity score-matched (PSM) analysis were performed. Adjusted hazard ratios (aHR) with 95% confidence intervals (95% CI) were computed.

Results: Median follow-up and median OS for all patients were 49.5 and 118 months, respectively. The estimated 5-year OS for surgery and RT was 77.5% and 72.6%, respectively (P < 0.0001). On multivariate analysis, aHR (95% CI) for surgery compared to RT was 0.87 (0.81-0.94, P = 0.0004). Compared to RT regimen 63-67.5 Gray (Gy) in 28-30 fractions, worse survival was noted for RT regimen 66-70 Gy in 33-35 fractions (aHR 1.15, 95% CI 1.07-1.23, P = 0.0003). When compared with hypofractionated RT (63-67.5 Gy in 28-30 fractions), patients undergoing surgery no longer showed improved OS (aHR 0.94, 95% CI 0.86-1.02, P = 0.154). The finding was confirmed on PSM analysis (surgery aHR 0.95, 95% CI 0.87-1.05, P = 0.322).

Conclusion: In early glottic tumors, patients treated with surgery demonstrated improved survival compared to RT, but when hypofractionation was considered, there were no significant differences in OS between patients undergoing surgery or RT.
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http://dx.doi.org/10.1016/j.amjoto.2020.102544DOI Listing
November 2020

Immune checkpoint inhibitors in sinonasal squamous cell carcinoma.

Oral Oncol 2020 10 12;109:104776. Epub 2020 May 12.

Massachusetts Eye and Ear, Boston, MA, USA; Massachusetts General Hospital, USA; Harvard Medical School, USA. Electronic address:

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http://dx.doi.org/10.1016/j.oraloncology.2020.104776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508759PMC
October 2020

Two for the price of one: Prevalence, demographics and treatment implications of multiple HPV mediated Head and Neck Cancers.

Oral Oncol 2020 01 22;100:104475. Epub 2019 Nov 22.

Massachusetts Eye and Ear, Boston, MA, United States; Harvard Medical School, Boston, MA, United States. Electronic address:

Objectives: HPV mediated head and neck squamous cell carcinoma (HPVmHNSCC) is increasing in prevalence in the United States, as are reports of patients with multiple HPVmHNSCCs. The prevalence, demographics, and treatment implications of this emerging clinical entity are poorly understood.

Materials And Methods: We performed a multitiered assessment of patients with multiple HPVmHNSCC including: 1. systematic review of the literature, 2. query of the 2017 Surveillance, Epidemiology and End Results (SEER) database and 3. institutional level reporting at two high volume academic centers.

Results: Systematic literature review: 13 articles met inclusion criteria (48 patients with multiple HPVmHNSCC). Pooled prevalence rate of multiple HPVmHNSCC was 2.64%. SEER database: 60(0.95%) patients with HPVmHNSCC had two tumors. Patients with multiple HPVmHNSCC were more likely to be younger and present with a lower T and N stage (p < 0.025 for all). The second identified tumor was more likely to be contralateral, found synchronously, of smaller size, and to occur in the tonsil (p < 0.05 for all). Institutional reporting: 17(1.69%) patients with HPVmHNSCC had two primary tumors. Similar to the SEER database, patients with multiple HPVmHNSCC were more likely to present with a low T stage and tonsil location (p < 0.007 for both).

Conclusion: Multiple HPVmHNSCCs occur in a subset of HPVmHNSCC cases with distinct characteristics. Thorough interrogation of all oropharyngeal subsites should be performed as part of the initial workup for HPVmHNSCC, with consideration given to contralateral tonsillectomy at the time of surgical resection for HPV mediated tonsil cancers due to the prevalence of contralateral tonsil primaries.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017724PMC
January 2020

Genomic Correlates of Exceptional Response to ErbB3 Inhibition in Head and Neck Squamous Cell Carcinoma.

JCO Precis Oncol 2019 25;3. Epub 2019 Mar 25.

University of Pittsburgh, Pittsburgh, PA.

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http://dx.doi.org/10.1200/PO.18.00174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705601PMC
March 2019

APOBEC mutagenesis is tightly linked to the immune landscape and immunotherapy biomarkers in head and neck squamous cell carcinoma.

Oral Oncol 2019 09 30;96:140-147. Epub 2019 Jul 30.

Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States; Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address:

HNSCC is an immunologically active tumor with high levels of immune cell infiltration, high mutational burden and a subset of patients who respond to immunotherapy. One of the primary sources of mutations in HNSCC is the cytidine deaminase APOBEC3, which is a known participant in innate immunity. Why particular HNSCCs have higher rates of APOBEC mutations and how these mutations relate to the immune microenvironment remains unknown. Utilizing whole exome and RNA-Seq datasets from TCGA HNSCCs we annotated APOBEC mutations, immune cell populations, activating and end effectors of immunity and neoantigens in order to interrogate the relationship between APOBEC mutations and the immune landscape. Immune cell populations and composite scores of immune activation were tightly associated with APOBEC mutational burden (p = 0.04-1.17e-5). HNSCC had the highest levels of IFNy across cancer types with high APOBEC mutational burden, with the highest IFNy scores in HPV mediated HNSCC. Tumor specific neoantigens were significantly correlated with APOBEC mutational burden while other sources of neoantigens were not (0.53 [0.24, 0.76] p = 8e-5). The presence of a germline APOBEC polymorphism was more prevalent in non-white, non-black patients and within this group, patients with the polymorphism had higher APOBEC mutational burden (p = 0.002). APOBEC mutations are tightly linked to immune activation and infiltration in HNSCC. Multiple mechanisms may exist within HNSCC leading to APOBEC mutations including immune upregulation in response to neoantigens and viral infection, via induction of IFNy. These mechanisms may be additive and not mutually exclusive, which could explain higher levels of APOBEC mutations in HPV mediated HNSCC.
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http://dx.doi.org/10.1016/j.oraloncology.2019.07.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492081PMC
September 2019

Immunogenomic correlates of response to cetuximab monotherapy in head and neck squamous cell carcinoma.

Head Neck 2019 08 4;41(8):2591-2601. Epub 2019 Mar 4.

Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Mechanisms of resistance to immune-modulating cancer treatments are poorly understood. Using a novel cohort of patients with head and neck squamous cell carcinoma (HNSCC), we investigated mechanisms of immune escape from epidermal growth factor receptor-specific monoclonal antibody (mAb) therapy.

Methods: HNSCC tumors (n = 20) from a prospective trial of neoadjuvant cetuximab monotherapy underwent whole-exome sequencing. Expression of killer-cell immunoglobulin-like receptor (KIR) and human leukocyte antigen-C (HLA-C) and the effect of KIR blockade were assessed in HNSCC cell lines.

Results: Nonresponders to cetuximab had an increased rate of mutations in HLA-C compared to responders and HNSCC tumors (n = 528) in The Cancer Genome Atlas (P < 0.00001). In vitro, cetuximab-activated natural killer (NK) cells induced upregulation of HLA-C on HNSCC cells (P < 0.01) via interferon gamma. Treatment of NK cells with the anti-KIR mAb lirilumab increased killing of HNSCC cells (P < 0.001).

Conclusions: Alterations in HLA-C may provide a mechanism of immune evasion through disruption of NK activation.
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http://dx.doi.org/10.1002/hed.25726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625877PMC
August 2019

Complications of Nasoseptal Flap Reconstruction: A Systematic Review.

J Neurol Surg B Skull Base 2018 Oct 20;79(Suppl 4):S291-S299. Epub 2018 Aug 20.

Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States.

 The nasoseptal flap (NSF) is considered the primary vascularized flap for reconstruction of dural defects with endoscopic endonasal surgery (EES) of the skull base. However, the complications and morbidities associated with this reconstructive flap are poorly understood. This article presents a systematic review of the complications and morbidities related to the use of the NSF in skull base surgery.  A systematic review of the literature based on published guidelines was performed to identify potential complications and morbidities related to the NSF. The MEDLINE and Embase databases were searched from January 1, 1950 to February 5, 2018.  Twenty-seven articles were identified. Reported complications were as follows: NSF necrosis (4 studies; [0-1.3%]), mucocele formation (5 studies; [0-3.6%]), septal perforation (6 studies, [0-14.4%]), nasal dorsum collapse (2 studies, [0.7-5.8%]), effects on quality of life (QoL) (8 studies), and olfactory loss (11 studies).  Although complications associated with the NSF may be underreported in the literature, the NSF appears to be a safe and reliable reconstructive flap in EES of the skull base.
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http://dx.doi.org/10.1055/s-0038-1668158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133677PMC
October 2018

Diagnosis and endoscopic endonasal management of nontraumatic pseudoaneurysms of the cranial base.

