Survivin in Insulin-Like Growth Factor-Induced Resistance to Lapatinib in Head and Neck Squamous Carcinoma Cells.

Epidermal growth factor receptor (EGFR) inhibitors have limited efficacy in head and neck squamous cell carcinoma (HNSCC) due to various resistance mechanisms, such as activation of the insulin-like growth factor-1 receptor (IGF1R), which initiates pro-survival signaling. Survivin, a member of the inhibitor of apoptosis proteins family, is expressed at relatively high levels in malignant tissues and plays a role in cell division. Expression of survivin in tumors has been shown to correlate with poor prognosis due to chemotherapy resistance and anti-apoptotic behavior. We previously demonstrated that activation of the IGF1R reduces sensitivity to EGFR-tyrosine kinase inhibitors (TKIs) via reduced apoptosis suggesting a role of survivin in this process. This study evaluates the role of survivin in IGF1R-mediated lapatinib resistance. Using HNSCC cell lines FaDu and SCC25, survivin expression increased and lapatinib sensitivity decreased with IGF1R activation. Further, these effects were reversed by the survivin inhibitor YM-155. Conversely, survivin expression and lapatinib sensitivity were unchanged with IGF1R activation in UNC10 cells. YM-155 enhanced the inhibitory effect of lapatinib on UNC10 cells, regardless of activation of the IGF1R. These results demonstrate that enhanced survivin expression correlates with IGF1R-mediated lapatinib resistance in HNSCC cells and suggest that regulation of survivin expression may be a key mechanistic element in IGF1R-based therapeutic resistance. Combinatorial treatment with survivin antagonists and EGFR-TKIs warrants further investigation.

The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors.

The cullin RING E3 ubiquitin ligase 4 (CRL4) with its substrate receptor CDT2 (CRL4-CDT2) is emerging as a critical regulator of DNA replication through targeting CDT1, SET8, and p21 for ubiquitin-dependent proteolysis. The aberrant increased stability of these proteins in cells with inactivated CRL4-CDT2 results in DNA rereplication, which is deleterious to cells due to the accumulation of replication intermediates and stalled replication forks. Here, we demonstrate that CDT2 is overexpressed in head and neck squamous cell carcinoma (HNSCC), and its depletion by siRNA inhibits the proliferation of human papilloma virus-negative (HPV-ve) HNSCC cells primarily through the induction of rereplication. Treatment of HNSCC with the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924), which inhibits all cullin-based ligases, induces significant rereplication and inhibits HNSCC cell proliferation in culture and HNSCC xenografts in mice. Pevonedistat additionally sensitizes HNSCC cells to ionizing radiation (IR) and enhances IR-induced suppression of xenografts in mice. Induction of rereplication via CDT2 depletion, or via the stabilization or activation of CDT1, also radiosensitizes HNSCC cells. Collectively, these results demonstrate that induction of rereplication represents a novel approach to treating radioresistant HNSCC tumors and suggest that pevonedistat may be considered as an adjuvant for IR-based treatments. Mol Cancer Ther; 17(2); 368-80. ©2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology."

Future Applications of Deoxycholic Acid in Body Contouring.

Deoxycholic acid (KybellaTM, Allergan Pharmaceuticals, Irvine, CA) is a novel injectable treatment used for the cosmetic reduction of redundant submental fat. By inducing adipose cell lysis, the soft tissue alteration induces subsequent contour change and sharpening of the cervicomental angle.The safety and efficacy have been well established in several prospective clinical trials and subsequent FDA approval for this purpose. This has provided an effective and less invasive alternative to surgical liposuction with virtually no recovery time and less overall discomfort. Given its success for use in this context, a logical step would be to extrapolate to other regions of the body where cosmetic deformity is caused by excessive adipose tissue. In the current article, the authors propose potential options for further use in various targeted areas where subcutaneous fat may be amenable to reduction with deoxycholic acid injection, understanding that such uses would be off-label and require an understanding of the regional anatomy and possible complications. J Drugs Dermatol. 2017;16(1):43-46.

Development and evaluation of a rigid esophagoscopy simulator for residency training.

