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Year of Publication
1.  Effect of Induction Chemotherapy on Swallow Physiology and Saliva Production in Patients with Head and Neck Cancer: A Pilot Study 
Head & neck  2014;37(4):567-572.
Background
No objective data are available to assess the potential damage induction chemotherapy alone contributes to swallowing physiology and salivary production in patients with locally and regionally confined head and neck cancer.
Methods
Thirteen patients with head and neck cancer were evaluated pre- and post-induction chemotherapy. Assessment included 1) percent nutrition taken orally and food consistencies in diet; 2) videofluorographic swallow evaluation; 3) whole mouth saliva collection; 4) quality-of-life questionnaire; 5) pain and oral mucositis scores.
Results
All patients were able to consume most foods and took 100% of their nutrition orally both pre- and post-induction chemotherapy. While a number of swallow measures worsened, no statistically significant differences were observed in diet, quality of life measures, pain, or saliva weight, or in most temporal swallow measures. Pharyngeal residue decreased significantly following chemotherapy.
Conclusions
Induction chemotherapy alone did not significantly negatively alter swallowing physiology and salivary secretion although the trend was toward worsening in function.
doi:10.1002/hed.23635
PMCID: PMC4139482  PMID: 24677442
chemotherapy; swallow physiology; saliva; videofluorography; head & neck cancer; quality of life
2.  Oropharyngeal Cancer (OPC) Drives Racial Outcome Disparities in Squamous Cell Carcinoma of the Head and Neck (HNSCC): Ten Year Experience at the University of Maryland Greenebaum Cancer Center (UMGCC) 
Head & neck  2015;38(4):564-572.
Background
Racial outcome disparities have been observed in HNSCC with diminished survival for black patients compared to whites.
Methods
We retrospectively analyzed 1318 patients with primary HNSCC treated at the UMGCC from 2000 to 2010.
Results
65.9% were white, 30.7% were black and 3.3% were of other races. Blacks were less likely to present with oral cavity cancer (OC), and more likely to present with laryngeal or hypopharyngeal cancers. Whites were more likely to have early stage disease, especially in the OC. Black race was independently associated with worse OS in the entire cohort. Blacks had a significantly worse OS amongst OC and oropharyngeal cancers (OPC), with the largest disparity in OPC. However in multivariate analysis race was only still significant in OPC.
Conclusion
We observed differences by race in distribution of disease site, stage, and OS. Survival disparity in the entire cohort was driven mostly by differences amongst OPC.
doi:10.1002/hed.23933
PMCID: PMC4461547  PMID: 25488341
Race; HNSCC; Oropharyngeal; Survival; Disparity
3.  Targeting angiogenesis as a therapeutic means to reinforce osteocyte survival and prevent nonunions in the aftermath of radiotherapy 
Head & neck  2014;37(9):1261-1267.
Background
Radiotherapy (XRT) exerts detrimental collateral effects on bone tissue through mechanisms of vascular damage and impediments to osteocytes, ultimately predisposing patients to the debilitating problems of late pathologic fractures and nonunions. We posit that angiogenic therapy will reverse these pathologic effects in a rat model of radiated fracture healing.
Methods
Three groups of rats underwent mandibular osteotomy. Radiated groups received a fractionated 35 Gy dose before surgery. The deferoxamine (DFO) group received local injections postoperatively. A 40-day healing period was allowed before histology. Analysis of variance (ANOVA; p < .05) was used for group comparisons.
Results
Radiated fractures revealed a significantly decreased osteocyte count and corresponding increase in empty lacunae when compared to nonradiated fractures (p = .001). With the addition of DFO, these differences were not appreciated. Further, a 42% increase in bony unions was observed after DFO therapy.
Conclusion
Targeting angiogenesis is a useful means for promoting osteocyte survival and preventing bone pathology after XRT.
doi:10.1002/hed.23744
PMCID: PMC4788100  PMID: 24801669
deferoxamine; radiation; mandible; angiogenesis; nonunion
4.  Cancer stem cells mediate tumorigenesis and metastasis in head and neck squamous cell carcinoma 
Head & neck  2014;37(3):317-326.