Int Forum Allergy Rhinol 2018 05 27;8(5):641-647. Epub 2018 Feb 27.

Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Background: Nontraumatic pseudoaneurysms of the cranial base are rare and present unique diagnostic and treatment dilemmas compared with both true aneurysms and pseudoaneurysms outside of the cranial base. There is a dearth of knowledge regarding the management of these complicated lesions.

Methods: Nontraumatic pseudoaneurysms of the cranial base internal carotid artery (ICA) were retrospectively identified at the University of Pittsburgh Medical Center through a key word search of cranial base cases from 2010 to 2017.

Results: Three cases were identified, demonstrating pseudoaneurysms of the cavernous and petrous ICA. Each patient underwent diagnostic work-up with computed tomography, magnetic resonance imaging, and angiography, followed by endovascular occlusion and endoscopic endonasal surgery, which resulted in relief of presenting complaints and ablation of the pseudoaneurysm.

Conclusion: Symptomatic cranial base pseudoaneurysms should undergo treatment to obliterate the aneurysm and relieve the mass effect. First, formal angiography is necessary for accurate diagnosis and treatment planning. Next, endovascular occlusion is performed, with a preference for coiling or endoluminal reconstruction with a flow diverter. Last, endoscopic intervention follows in cases where: (1) decompression of vital structures is indicated; (2) diagnosis of the pseudoaneurysm cannot be definitively confirmed with angiography; or (3) the etiology of the confirmed pseudoaneurysm requires further investigation.
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http://dx.doi.org/10.1002/alr.22080DOI Listing
May 2018

Multi-modality analysis supports APOBEC as a major source of mutations in head and neck squamous cell carcinoma.

Oral Oncol 2017 11 13;74:8-14. Epub 2017 Sep 13.

Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.

Objectives: The mutagenic processes underlying head and neck squamous cell carcinoma (HNSCC) are poorly understood. Pan-cancer mutational signature analyses have identified a signature for APOBEC, a cytosine deaminase, in a subset of cancers, including HNSCC. The role of APOBEC activity in HNSCC remains poorly understood. Therefore, we sought to determine the role of APOBEC in HNSCC pathogenesis.

Material And Methods: Utilizing bioinformatic approaches we explored the role of APOBEC mediated mutations in tumor exomes, transcriptomes and germline exomes from 511HNSCC patients in the TCGA.

Results: 58% of HNSCC were statistically enriched for the APOBEC signature. APOBEC3A expression had the highest correlation coefficient with APOBEC mutation rate. Gene specific motif analysis revealed a slight predominance of APOBEC3A mutations. Canonical pathway analysis demonstrated immune pathway upregulation in APOBEC mutation rich samples. Overall mutational burden was positively correlated with APOBEC enrichment.

Conclusions: APOBEC mediated mutations are highly prevalent in HNSCC. APOBEC3A is the most likely gene to be active in HPV+ HNSCC. APOBEC activity correlates with upregulation of immune signaling pathways, supporting the hypothesis that APOBEC activity could be activated as part of the innate immune response.
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http://dx.doi.org/10.1016/j.oraloncology.2017.09.002DOI Listing
November 2017

Spontaneous Iliopsoas Hematoma following Microvascular Free Tissue Transfer.

Case Rep Otolaryngol 2017 26;2017:7631673. Epub 2017 Mar 26.

Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA, USA.

Spontaneous hematoma within the iliopsoas muscle (SIH) is a rare complication most commonly seen in coagulopathic patients. Often, patients undergoing microvascular free tissue transfer are anticoagulated for anastomotic patency. Here we describe two cases of postoperative SIH following contralateral anterolateral thigh (ALT) free tissue transfer for reconstruction of oncologic head and neck defects. Both patients described hip pain after mobilization and had a corresponding acute blood loss anemia. Diagnosis of SIH was confirmed by CT and both patients were managed conservatively. Given that anticoagulation is a common practice following head and neck free tissue transfer, surgeons should be aware of this potential complication.
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http://dx.doi.org/10.1155/2017/7631673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425841PMC
March 2017

Whole Exome Sequencing of Growing and Non-Growing Cutaneous Neurofibromas from a Single Patient with Neurofibromatosis Type 1.

