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Background: Despite its increasingly widespread adoption of transoral robotic surgery (TORS), there is still no uniform training curriculum. The purpose of this study was to describe the results of our novel TORS curriculum training program in which we introduce ex vivo dissection models for radical tonsillectomy and base of tongue (BOT) resections. Methods: Prospective blinded data collection and objective assessment of a novel training curriculum. Trainee performance was evaluated on objective structured assessments of technical skills (OSATS) metrics, measured resection time, and margin analysis. Additionally, 4 expert TORS surgeons completed the ex vivo dissections. Results: Trainees achieved OSATS scores similar to those of experts in both the BOT resection and radical tonsillectomy models. Peripheral and deep surgical margin measurements in the BOT model were significantly improved after training and were comparable to experts. Conclusion: This graduated curriculum provides a realistic training experience to develop competency with oropharyngeal resections before transition to the operating room. © 2016 Wiley Periodicals, Inc.


Fakhry C.,Milton nce Jr Head And Neck Center | Andersen K.K.,Danish Cancer Society | Christensen J.,Danish Cancer Society
Cancer Prevention Research | Year: 2015

The incidence of oropharyngeal carcinoma, involving palatine and lingual tonsils, is increasing globally. This significant rise is driven by human papillomavirus. Whether palatine tonsillectomy affects risk of diagnosis with oropharyngeal carcinoma is unknown. The association between tonsillectomy and incidence of oropharyngeal carcinoma was explored in the Danish Cancer Registry. The association between tonsillectomy and oropharyngeal carcinoma was analyzed by time since first registration of tonsillectomy. Tonsillectomy was a time-dependent variable. Individuals were censored for death, emigration, or tonsillectomy within incident year of diagnosis. Incidence rate ratios (RR) were estimated by Poisson regression models and adjusted for confounders. Kaplan-Meier survival analyses were compared by the log-rank test, and HRs were estimated by Cox proportional hazards models. From 1977 to 2012, the incidence of tonsillectomies significantly decreased, whereas the incidence of oropharyngeal carcinoma significantly increased. Tonsillectomy was not associated with risk of oropharyngeal carcinoma or malignancies of other anatomic sites, including base of tongue. However, tonsillectomy significantly reduced risk of diagnosis with tonsil carcinoma [RR, 0.40; 95% confidence interval (CI), 0.22-0.70]. The risk of diagnosis with tonsil carcinoma at age <60 years was significantly decreased (RRadj, 0.15; 95% CI, 0.06-0.41) after tonsillectomy. Tonsillectomy within 1 year of diagnosis with tonsil carcinoma was associated with significantly improved overall survival (HR, 0.53; 95% CI, 0.38-0.74). In conclusion, remote history of tonsillectomy reduces the risk of diagnosis with tonsil carcinoma. These data inform risk and benefit of tonsillectomy, a common procedure and design of secondary prevention trials. ©2015 AACR.


Rettig E.M.,University of Baltimore | Chung C.H.,University of Baltimore | Chung C.H.,Sidney KimmelComprehensive Cancer Center | Chung C.H.,Johns Hopkins University | And 16 more authors.
Cancer Prevention Research | Year: 2015

The Notch pathway is frequently altered in head and neck squamous cell carcinomas (HNSCC); however, the clinical significance of NOTCH1 dysregulation is poorly understood. This study was designed to characterize expression of the transcriptionally active NOTCH1 intracellular domain (NICD1) in HNSCCs and evaluate its association with NOTCH1 mutation status and clinical parameters. IHC for NICD1 was performed on 79 previously sequenced archival HNSCCs with known NOTCH1 mutation status. Three distinct immunohistochemical staining patterns were identified: positive/peripheral (47%), positive/nonperipheral (34%), and negative (19%). NICD1 expression was associated with NOTCH1 mutation status (P < 0.001). Most NOTCH1-wild-type tumors were peripheral (55%), whereas mutated NOTCH1 tumors were most commonly negative (47%). Nonperipheral tumors were more likely than peripheral tumors to have extracapsular spread [adjusted odds ratio (aOR), 16.01; 95% confidence interval (CI), 1.92-133.46; P = 0.010] and poor differentiation (aOR, 5.27; 95% CI, 0.90-30.86; P = 0.066). Negative staining tumors tended to be poorly differentiated (aOR, 24.71; 95% CI, 1.53-399.33; P = 0.024) and were less likely to be human papillomavirus (HPV) positive (aOR, 0.043; 95% CI, 0.001-1.59; P = 0.087). NOTCH1 mutagenesis was significantly associated with HPV status, with NOTCH1-wild-type tumors more likely to be HPV positive than NOTCH1-mutated tumors (aOR, 19.06; 95% CI, 1.31-276.15; P = 0.031). TP53 disruptivemutations were not associated with NICD1 expression or NOTCH1 mutation. In conclusion, NICD1 is expressed in three distinct patterns in HNSCC that are significantly associated with high-risk features. These findings further support a dual role for NOTCH1 as both tumor suppressor and oncogene in HNSCC. Further research is necessary to clarify the role of NOTCH1 in HNSCC and understand the clinical and therapeutic implications therein. ©2015 AACR.