Background
Cancer stem cells (CSC) represent a subpopulation of cells responsible for tumor growth. Their role in head and neck squamous cell carcinoma (HNSCC) tumorigenesis and metastasis remains uncertain.
Methods
Wound healing and an orthootopic animal model were used to study cells expressing the CSC phenotype (CD44high and ALDH+) and assess mobility, tumorigenesis and metastasis. A prospective collection of 40 patient-derived primary HNSCC specimens were analyzed for CSC-proportion compared to clinical variables.
Results
CSC exhibited significantly faster wound closure and greater tumorigenesis and regional metastasis in-vivo than non-CSC. In primary patient tumors, size and advanced stage were correlated with elevated proportion of CSC, however not with survival.
Conclusion
HNSCC CSC mediate tumorigenesis and regional metastasis in-vivo. In primary patient tumors, CSC-proportion was associated with tumor size and stage, but not with metastatic spread or survival. CSC burden alone may only represent a minor variable in understanding CSC and metastasis.
doi:10.1002/hed.23600
PMCID: PMC4127160  PMID: 24415402
Cancer stem cells; CD44; Head and neck squamous cell carcinoma; metastasis; animal model
5.  Posttraumatic Stress Disorder (PTSD) Symptoms in Newly Diagnosed Head and Neck Cancer Patients and their Partners 
Head & neck  2014;37(9):1282-1289.
Background
Head and neck cancer is a life threatening illness requiring aversive treatments. Despite clear potential for posttraumatic stress disorder (PTSD) symptoms in both patients and their partners, research is scant.
Methods
Newly diagnosed patients and partners (no. of dyads=42) completed questionnaires to assess symptoms of PTSD, anxiety, and depression, as well as demographic, medical, and attitudinal variables.
Results
Partners had higher average levels of PTSD symptoms than patients (p=.023). More partners (28.6%) met criteria for estimated PTSD caseness than did patients (11.9%). There were no significant differences in levels of other anxiety or depression symptoms. Perceived threat of disease appears to be a stronger correlate of PTSD symptom levels than medical variables in patients and partners.
Conclusions
A diagnosis of head and neck cancer elicits significant levels of PTSD symptoms in patients, and even higher levels among partners. Identified correlates of distress, including perceived threat of disease, are potential intervention targets.
doi:10.1002/hed.23760
PMCID: PMC4229455  PMID: 24817018
Stress; PTSD; couples; blame; head and neck cancer
6.  The Use of Inpatient Palliative Care Services In Patients With Metastatic Incurable Head and Neck Cancer 
Head & neck  2015;38(3):355-363.
Background
Substantial health care resources are used on aggressive end-of-life care, despite an increasing recognition that palliative care improves quality of life and reduces health care costs. We examined the incidence of palliative care encounters in inpatients with incurable head and neck cancer (HNCA) and associations with in-hospital mortality, length of hospitalization, and costs.
Methods
Data from the Nationwide Inpatient Sample for 80,514 HNCA patients with distant metastatic disease in 2001–2010 was analyzed using cross-tabulations and multivariate regressions.
Results
Palliative care encounters occurred in 4,029 cases (5%) and were significantly associated with age ≥80 years, female sex, self-pay pay or status, and prior radiation. Palliative care was significantly associated with increased in-hospital mortality and reduced hospital-related costs.
Conclusions
Inpatient palliative care consultation in terminal HNCA is associated with reduced hospital-related costs, but appears to be underutilized and restricted to the elderly, uninsured, and patients with an increased risk of mortality.
doi:10.1002/hed.23895
PMCID: PMC4405456  PMID: 25331744
palliative care; complications; head and neck neoplasms; costs; Nationwide Inpatient Sample
7.  Phase I study of vandetanib with radiation therapy with or without cisplatin in locally advanced head and neck squamous cell carcinoma 
Head & neck  2015;38(3):439-447.
Background
Vandetanib, added to cisplatin and radiation (RT) overcomes chemo RT and EGFR inhibitor resistance in head and neck squamous cell carcinoma (HNSCC) lines and models.
