[Show abstract][Hide abstract] ABSTRACT: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. Pathologic activation of PI3K/mTOR pathway and elevated expression of c-Myc are frequently detected in MCC. Yet, there is no targeted therapy presently available for this lethal disease. Recently, MLN0128, a second-generation dual TORC1/2 inhibitor is shown to have therapeutic efficacy in preclinical studies. MLN0128 is currently in clinical trials as a potential therapy for advanced cancers. Here we characterize the therapeutic efficacy of MLN0128 in the preclinical setting of MCC and delineate downstream targets of mTORC1/2 in MCC cellular systems. MLN0128 significantly attenuates xenograft MCC tumor growth independent of Merkel cell polyomavirus. Moreover, MLN0128 markedly diminishes MCC cell proliferation and induces apoptosis. Further investigations indicate that senescence does not contribute to MLN0128-mediated repression of xenograft MCC tumor growth. Finally, we also observe robust antitumor effects of MLN0128 when administered as a dual therapy with JQ1, a bromodomain protein BRD4 inhibitor. These results suggest dual blockade of PI3K/mTOR pathway and c-Myc axis is effective in the control of MCC tumor growth. Our results demonstrate that MLN0128 is potent as monotherapy or as a member of combination therapy with JQ1 for advanced MCC.
[Show abstract][Hide abstract] ABSTRACT: Pathologic c-Myc expression is frequently detected in human cancers, including Merkel cell carcinoma (MCC), an aggressive skin cancer with no cure for metastatic disease. Bromodomain protein 4 (BRD4) regulates gene transcription by binding to acetylated histone H3 lysine 27 (H3K27Ac) on the chromatin. Super-enhancers of transcription are identified by enrichment of H3K27Ac. BET inhibitor JQ1 disrupts BRD4 association with super-enhancers, downregulates proto-oncogenes, such as c-Myc, and displays antitumor activity in preclinical animal models of human cancers. Here we show that an enhancer proximal to the c-Myc promoter is enriched in H3K27Ac and associated with high occupancy of BRD4, and coincides with a putative c-Myc super-enhancer in MCC cells. This observation is mirrored in tumors from MCC patients. Importantly, depleted BRD4 occupancy at the putative c-Myc super-enhancer region by JQ1 correlates with decreased c-Myc expression. Thus, our study provides initial evidence that super-enhancers regulate c-Myc expression in MCC.
Epigenetics: official journal of the DNA Methylation Society 05/2015; 10(6):1-7. DOI:10.1080/15592294.2015.1034416 · 4.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: (1) Evaluate the outcomes of patients who underwent total rhinectomies. (2) Give physicians a better understanding of prior treatment modalities, postoperative survival outcomes, and rehabilitation options.
Otolaryngology Head and Neck Surgery 09/2014; 151(1 Suppl):P176-P176. DOI:10.1177/0194599814541629a121 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: Most patients treated with organ-preservation schemas for laryngeal cancer have no nodal disease at the time of recurrence. The oncologic benefit of an elective neck dissection (END) in a patient with clinically N0 neck at the time of salvage laryngectomy (SL) is still controversial. We sought to determine the oncologic outcomes for END and identify predictors for pN(+) status.
Otolaryngology Head and Neck Surgery 09/2014; 151(1 Suppl):P61-P61. DOI:10.1177/0194599814541627a102 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: (1) Defining functional swallowing outcomes as well as determining an expected length of time for patients to safely return to a normal oral diet in transoral robotic surgery (TORS) for resection of supraglottic laryngeal cancer.
Otolaryngology Head and Neck Surgery 09/2014; 151(1 Suppl):P166-P167. DOI:10.1177/0194599814541629a92 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare the removal rates of 8-hole angle strut plate and Champy line plate in repairing mandibular angle fractures.
Retrospective chart review at a tertiary care academic center of adults who were at least 18 years old with at least 1 mandibular angle fracture of a traumatic origin who underwent open reduction and internal fixation by using single monocortical miniplate fixation in Champy line or by using 8-hole angle strut plate via transbuccal approach. The outcome measures were hardware removal rates and the reason for removal of the hardware.