Peng S.,Johns Hopkins Medical Institutions | Lyford-Pike S.,Johns Hopkins Medical Institutions | Akpeng B.,Johns Hopkins Medical Institutions | Wu A.,Johns Hopkins Medical Institutions | And 4 more authors.
Cancer Immunology, Immunotherapy | Year: 2013

Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8+ T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8+ T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8+ T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic antitumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8+ T cells, which led to higher ratios of CD8+/Treg and CD8+/CD11b +Gr-1+ myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8+ T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells. © 2012 Springer-Verlag.


Liu J.,University of Pittsburgh | Ferris R.L.,University of Pittsburgh | Ha P.K.,Milton nce Jr Head And Neck Center
Head and Neck | Year: 2012

Background. Adenoid cystic carcinoma (ACC) is an unusual salivary gland malignancy that remains poorly understood. Standard treatment, including surgery with postoperative radiation therapy, has attained reasonable local control rates, but the propensity for distant metastases has limited any improvement in survival over time. Our understanding of the molecular mechanisms driving ACC is quite rudimentary, due to the infrequent nature of its occurrence. Methods. An extensive literature review was performed on salivary gland ACCs and basic science research findings. Results. This review highlights many findings that are emerging about the carcinogenesis of ACC including cytogenetics, tumor suppressor genes, oncogenes, epigenetic alterations, mitochondrial alterations, and biomarker studies. Conclusion. Although there have been many discoveries, much still remains unknown about this rare malignancy. © 2011 Wiley Periodicals, Inc.


Yonescu R.,Johns Hopkins University | Bishop J.A.,Johns Hopkins University | Fakhry C.,Milton nce Jr Head And Neck Center | Ha P.K.,Milton nce Jr Head And Neck Center
Laryngoscope | Year: 2015

Objectives Salivary gland adenoid cystic carcinoma (ACC) is rare, aggressive, and challenging to treat. Many ACCs have a t(6;9) chromosomal translocation resulting in a MYB-NFIB fusion gene, but the clinical significance is unclear. The purposes of this study were to describe the clinicopathologic factors impacting survival and to determine the prevalence and clinical significance of MYB-NFIB fusion. Study Design Case series. Methods Medical records of patients treated for ACC of the head and neck from 1974 to 2011 were reviewed and clinicopathologic data recorded. Fluorescence in situ hybridization (FISH) was used to detect MYB rearrangement in archival tumor tissue as a marker of MYB-NFIB fusion. Results One hundred fifty-eight patients were included, with median follow-up 75.1 months. Median overall survival was 171.5 months (95% confidence interval [CI]=131.9-191.6), and median disease-free survival was 112.0 months (95% CI=88.7-180.4). Advanced stage was associated with decreased overall survival (adjusted ptrend<0.001), and positive margins were associated with decreased disease-free survival (adjusted hazard ratio [aHR]=8.80, 95% CI=1.25-62.12, P = 0.029). Ninety-one tumors were evaluable using FISH, and 59 (65%) had evidence of a MYB-NFIB fusion. MYB-NFIB positive tumors were more likely than MYB-NFIB negative tumors to originate in minor salivary glands (adjusted prevalence ratios=1.51, 95% CI=1.07-2.12, P = 0.019). MYB-NFIB tumor status was not significantly associated with disease-free or overall survival (hazard ratio [HR]=1.53, 95% CI=0.77-3.02, P = 0.22 and HR=0.91, 95% CI=0.46-1.83, P = 0.80, respectively, for MYB-NFIB positive compared with MYB-NFIB negative tumors). Conclusion Stage and margin status were important prognostic factors for ACC. Tumors with evidence of MYB-NFIB fusion were more likely to originate in minor salivary glands, but MYB-NFIB tumor status was not significantly associated with prognosis. Level of Evidence 4. Laryngoscope, 125:E292-E299, 2015 © 2015 The American Laryngological, Rhinological and Otological Society, Inc.


Shikani A.H.,Union Memorial Hospital | Shikani A.H.,Johns Hopkins Hospital | Dietrich-Burns K.,Milton nce Jr Head And Neck Center
International Forum of Allergy and Rhinology | Year: 2012

Background: The objective of this work was to obtain a controlled subjective and objective in vivo clinical comparison of the Passy-Muir, Shiley, and Ball speaking valves. Methods: Ten patients free of laryngeal pathology but dependent on tracheotomy for respiration were tested with each of the speaking valves. Olfaction was assessed for each patient using the University of Pennsylvania Smell Identification Test (UPSIT). Acoustic and perceptual analyses included subjective assessments, noninstrumental objective assessments (including maximum phonation time, and S:Z ratio), and instrumental objective assessments (including fundamental frequency:maximum phonation range, vocal intensity, perturbation, naturalness, and turbulence). Oxygen saturation was assessed by pulse oximetry. Results: There was a highly significant statistical difference in olfaction and speech naturalness, in favor of the Ball valve (The Airway Company, Forest Hill, MD). The Ball valve's speech parameters were generally better than with the Passy-Muir and Shiley valves, including maximum phonation, S:Z ratio, jitter, noise, and turbulence, although the differences were not statistically significant. There were no differences among the valves in oxygen saturation levels. Conclusion: This study illustrates that olfaction and certain speech parameters, most noticeably speech naturalness, are significantly improved with the Ball valve as compared to the Passy-Muir and Shiley valves. © 2012 ARS-AAOA, LLC. Copyright © 2012 American Rhinologic Society-American Academy of Otolaryngic Allergy, LLC.