Methods
Patients with previously untreated HNSCC received vandetanib daily for 14 days (starting dose 100 mg) then vandetanib +RT (2.2 Gy/day, 5 days/week) for 6 weeks (regimen 1) or vandetanib +RT (2 Gy/day, 5 days/week) + cisplatin (30 mg/m2 weekly) for 7 weeks (regimen 2). Primary objective was the maximum tolerated dose (MTD) of vandetanib with RT +/− cisplatin.
Results
Of 33 treated patients, 30 completed therapy (regimen 1, n=12; regimen 2, n=18). MTD in regimen 2 was 100 mg [3 dose limiting toxicities (DLT) at 200 mg], while regimen 1 was stopped due to poor recruitment (one DLT at 200 mg). Most common grade ≥3 AEs were dysphagia (30%), stomatitis (33%) and mucosal inflammation (27%). Five patients discontinued vandetanib due to AEs.
Conclusions
Vandetanib with chemo RT was feasible.
doi:10.1002/hed.23922
PMCID: PMC4414661  PMID: 25352401
vandetanib; cisplatin; radiation therapy; head and neck squamous cell cancer
8.  CD200 is related to cancer-stem-cell features and modulates response to chemoradiation in head and neck squamous cell carcinoma 
Head & neck  2014;37(3):327-335.
Background
We sought to characterize the expression of CD200, a membrane protein that functions in immune evasion, to examine its correlations with cancer stem cell-like features and analyze its response to chemotherapy and radiation, in human papillomavirus (HPV) positive and negative head and neck squamous cell carcinomas (HNSCCs).
Methods
CD200 expression was analyzed in several HNSCC cell lines. CD200 was over-expressed in HPV(+) murine tonsil epithelial cells, its effects on Shh and Bmi-1 examined in vitro, and tumor growth and response to chemoradiation analyzed in vitro and in vivo.
Results
CD200 was diversely expressed, consistently associated with expression of Bmi-1 and Shh. Overexpression of CD200 induced Bmi-1 and Shh. Tumor grew similarly between C57BL/6 and Rag1−/− C57BL6 mice. ,. CD200 expression enhanced the resistance to chemoradiation only in vivo.
Conclusions
CD200 was related to cancer-stem-cell features and modulates response to chemoradiation in vivo. Attenuating this might be a potential therapeutic strategy.
doi:10.1002/hed.23608
PMCID: PMC4557697  PMID: 24700450
oropharyngeal cancer; human papillomavirus; CD200; immune tolerance; neoplastic stem cells
9.  DIAGNOSIS AND MANAGEMENT OF HEREDITARY PARAGANGLIOMA SYNDROME DUE TO THE F933>X67 SDHD MUTATION 
Head & neck  2009;31(5):689-694.
Background
The hereditary paraganglioma syndromes (PGLs) are autosomal dominant conditions with an increased risk for tumors of the sympathetic and parasympathetic neuroendocrine systems. The recognition of patients with hereditary PGL and identification of the responsible gene are important for the management of index patients and family members.
Methods
We present the clinical, radiological, biochemical, and family history findings of a 15-year-old boy patient with a glomus vagale versus glomus jugulare tumor.
Results
Evaluation of the family history and the patient's history led to the identification of a familial succinate dehydrogenase subunit D (SDHD) gene mutation (F933>X67), consistent with a diagnosis of hereditary PGL1. Although this family had all head and neck tumors, this SDHD mutation has previously been described in a family with primarily functional pheochromocytomas.
Conclusions
This case report highlights the variable expressivity of a single mutation in SDHD, (F933>X67). Careful and comprehensive screening is warranted for individuals at risk.
doi:10.1002/hed.20930
PMCID: PMC4758329  PMID: 19072999
paraganglioma; SDHD; hereditary; counseling; management
10.  Definitive Radiation Therapy Without Chemotherapy for Human Papillomavirus-Positive Head and Neck Cancer 
Head & neck  2013;35(11):1652-1656.