One hundred four patients with a total of 106 angle fractures met the inclusion criteria for this study. Seventy-three angle fractures were treated with the 8-hole strut, and 33 angle fractures were treated with the Champy line plates. There were 6 plates removed in both groups. This resulted in 8.2% of plates removed in the 8-hole strut plate group and 18.2% in the Champy line group (P = 0.133). Loose hardware was determined to be the cause of plate removal in 2 (2.7%) of the 8-hole strut plate group compared with all 6 (18.2%) of the Champy group (P = 0.005).
Overall, removal rates between Champy line and 8-hole strut plates are not different in treating mandibular angle fractures, although the 8-hole strut plate has a lower rate of loose hardware-related plate removal compared with the Champy line plate.
The Journal of craniofacial surgery 01/2013; 24(1):163-5. DOI:10.1097/SCS.0b013e31826468f5 · 0.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To report the technical feasibility of performing transoral robotic supracricoid partial laryngectomy with preservation of the thyroid cartilage. This is a case report from a tertiary-care academic institution. A patient with recurrent T2 glottic squamous cell carcinoma of the larynx underwent supracricoid partial laryngectomy with negative margins and preservation of the laryngeal framework using transoral robotic surgery, where an adequate exposure to the endolarynx was obtained by using a Feyh-Kastenbauer retractor. The patient was successfully decannulated in postoperative week 4, and his gastrostomy tube was removed in postoperative week 6. Transoral robotic surgery may be feasible in select glottic/subglottic laryngeal lesions, if adequate exposure is obtained.
Journal of Robotic Surgery 12/2012; 6(4). DOI:10.1007/s11701-012-0349-0
[Show abstract][Hide abstract] ABSTRACT: Objective
Concurrent chemoradiotherapy (CCRT) has become the treatment of choice for oropharyngeal and hypopharyngolaryngeal cancers in many centers. Although it has increased the rates of organ preservation, there has also been an increase in treatment-related complications. We aimed to evaluate the functional outcomes of CCRT in head and neck cancer.Study DesignCase series with chart review.SettingTertiary cancer center.Subjects and MethodsA retrospective study of patients treated with CCRT at the University of Arkansas for Medical Sciences was performed. Demographic data and treatment outcomes were extracted, specifically feeding tube and tracheotomy dependence and number of esophageal dilatations.ResultsOf the 243 patients treated with concurrent chemoradiotherapy (5-flourouracil + cysplatin and radiotherapy), 152 patients received a feeding tube. The median percutaneous gastrostomy tube (PEG) use was 9 months (range, 1-96 months). More than 70% of the patients who had a PEG more than 6 months had a T3 or T4 tumor. Thirty-seven patients underwent esophageal dilatations, (median, 1; range, 1-7). The median use of a tracheotomy was 7 months, and 77% of these patients were treated for hypopharyngolaryngeal cancer.Conclusions
Despite major improvement in locoregional control rates, CCRT has a significant negative impact on the functional outcomes of head and neck cancer patients, with a high number of patients remaining PEG and tracheotomy dependent.
Otolaryngology Head and Neck Surgery 09/2012; 145(2 Suppl). DOI:10.1177/0194599812459325 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Edward Ellis Ill, Robert M. Kellman, and Emre Vural address questions for discussion and debate: 1. Are there specific indications for open versus closed treatment of subcondylar fractures? Are there any contraindications to open treatment, and do they supercede the indications for open treatment? 2. Does the presence of other fractures (mandible and/or midface) affect your choice of open versus closed treatment? (Is the selection of closed vs open treatment the same for unilateral vs bilateral fractures?) 3. If one chooses to perform closed treatment, how long a period of MMF is required? 4. What are the most important factors for success when closed treatment is used? 5. What is the best surgical approach to ORIF of subcondylar fractures? 6. Analysis: Over the past 5 years, how has your technique or approach evolved or what is the most important thing you have learned/observed in working with subcondylar fractures?
Facial plastic surgery clinics of North America 08/2012; 20(3):365-82. DOI:10.1016/j.fsc.2012.05.002 · 0.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the factors contributing to failure of interpolation flaps in nasal reconstruction.
Retrospective medical chart review.
Tertiary care academic center.
A total of 107 patients with nasal defects needing reconstruction, performed at the University of Arkansas for Medical Sciences, Little Rock.