Sen T.,Johns Hopkins University | Sen N.,Johns Hopkins University | Noordhuis M.G.,Johns Hopkins University | Ravi R.,Johns Hopkins University | And 5 more authors.
PLoS ONE | Year: 2012

Oxoglutarate dehydrogenase (OGDH) is the first and rate-limiting component of the multi-enzyme OGDH complex (OGDHC) whose malfunction is associated with neuro-degeneration. The essential role of this complex is in the degradation of glucose and glutamate and the OGDHL gene (one component of OGDHC) is down-regulated by promoter hypermethylation in many different cancer types. These properties suggest a potential growth modulating role of OGDHL in cancer; however, the molecular mechanism through which OGDHL exerts its growth modulating function has not been elucidated. Here, we report that restoration of OGDHL expression in cervical cancer cells lacking endogenous OGDHL expression suppressed cell proliferation, invasion and soft agar colony formation in vitro. Knockdown of OGDHL expression in cervical cancer cells expressing endogenous OGDHL had the opposite effect. Forced expression of OGDHL increased the production of reactive oxygen species (ROS) leading to apoptosis through caspase 3 mediated down-regulation of the AKT signaling cascade and decreased NF-κB phosphorylation. Conversely, silencing OGDHL stimulated the signaling pathway via increased AKT phosphorylation. Moreover, the addition of caspase 3 or ROS inhibitors in the presence of OGDHL increased AKT signaling and cervical cancer cell proliferation. Taken together, these data suggest that inactivation of OGDHL can contribute to cervical tumorigenesis via activation of the AKT signaling pathway and thus support it as an important anti-proliferative gene in cervical cancer. © 2012 Sen et al.


PubMed | Johns Hopkins Hospital, Milton nce Jr Head And Neck Center and Johns Hopkins University
Type: Journal Article | Journal: Head & neck | Year: 2016

Despite its increasingly widespread adoption of transoral robotic surgery (TORS), there is still no uniform training curriculum. The purpose of this study was to describe the results of our novel TORS curriculum training program in which we introduce ex vivo dissection models for radical tonsillectomy and base of tongue (BOT) resections.Prospective blinded data collection and objective assessment of a novel training curriculum. Trainee performance was evaluated on objective structured assessments of technical skills (OSATS) metrics, measured resection time, and margin analysis. Additionally, 4 expert TORS surgeons completed the ex vivo dissections.Trainees achieved OSATS scores similar to those of experts in both the BOT resection and radical tonsillectomy models. Peripheral and deep surgical margin measurements in the BOT model were significantly improved after training and were comparable to experts.This graduated curriculum provides a realistic training experience to develop competency with oropharyngeal resections before transition to the operating room. 2016 Wiley Periodicals, Inc. Head Neck 38: First-1563, 2016.


Guo T.,Johns Hopkins Medical Institutions | Rettig E.,Johns Hopkins Medical Institutions | Fakhry C.,Johns Hopkins Medical Institutions | Fakhry C.,Milton nce Jr Head And Neck Center
Oral Oncology | Year: 2016

Objectives: Human papillomavirus (HPV)-positive tumor status is associated with improved prognosis after disease recurrence in oropharyngeal squamous cell carcinoma (OPSCC). In this study the potential role of survival bias in the relationship between HPV tumor status and the timing of recurrence was evaluated, given conflicting evidence in the literature. Materials & methods: A secondary analysis was performed on a previously published retrospective two institution study of recurrent OPSCC with known HPV tumor status. Patients were categorized as "early" (surviving "24 months) or "late" survivors (P24 months). Timing of first recurrence and overall survival were analyzed using Kaplan-Meier and cox proportional hazard methods. Two-sided p-values >0.05 were considered significant. Results: In total 101 patients met criteria including 81 late and 20 early survivors. HPV-positive tumor status was associated with longer time to recurrence in late survivors (median 21.8 vs. 13.8 months, p = 0.028). Late survivors had later recurrences in HPV-positive (p > 0.001) and HPV-negative patients (p = 0.0096), as well as in both locoregional (p > 0.0001) and distant metastatic recurrence (p > 0.0001). In multivariate analysis, both HPV-positive tumor status (adjusted HR [aHR] 0.48, p = 0.006) and survival beyond 24 months (aHR 0.21, p " 0.001) were associated with later recurrence. When stratified, HPV tumor status was only associated with later recurrence in late survivors (aHR 0.47, p = 0.015). Conclusions: Late survivorship was associated with late recurrence for both HPV-positive and HPVnegative patients. Stratification by survival illustrates how survival bias links late survivorship with late recurrences and contributes to our understanding of the impact of HPV tumor status on the timing of recurrence. © 2015 Elsevier Ltd. All rights reserved.

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