Purpose
To report a single institutional experience with definitive radiation therapy alone for human papillomavirus (HPV)-positive head and neck cancer
Methods and Materials
Sixty-seven patients were treated by radiation therapy alone to a median dose of 70 Gy (range, 66 to 72 Gy) for squamous cell carcinoma of the head and neck. Paraffin-embedded, formalin-fixed pre-treatment tumor tissues were used to establish HPV-positivity using standardized techniques of immunohistochemistry for p16 and polymerase chain reaction for HPV.
Results
Twenty-three patients with HPV-positive cancers were identified. With a median follow-up of 28 months (range, 6 to 85 months), the 3-year actuarial rates of overall survival, local-regional control, and distant metastasis-free survival were 83%, 90%, and 88%, respectively.
Conclusion
These findings attest to the exquisite radiosensitivity of HPV-positive head and neck cancer. The clinical outcomes observed from this selected series compare favorably to historical controls treated by more intensive chemoradiotherapy strategies.
doi:10.1002/hed.23209
PMCID: PMC4757483  PMID: 23335285
human papillomavirus; head and neck cancer; radiation therapy; squamous cell carcinoma; radiosensitivity
11.  Matted Nodes Predict Distant Metastasis in Advanced Stage III/IV Oropharyngeal Squamous Cell Carcinoma 
Head & neck  2015;38(2):184-190.
Background
We recently described the imaging characteristics of multiple confluent regional metastases (matted nodes) and found that this characteristic was associated with distant metastasis in patients with oropharyngeal squamous cell carcinoma (OPSCC). The purpose of this study is to determine if matted nodes are a predictive marker for distant metastasis.
Methods
Radiologic lymph node characteristics on 205 untreated stage III/IV with OPSCC patients of whom 192 had known HPV status underwent weekly carboplatin and paclitaxel with concomitant IMRT between 2003–2010 with minimum 2 years of follow-up.
Results
The 3-year DSS for patients with matted nodes was 58% versus 97% with non-matted nodes(p=0.0001). The prevalence of matted nodes in the population was 20%. The positive predictive value of matted nodes for distant metastasis is 66%, and the negative predictive value is 99%.
Conclusions
Matted nodes are a predictive marker for distant disease and can be used for planning new clinical interventions.
doi:10.1002/hed.23882
PMCID: PMC4370799  PMID: 25251643
oropharyngeal squamous cell carcinoma; matted nodes; predictor; prognosis; biomarkers; distant metastasis
12.  Serum Biomarkers for detection of Head and Neck Squamous Cell Carcinoma 
Head & neck  2015;38(1):9-14.
Background
Detection of hypermethylated circulating tumor DNA has the potential to be a minimally invasive, low cost, and reproducible method for cancer detection.
Methods
We evaluated serum from 100 patients with known head and neck squamous cell carcinoma (HNSCC) and 50 healthy control patients for three previously described methylation targets, EDNRB, p16 and DCC, using quantitative methylation specific PCR (qMSP).
Results
EDNRB hypermethylation was identified in the serum of 10% HNSCC patients but in none of the control patients. DCC hypermethylation was detected in two serum samples from cancer patients that also amplified EDNRB and one of these samples also had p16 hypermethylation. ENDRB hypermethylation was statistically significant by Fisher’s exact test (p=0.03) when comparing HNSCC to controls.
Conclusions
Serum EDNRB hypermethylation is highly specific but not sensitive serum biomarker for HNSCC.
doi:10.1002/hed.23842
PMCID: PMC4317379  PMID: 24995714
13.  Human Papillomavirus-related Oropharyngeal Cancer: Are Recurrences Similar to the Parent Tumor? 
Head & neck  2014;37(1):8-11.
Background
Although typically associated with a favorable prognosis, a minority of human papillomavirus (HPV)-related oropharyngeal cancers (OPC) recur after chemoradiation. We postulated that a minor HPV-negative tumor sub-fraction may be responsible for recurrences of HPV+ OPC.
Methods
Paired untreated primary and recurrent tumor specimens were identified for 37 OPC patients who received definitive chemoradiotherapy at our institution. Concordance in HPV/p16 expression between primary and recurrent tumors was assessed.