Patients underwent nasal reconstruction with 2-stage paramedian forehead or nasolabial flaps (PMFF and NLF, respectively) from 2002 to 2011. Defect thickness, location, flap type, use of cartilage grafts, and comorbidities, including diabetes mellitus, peripheral vascular or coronary artery disease, and smoking habits, were recorded.
Full success, partial failure, or full failure of the respective flap.
Eighty-two of the patients (77%) underwent 2-stage PMFF repair and 25 (23%) underwent 2-stage NLF repair. Fifty-eight defects (54%) were full thickness, in which 46 repairs used PMFF and 12 used NLF for reconstruction. The overall failure rate was 6%. Five PMFF failed (6%); 3 of these were used for full-thickness repairs. There was only 1 NLF failure (4%), which was also performed for the repair of a full-thickness defect. Use of cartilage in the reconstruction did not affect failure rates of the different soft tissue flaps. No single comorbidity was noted to have a statistically significant effect on failure rates, although 83% of failures were observed in smokers.
The overall success rate of interpolation flaps in nasal reconstruction was 94.4%. Defect thickness, use of a cartilage graft, type of flap used, and presence of comorbidities did not affect outcome. Although the comparison was not statistically significant (P = .21), flap failures were more commonly observed in smokers.
Archives of otolaryngology--head & neck surgery 03/2012; 138(4):367-71. DOI:10.1001/archoto.2012.69 · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the safety and efficacy of photodynamic therapy in the treatment of oral leukoplakia with 5-aminolevulinic acid and pulsed dye laser.
Nonrandomized, single-arm, single-site phase 1/2 pilot study.
Academic referral center.
A total of 23 patients, aged 37 to 79 years, having a confirmed diagnosis of leukoplakia with or without dysplasia measuring at least 10 mm in diameter.
Application of 5-aminolevulinic acid to lesions followed by activation with high-power 585-nm pulsed dye laser.
Maximum tolerated dose of laser, postprocedure complications, objective response to treatment, and immunohistochemical changes in treated tissue.
No significant adverse events occurred; minor local adverse effects were observed during and following photodynamic therapy in the safety phase of the study. The maximum tolerated dose was 8 J/cm(2). Of 17 patients, 7 (41%) had more than 75% regression (significant response) and 9 (53%) had more than 25% regression (partial response), for an overall response rate of 94% at 90 days. This response rate was far higher than the null-hypothesis 20% rate (P < 10(-10)) and the alternative-hypothesis 50% rate (P = .0001) for which the study was powered. When compared with baseline levels immunohistochemically, p53 expression was increased in 8 of 11 available samples (73%) and Ki-67 expression was decreased in 7 of 12 available samples (58%).
Photodynamic therapy with 5-aminolevulinic acid and pulsed dye laser could be used to achieve regression of oral leukoplakia. The treatment is safe and well tolerated. An application time of 1.5 hours and laser radiant exposure of 8 J/cm(2) with 1.5-ms pulse time were found to be the optimal settings in this study. The high-power laser used in this study allows completion of laser therapy within 1 to 3 minutes. Further studies are necessary to determine the optimal laser radiant exposure and drug application to maximize the response rate.
Archives of otolaryngology--head & neck surgery 11/2011; 137(11):1117-23. DOI:10.1001/archoto.2011.178 · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: 1) Compare the rate of removal of Champy’s plates vs 8-hole strut plates used for repair of mandible angle fracture. 2) Determine the reason for removal of these plates.
Otolaryngology Head and Neck Surgery 09/2011; 145(2 Suppl):P53-P53. DOI:10.1177/0194599811416318a41 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: Determine whether the type (paramedian forehead [PMFF] vs nasolabial [NLF]) or the defect thickness (full vs partial) play a role in take rates of interpolation flaps in nasal reconstruction.
Otolaryngology Head and Neck Surgery 09/2011; 145(2 Suppl):P48-P48. DOI:10.1177/0194599811416318a24 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: Provide prognostic data for the physicians and patients when a decision is made for primary or salvage ablative surgery of the upper aerodigestive tract with the aide of microvascular reconstruction.
Otolaryngology Head and Neck Surgery 09/2011; 145(2 Suppl):P159-P160. DOI:10.1177/0194599811415823a84 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: There is continued debate as to whether to perform a neck dissection as a planned vs “wait and see” procedure in patients with head and neck cancer treated with chemoradiotherapy. In this study we aimed to review our results to help with the decision making process.