PLoS One 2017 18;12(1):e0170348. Epub 2017 Jan 18.

Department of Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.

The growth behaviors of cutaneous neurofibromas in patients with Neurofibromatosis type 1 are highly variable. The role of the germline NF1 mutation, somatic NF1 mutation and mutations at modifying loci, are poorly understood. We performed whole exome sequencing of three growing and three non-growing neurofibromas from a single individual to assess the role of acquired somatic mutations in neurofibroma growth behavior. 1-11 mutations were identified in each sample, including two deleterious NF1 mutations. No trends were present between the types of somatic mutations identified and growth behavior. Mutations in the HIPPO signaling pathway appeared to be overrepresented.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170348PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242532PMC
August 2017

Durable treatment of ameloblastoma with single agent BRAFi Re: Clinical and radiographic response with combined BRAF-targeted therapy in stage 4 ameloblastoma.

J Natl Cancer Inst 2017 01 26;109(1). Epub 2016 Sep 26.

Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, San Francisco, CA, USA.

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http://dx.doi.org/10.1093/jnci/djw190DOI Listing
January 2017

Targeted next-generation sequencing of TP53 in oral tongue carcinoma from non-smokers.

J Otolaryngol Head Neck Surg 2016 Sep 17;45(1):47. Epub 2016 Sep 17.

Department of Otolaryngology-Head and Neck Surgery, University of California, 2380 Sutter St First Floor, San Francisco, CA, 94115, USA.

Background: Little is known regarding the etiology and genomic underpinnings of Oral Tongue Squamous Cell Carcinoma (OTSCC) in patients who lack traditional risk factors, yet the incidence is increasing. In particular, the rate, and role, of TP53 mutations in this cohort has been heavily debated in the literature.

Methods: Tumor DNA from forty-three non-smokers with OTSCC underwent next generation sequencing of TP53.

Results: Sixty percent of samples contained a TP53 mutation. The G > T transversion rate was 5.7 %. TP53 status did not differ by age.

Conclusions: OTSCC in non-smokers have TP53 mutation rates similar to other Head and Neck cancers yet these mutations do not appear related to carcinogen exposure based on the mutational spectrum and clinical history. The mechanisms driving tumorigenesis in this cohort, including mutations in TP53, remain elusive and further studies are needed.
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http://dx.doi.org/10.1186/s40463-016-0160-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027093PMC
September 2016

Otolaryngologic Manifestations of Levamisole-Induced Vasculitis.

JAMA Otolaryngol Head Neck Surg 2016 Mar;142(3):299-300

Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco.

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http://dx.doi.org/10.1001/jamaoto.2015.3565DOI Listing
March 2016

Stimulation threshold greatly affects the predictive value of intraoperative nerve monitoring.

Laryngoscope 2015 May 9;125(5):1265-70. Epub 2014 Oct 9.

Department of Otolaryngology-Head and Neck Surgery , University of California, San Francisco, San Francisco, California; School of Medicine , University of California, San Francisco, San Francisco, California.

Objectives/hypothesis: Using a standardized, graded, intraoperative stimulation protocol, we aimed to delineate the effects of various stimulation levels applied to the recurrent laryngeal nerve on the postoperative predictive value of intraoperative nerve monitoring.

Study Design: A total of 917 nerves at risk were included for analysis. Intraoperatively, patients underwent stimulation of the recurrent laryngeal nerve at 0.3, 0.5, 0.8, and 1.0 mA followed by postoperative laryngoscopy for correlation with intraoperative findings.

Methods: Sensitivity, specificity, positive predictive value, and negative predictive value were calculated at each stimulation level.

Results: Sensitivity, specificity, positive predictive value, and negative predicative values ranged from 100% to 37%, 6% to 99%, 2% to 39%, and 100% to 99%, respectively at 0.3 to 1.0 mA. No demographic variables affected sensitivity or specificity. Receiver operating characteristic analysis identified 0.5 mA as the level of stimulation that optimizes sensitivity and specificity.