Results
Among 31 patients with HPV+/p16+ primary tumors, 30 (97%) retained evidence of both HPV and p16+ expression at recurrence (27 HPV+/p16+; 3 HPV+/p16-partial). One (3%) initially HPV+/p16+ patient developed a HPV-/p16- lung squamous cell carcinoma, representing either a discordant OPC metastasis or second primary tumor.
Conclusion
HPV-related OPCs retain HPV+/p16+ expression at recurrence. Our results fail to provide evidence that a minor HPV-negative tumor sub-fraction is responsible for biologically aggressive behavior of HPV+ OPC that recurs after chemoradiation.
doi:10.1002/hed.23548
PMCID: PMC4153786  PMID: 24962247
Human papillomavirus; p16; Oropharyngeal Cancer; Expression profiling; Chemoradiation
14.  Factors Associated With Pharyngoesophageal Stricture In Patients Treated With Concurrent Chemotherapy And Radiation Therapy For Oropharyngeal Squamous Cell Carcinoma 
Head & neck  2011;33(12):1727-1734.
Background
The purpose of this study was to elucidate factors associated with pharyngoesophageal strictures after treatment for head and neck squamous cell carcinoma (SCC).
Methods
We conducted a retrospective review of patients receiving cisplatin and 5-fluorouracil chemotherapy combined with concurrent hyperfractionated radiation therapy for oropharyngeal squamous cell carcinoma.
Results
Strictures developed in 13 of 67 patients (19%). Strictures were associated with tumor location (tonsil vs base of tongue; p = .03), neck dissection after completion of therapy (p = .03), and the duration of treatment-induced mucositis (weeks with mucositis grade ≥2; National Cancer Institute (NCI) Common Toxicity Criteria; p < .001). Age, sex, race, tumor stage, nodal stage, American Joint Committee on Cancer (AJCC) stage, human papillomavirus (HPV) status, smoking, radiation dose, maximum severity of mucositis, amifostine use, and pretreatment swallow dysfunction were not significantly associated with stricture. In multivariate analysis, only duration of mucositis, after controlling for age, sex, and tumor location, remained highly significant (p < .01).
Conclusion
The duration of treatment-related mucositis is an independent risk factor for stricture formation in patients with oropharyngeal SCC treated with concurrent chemotherapy and radiation therapy.
doi:10.1002/hed.21657
PMCID: PMC4695991  PMID: 21246640
stricture; pharyngoesophageal; oropharyngeal; squamous cell carcinoma; chemoradiation
15.  p16 Status, Pathologic and Clinical Characteristics, Biomolecular Signature, and Long Term Outcomes in Unknown Primary Carcinomas of the Head and Neck 
Head & neck  2014;36(12):1677-1684.
Background
To report associations between p16 status, clinicopathologic characteristics, and outcomes for unknown primary head and neck squamous cell carcinoma (SCCUPS).
Methods
Specimens of SCCUPS were re-analyzed. HPV status was determined by p16 stain. A tissue microarray (TMA) was constructed to evaluate biomarkers potentially prognostic in HNSCC.
Results
A majority of the population (n = 26, 74%) was p16+. Prognostic factors benefitting survival were p16+ status (p < 0.0001), absence of macroscopic extracapsular extension [ECE] (p = 0.004), younger age (p = 0.01), and higher grade (p = 0.007). The prognostic implication of worse OS with macroscopic ECE (p = 0.009) remained significant when limited to p16+ patients (p=0.002). Exploratory TMA between unknown primary and controls suggested a biomolecular difference between SCCUPS and known-primary cancer.
Conclusions
The majority of SCCUPS patients were p16+, indicative of HPV association. p16 staining and ECE appear to be the most prognostic features in SCCUPS.
doi:10.1002/hed.23514
PMCID: PMC3972378  PMID: 24115269
16.  The association between severe treatment-related lymphopenia and progression free survival in patients with newly diagnosed squamous cell head and neck cancer 
Head & neck  2014;36(12):1747-1753.