Otolaryngology Head and Neck Surgery 09/2011; 145(2 Suppl):P63-P63. DOI:10.1177/0194599811416318a72 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to investigate the potential role of variable microRNA (miRNA) expression in the development of multidrug resistance (MDR) in head and neck cancer.
Head and neck squamous cell carcinoma cell lines UMSCC-1 and SQ20B were treated with docetaxel at increasing concentrations to develop resistant cell lines. Parental and resistant cells were treated with cisplatin, 5-fluorouracil, paclitaxel, methotrexate, and doxorubicin to confirm cross-resistance. The miRNA pattern of resistant cells was then compared with their parental cells.
Docetaxel treatment successfully induced resistance primarily and induced multidrug cross-resistance. Resistant cells showed significant downregulation of miR-100, miR-130a, and miR-197 and upregulation in miR-101, miR-181b, miR-181d, and miR-195 expression when compared with their parent cells (p < .01). Real-time polymerase chain reaction (PCR) analysis confirmed statistically significant downregulation in miR-100 and miR-130a and upregulation in miR-181d expression (p < .001).
Alterations in miRNA expression has direct relationship to MDR in head and neck cancer and may serve as biomolecular targets for reversal of MDR.
Head & Neck 06/2011; 33(6):786-91. DOI:10.1002/hed.21540 · 2.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To identify unique epigenetic signature in cancer stem cells (CSCs) in head and neck squamous cell carcinoma (HNSCC).
Molecular and microarray studies.
Tertiary referral center.
Head and neck CSCs were isolated in HNSCC cells by CD44 staining and flow cytometry sorting. CSCs with highest CD44 expression (CD44(hi)) and non-stem cells (non-SCs) with lowest CD44 expression (CD44(low)) were then characterized for stemness gene expression and their responses to chemotherapeutic agents, followed by high-throughput epigenetic profiling using the Illumina BeadChip Array, targeting 28,544 CpG sites covering more than 14,956 genes.
CD44(hi) CSCs expressed higher levels of stem cell markers and were more resistant to chemotherapeutic agents as compared to CD44(low) non-SCs. By DNA methylation microarray analysis, 17 hypomethylated and 9 hypermethylated genes were identified in CD44(hi) CSCs as compared to non-SCs in most HNSCC cell lines. Cluster analysis using these 26 genes showed that CD44(hi) CSCs were epigenetically distinct from the CD44(low) non-SCs in all 5 HNSCC cell lines.
A unique epigenetic profile consisting of 17 hypomethylated and 9 hypermethylated genes was seen in HNSCC CSCs. These genes may be critically required in maintaining the stemness or pluripotency of CSCs and may represent novel molecular targets for anticancer therapies aimed at eradicating CSCs in HNSCC.
Otolaryngology Head and Neck Surgery 06/2011; 144(6):900-9. DOI:10.1177/0194599811398786 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To present the authors' experience and outcomes in the reconstruction of midfacial defects using cervicofacial advancement-rotation flaps (CARFs) based on a method of determining forward or reverse design in relation to the proportions of the defect.
Case series with retrospective chart review.
Tertiary care academic medical center.
Patients who underwent CARF reconstruction and the subset of patients with midfacial defects medial to the lateral canthus were included. CARF was designed in a forward fashion with an anteromedial movement for the defects with a larger vertical dimension and in a reverse fashion with a posterosuperior movement for the defects with a larger horizontal dimension.
Thirteen of 45 patients who underwent CARF reconstruction qualified for the analysis as a subset based on defect location. CARF was used in a forward fashion in 7 patients and in a reverse fashion in 6 patients. The largest defect in this subset was measured as 9 × 6 cm, while the smallest defect was 3 × 2 cm. Average follow-up was 11.5 months. None of the patients developed partial or total flap loss. Six patients had mild ectropion, which was managed with conservative measures only. The outcome of the reconstruction was satisfactory in all cases.
Designing the CARF based on the proportion of the vertical and horizontal diameters of the selected midfacial defects as described allows for closure of the defects with minimal tension and minimizes the amount of discarded healthy skin overlapping at the suture lines.
Otolaryngology Head and Neck Surgery 02/2011; 144(2):196-200. DOI:10.1177/0194599810391391 · 2.02 Impact Factor