Conclusions: The predictive value of intraoperative nerve monitoring varies greatly depending on the stimulation levels used. At low amplitudes of stimulation, nerve monitoring has high sensitivity and negative predictive value but low specificity and positive predictive value, related to the high rate of false positives. At high levels of stimulation, specificity and negative predictive value are high, sensitivity is low, and the positive predictive value rises as the rate of false negatives increase and the rate of false positives decrease. A stimulation level of 0.5 mA optimizes the predictive value of nerve monitoring; however, stimulation at multiple levels significantly improves the predictive value of intraoperative nerve monitoring.

Level Of Evidence: 2b.
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http://dx.doi.org/10.1002/lary.24960DOI Listing
May 2015

Clinical, genomic, and metagenomic characterization of oral tongue squamous cell carcinoma in patients who do not smoke.

Head Neck 2015 Nov 23;37(11):1642-9. Epub 2014 Aug 23.

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: Evidence suggests the incidence of oral tongue squamous cell carcinoma is increasing in young patients, many who have no history of tobacco use.

Methods: We clinically reviewed 89 patients with oral tongue cancer. Exomic sequencing of tumor DNA from 6 nonsmokers was performed and compared to previously sequenced cases. RNA from 20 tumors was evaluated by massively parallel sequencing to search for potentially oncogenic viruses.

Results: Non-smokers (53 of 89) were younger than smokers (36 of 89; mean, 50.4 vs 61.9 years; p < .001), and seemed more likely to be women (58.5% vs 38.9%; p = .069). Nonsmokers had fewer TP53 mutations (p = .02) than smokers. No tumor-associated viruses were detected.

Conclusion: The young age of nonsmoking patients with oral tongue cancer and fewer TP53 mutations suggest a viral role in this disease. Our efforts to identify such a virus were unsuccessful. Further studies are warranted to elucidate the drivers of carcinogenesis in these patients.
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http://dx.doi.org/10.1002/hed.23807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272912PMC
November 2015

Variation of BMP3 contributes to dog breed skull diversity.

PLoS Genet 2012 2;8(8):e1002849. Epub 2012 Aug 2.

Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland, United States of America.

Since the beginnings of domestication, the craniofacial architecture of the domestic dog has morphed and radiated to human whims. By beginning to define the genetic underpinnings of breed skull shapes, we can elucidate mechanisms of morphological diversification while presenting a framework for understanding human cephalic disorders. Using intrabreed association mapping with museum specimen measurements, we show that skull shape is regulated by at least five quantitative trait loci (QTLs). Our detailed analysis using whole-genome sequencing uncovers a missense mutation in BMP3. Validation studies in zebrafish show that Bmp3 function in cranial development is ancient. Our study reveals the causal variant for a canine QTL contributing to a major morphologic trait.
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http://dx.doi.org/10.1371/journal.pgen.1002849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410846PMC
December 2012

The MTAP-CDKN2A locus confers susceptibility to a naturally occurring canine cancer.

Cancer Epidemiol Biomarkers Prev 2012 Jul 23;21(7):1019-27. Epub 2012 May 23.

Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.

Background: Advantages offered by canine population substructure, combined with clinical presentations similar to human disorders, makes the dog an attractive system for studies of cancer genetics. Cancers that have been difficult to study in human families or populations are of particular interest. Histiocytic sarcoma is a rare and poorly understood neoplasm in humans that occurs in 15% to 25% of Bernese Mountain Dogs (BMD).

Methods: Genomic DNA was collected from affected and unaffected BMD in North America and Europe. Both independent and combined genome-wide association studies (GWAS) were used to identify cancer-associated loci. Fine mapping and sequencing narrowed the primary locus to a single gene region.

Results: Both populations shared the same primary locus, which features a single haplotype spanning MTAP and part of CDKN2A and is present in 96% of affected BMD. The haplotype is within the region homologous to human chromosome 9p21, which has been implicated in several types of cancer.

Conclusions: We present the first GWAS for histiocytic sarcoma in any species. The data identify an associated haplotype in the highly cited tumor suppressor locus near CDKN2A. These data show the power of studying distinctive malignancies in highly predisposed dog breeds.

Impact: Here, we establish a naturally occurring model of cancer susceptibility due to CDKN2 dysregulation, thus providing insight about this cancer-associated, complex, and poorly understood genomic region.
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http://dx.doi.org/10.1158/1055-9965.EPI-12-0190-TDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392365PMC
July 2012