Background
Severe treatment-related lymphopenia (TRL) occurs commonly in many cancers and is associated with early tumor progression. Data is lacking as to whether this occurs in squamous cell head/neck cancer.
Methods
Serial total lymphocyte counts (TLC) were retrospectively reviewed in patients with newly diagnosed squamous head and neck cancer undergoing chemoradiation and associated with treatment outcomes.
Results
The median baseline TLC in 56 patients was 1660 cells/mm3 which fell by 73% to 445 cells/mm3 two months after initiating chemoradiation (p<0.0001). HPV− patients with TLC<500 cells/mm3 at two months had significantly earlier disease progression than those with higher TLCs (HR 5.75, p=0.045).
Conclusions
Baseline TLCs were normal but at two months ~60% of patients had severe TRL regardless of HPV status. Severe TRL in HPV− patients is independently associated with earlier disease progression. Prospective studies are needed to confirm these findings which suggest that immune preservation is important in this cancer.
doi:10.1002/hed.23535
PMCID: PMC4081494  PMID: 24174270
Lymphopenia; Head and neck squamous cell carcinoma; Radiation; Chemotherapy; Treatment-related toxicities
17.  A phase II trial of biweekly gemcitabine and paclitaxel with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN): SWOG study S0329 
Head & neck  2014;36(12):1712-1717.
Background
A phase I study and an institutional pilot study in patients with metastatic/recurrent squamous cell carcinoma of the head and neck (SCCHN), utilizing biweekly gemcitabine-paclitaxel showed an overall response rate of 53%. This phase II trial was conducted to determine the feasibility, tolerability and efficacy of this combination.
Methods
Patients with metastatic/recurrent SCCHN were treated with gemcitabine (3,000 mg/m2) and paclitaxel (150mg/m2) on days 1 and 15 of every 28 day cycle.
Results
In 57 patients with measurable disease, median progression free survival was 4 months and median overall survival was 8 months. Overall response rate of 28% and disease stabilization in 19% was seen. There were no treatment related deaths with Grade 3/4 hematologic toxicity seen in 20% of the patients.
Conclusions
Biweekly gemcitabine-paclitaxel is feasible, well tolerated and demonstrated reasonable efficacy. This may be an alternative for patients who are not candidates for platinum-based chemotherapy.
doi:10.1002/hed.23522
PMCID: PMC4640463  PMID: 24166832
gemcitabine; paclitaxel; recurrent; metastatic; squamous cell carcinoma of the head and neck
18.  Human papillomavirus and Epstein–Barr virus in nasopharyngeal carcinoma in a low-incidence population 
Head & neck  2013;36(4):511-516.
Background
The significance of human papillomavirus (HPV) in nasopharyngeal carcinomas (NPCs) in a low-incidence population remains unknown.
Methods
Samples from 90 patients with NPC (years, 1957–2012) were analyzed for Epstein–Barr virus (EBV). Clinical data, EBV, HPV, and p16 status were correlated with overall survival (OS; 63 cases; years, 1981–2012).
Results
Of 9 HPV-positive cases, 3 extended from extra-nasopharyngeal sites. Nasopharyngeal origin was confirmed in 6 cases. HPV-positive NPC had OS similar to EBV-positive NPC (85 vs 141 months; p > .05). The OS of patients with EBV/HPV-negative NPC was worse (34 months; p = .004). Nonkeratinizing histology was associated with better outcome than keratinizing (115 vs 25 months; p = .001). Over the last several decades, the proportion of keratinizing NPC decreased from 34.5% to 14.3% (p = .026).
Conclusion
The etiologic role of HPV in NPC is confirmed. The favorable prognostic significance of HPV positivity is similar to that of EBV positivity.
doi:10.1002/hed.23318
PMCID: PMC4656191  PMID: 23780921
nasopharyngeal carcinoma; human papillomavirus; Epstein–Barr virus
19.  PRECLINICAL SAFETY AND ACTIVITY OF RECOMBINANT VSV-IFN-B IN AN IMMUNOCOMPETENT MODEL OF SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK 
Head & neck  2014;36(11):1619-1627.
Background
VSV-IFN-β, a recombinant vesicular stomatitis virus expressing interferon-β, has demonstrated antitumor activity in vitro and in vivo. In preparation for clinical testing in human squamous cell carcinoma (SCC) of the head and neck, we conducted preclinical studies of VSV-IFN-β in syngeneic SCC models.
Methods and Results
In vitro, VSV-IFN-β (expressing rat or mouse IFN-β) induced cytotoxicity and propagated in rat (FAT-7) or mouse (SCC-VII) SCC cells during normoxia and hypoxia. In vivo, intratumoral administration of VSV-rat-IFN-β or VSV-human-IFN-β in FAT-7 bearing or non-tumor bearing immunocompetent rats did not result in acute organ toxicity or death. VSV-r-IFN-β replicated predominantly in tumors and a dose dependent anti-VSV antibody response was observed. Intratumoral or intravenous administration of VSV-IFN-β resulted in growth delay and improved survival compared to controls.
Conclusions
The above data confirm safety and feasibility of VSV-IFN-β administration in immunocompetent animals and support its clinical evaluation in advanced human head and neck cancer.
doi:10.1002/hed.23502
PMCID: PMC3969865  PMID: 24115092
Squamous cell carcinoma; Vesicular Stomatitis Virus; biodistribution; preclinical studies; syngeneic models
20.  Temporal Characterization of Lymphatic Metastasis in an Orthotopic Mouse Model of Oral Cancer 
Head & neck  2014;36(11):1638-1647.
Background
Overall mortality rate of head and neck squamous cell carcinoma (HNSCC) has not improved over the past 30 years; mostly due to high treatment failure rate among patients with regionally metastatic disease. To better understand the pathobiological processes leading to lymphatic metastasis development there is an urgent need for relevant animal models.
Methods
HNSCC cell lines were implanted into the tongues of athymic, nude mice. Histology, immunohistochemistry and ex vivo two-photon microscopy were used to evaluate tumor progress and spread.
Results
Orthotopic xenografts of different HNSCC cell lines produced distinct patterns of survival, tumor histology, disease progression rate, and lymph node metastasis development. Remarkably, all injected cell types reached the lymph nodes within 24 hours after injection, but not all developed metastasis.
Conclusions
This orthotopic xenograft model closely mimics several characteristics of human cancer and could be extremely valuable for translational studies focusing on lymphatic metastasis development and pathobiology.
doi:10.1002/hed.23500
PMCID: PMC3969867  PMID: 24115017
Orthotopic xenograft mouse model; head and neck squamous cell carcinoma; lymph node metastasis; physiologic characterization; oral cancer
21.  HRAS Mutations and Resistance to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib in Head and Neck Squamous Cell Carcinoma Cells 
Head & neck  2014;36(11):1547-1554.
Background
This was to identify mechanisms of innate resistance to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. Specifically, we analyzed the role of HRAS mutations in erlotinib resistance.
Methods
Erlotinib sensitivity was determined by MTT assays. Molecular signaling pathways and somatic mutations were examined. Changes in sensitivity after modulation of HRAS expression were evaluated.
Results
All seven cell lines were wild-type for EGFR and KRAS regardless of erlotinib sensitivity; however, one erlotinib-resistant cell line (HN31) harbored an HRAS G12D mutation. Down regulation of HRAS expression by siRNA or shRNA in HN31 led to increased erlotinib sensitivity in vitro and in vivo. Transfection of activating HRAS-mutant (G12D and G12V) constructs into erlotinib-sensitive cell lines made them more resistant to erlotinib.
Conclusion
Activating HRAS mutations can confer erlotinib resistance in an HRAS mutant HNSCC cell line.
doi:10.1002/hed.23499
PMCID: PMC4010580  PMID: 24123531
Epidermal growth factor receptor; erlotinib; HRAS; resistance; head and neck squamous cell carcinoma
23.  Patterns of Nodal Metastasis and Prognosis in Human Papillomavirus Positive Oropharyngeal Squamous Cell Carcinoma 
Head & neck  2014;36(9):1233-1240.
Background
The current AJCC staging system may not accurately reflect survival in patients with HPV+OPSCC. The purpose of this study is to develop a system that more precisely predicts survival.
Methods
CT scans from 156 patients who underwent chemoradiation for advanced-stage OPSCC with >2years follow-up were reviewed. We modeled patterns of nodal metastasis associated with different survival rates. We defined HPV+N1 as a single node <6cm, ipsilaterally,contralaterally or bilaterally. HPV+N2 was defined as a single node ≥6cm or ≥2nodes ipsilaterally/contralaterally or ≥3nodes bilaterally. HPV+N3 was defined as matted nodes.
Results
There was no significant difference in DSS(p=0.14) or OS(p=0.16) by AJCC classification. In patients grouped by HPV+N1,HPV+N2,and HPV+N3 nodal classification, significant differences in DSS(100%,92%,55%,respectively,p=0.0001) and OS(100%,96%,55%,respectively,p=0.0001) were found.
Conclusions
A staging system with reclassification of size,bilaterality and matted nodes more accurately reflects survival differences in this cohort of patients. Review of the AJCC staging system with these criteria should be considered for HPV+OPSCC.
doi:10.1002/hed.23438
PMCID: PMC4112024  PMID: 23913653
Oropharyngeal Squamous Cell Carcinoma; Human Papillomavirus; American Joint Committee on Cancer Staging System; Matted Nodes; Nodal Metastasis
24.  Feasibility of Transoral Robotic-Assisted High Resolution Microendoscopic Imaging of Oropharyngeal Squamous Cell Carcinoma 
Head & neck  2015;37(8):E99-E102.
Background
Transoral robotic-assisted oncologic surgery of the head and neck offers promising functional results. Nonetheless, the efficacy of oncologic surgery remains critically dependent on obtaining negative margins. We aimed to integrate a miniaturized high resolution fiberoptic microendoscope (HRME), which provides real time histological assessment, with the da Vinci robotic system (Intuitive Surgical Inc., Sunnyvale, CA).
Methods
Three patients undergoing transoral robotic surgery were prospectively enrolled. Optical imaging of the oropharynx was performed intraoperatively with the robotic-assisted HRME.
Results
All patients underwent the procedure successfully with no complications. The HRME was successfully integrated with the Da Vinci Robotic system. Several sites of the oropharynx and associated malignancy were imaged, which correlated with the standard histopathological analysis.
Conclusions
Transoral robotic-assisted high resolution microendoscopic imaging of the oropharynx is a safe and technically feasible approach, providing a real time histological assessment and may serve as a valuable aid in oncologic surgery.
doi:10.1002/hed.23892
PMCID: PMC4478240  PMID: 25327825
Transoral robotic surgery; optical imaging; HRME; oropharynx; microendoscopy; squamous cell carcinoma
25.  Oropharyngeal squamous cell carcinoma (OPSCCA) in the veteran population is associated with traditional carcinogen exposure and poor clinical outcomes 
Head & neck  2015;37(9):1246-1253.
Background
A significant fraction of OPSCCA cases is associated with traditional carcinogens; in these patients treatment response and clinical outcomes remain poor.
Methods
We evaluated patient, tumor and treatment characteristics for 200 veterans with OPSCCA treated at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) between 2000 and 2012.
Results
Most patients (77%) were white and heavy smokers. Twenty seven patients required tracheostomy and 63 required gastrostomy placement during treatment. Overall survival at 5 years was 40%.. Survival was impacted by T stage, treatment intensity, completion of treatment and p16 tumor status. Almost 30% of patients were unable to complete a treatment regimen consistent with NCCN guidelines.
Conclusions
OPSCCA in veterans is associated with traditional carcinogens and poor clinical outcomes. Despite heavy smoking exposure, p16 tumor status significantly impacts survival. Careful consideration must be given to improving treatment paradigms for this cohort given their limited tolerance for treatment escalation.
doi:10.1002/hed.23740
PMCID: PMC4496314  PMID: 24801106
oropharyngeal cancer; smoking; veteran; tracheostomy; gastrostomy

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