OBJECTIVES/HYPOTHESIS: Rigid esophagoscopy is performed less frequently by resident trainees. Nonetheless, it remains important for certain indications, including foreign body extraction. This study describes the construction of a simulator and evaluates its utility in training residents. STUDY DESIGN: Simulator development, fabrication, and procedural evaluation of postgraduate trainees. METHODS: A simulator was developed and constructed in collaboration with a biomedical engineering team. Residents with varied experience in upper aerodigestive procedures performed rigid esophagoscopy on the model. Key steps and Accreditation Council for Graduate Medical Education's Objective Structured Assessment of Technical Skills (OSATS) criteria for rigid esophagoscopy were evaluated by a faculty surgeon. Pressure measurements were obtained from force sensors at the tip of the endoscope and incisors. RESULTS: Fourteen trainees were evaluated. Operative rigid esophagoscopy and direct laryngoscopy case numbers were noted for each subject. OSATS scores and key steps of the procedure correlated with resident experience (R(2) = 0.75, P < .0001 and R(2) = 0.66, P < .001, respectively). Maximal pressure exerted on the simulator esophagus by the esophagoscope was inversely correlated with case number and was statistically significant (R(2) = 0.51, P = .02), whereas length of procedure did not correlate (R(2) = 0.04, P = .49). Maximal pressure on the incisors did not correlate (R(2) = 0.25, P = .15). CONCLUSIONS: A simulator for training residents to perform rigid esophagoscopy was developed and utilized by a faculty proctor to objectively evaluate trainees. OSATS scores, performance of key procedural steps, and pressure exerted on the simulator tissue correlated with upper aerodigestive cases performed, demonstrating validity of the simulator. LEVEL OF EVIDENCE: NA Laryngoscope, 126:616-619, 2016.

Surgical Treatment of the Middle Nasal Vault.

The middle nasal vault is a sensitive region of the nose from both an esthetic and a functional perspective. It is critical for the rhinoplasty surgeon to properly evaluate and identify abnormalities of the middle vault when considering patients for primary or secondary surgery. This article addresses the surgical management of the cosmetic deformities and functional deficits of the middle vault and provides guidance for avoiding complications in this structurally critical region of the nose.

Update in disease-specific quality-of-life studies in facial plastic surgery.

PURPOSE OF REVIEW: Improvements in the quality of life (QOL) of patients undergoing facial plastic and reconstructive surgery are readily apparent to any practitioner performing these procedures and interacting with these patients. However, proving these benefits objectively has become ever more important in the current practice environment and there has been a body of literature reported to address this need. RECENT FINDINGS: As techniques for facial reanimation, revision cleft surgery and other procedures are further developed and the tailored treatments of these ailments are honed, the body of literature for QOL improvements is growing. A better understanding of the nature of these disorders and the elements that are more impactful to patients has led to procedures that more specifically address these objectives and improve functional and psychological outcomes. SUMMARY: Interest in QOL data to support the interventions performed by facial plastic and reconstructive surgeons has and will continue to expand. The addition of QOL surveys to everyday practice, reporting of objective data in the literature and most importantly the focus of the practitioner on improving the patient's overall health and welfare are testaments to the tailoring of practice to not only address the functional and cosmetic goals but also the overall wellbeing.

Nanoimmunoassay to Detect Responses in Head and Neck Cancer: Feasibility in a Mouse Model.

OBJECTIVE: To demonstrate the feasibility of detecting and quantifying extracellular signal-related kinase (ERK) phosphorylation status using nanoimmunoassay (NIA). STUDY DESIGN: Analyses using Cal27, SCC25, and OSC19 head and neck squamous carcinoma cell lines in vitro and in a murine xenograft model. SUBJECTS AND METHODS: NIA and immunoblot were performed on whole-cell lysates, tumor lysates, and fine-needle aspirate biopsies to detect ERK phosphorylation states. RESULTS: Using NIA, all 6 isoforms of ERK1/2, including nonphosphorylated, monophosphorylated, and diphosphorylated species, could be reliably detected, distinguished, and quantified in a single assay using a single antibody. In vitro treatment of Cal27 cells with the epidermal growth factor receptor inhibitor gefitinib abolished phospho-ERK detection by immunoblot but resulted in residual detectable species by NIA. Residual phospho-ERK in gefitinib-treated cells could be further reduced by the addition of the insulin-like growth factor 1 receptor inhibitor OSI-906; this correlated with an additional decrease in proliferation over gefitinib alone. In a pilot study of 4 murine xenograft tumors, NIA performed on tumor lysates and fine-needle aspirate biopsies demonstrated altered ERK profiles after 2 days of gefitinib treatment compared with untreated mice. CONCLUSION: NIA offers a novel approach to quantitating the activation state of signaling molecules such as ERK in nanoscale in vitro and in vivo samples across a wide dynamic range. As such, it has potential to provide molecular diagnostic information before, during, and after treatment using a minimally invasive technique. Further study is warranted to determine its utility in assessing signaling proteins as biomolecular outcome predictors in clinical trials.

Cyclin D1 and FADD as biomarkers in head and neck squamous cell carcinoma.

OBJECTIVE: Cyclin D1 and FADD (Fas-associated protein with death domain) regulate the cell cycle and apoptosis, respectively, and are located on chromosome 11q13, which is frequently amplified in head and neck squamous cell carcinoma (HNSCC). This study evaluates these proteins as predictors of clinical outcomes for HNSCC. STUDY DESIGN: Historical cohort study. SETTING: Academic tertiary care center. SUBJECTS: Two hundred twenty-two patients with upper aerodigestive HNSCC. RESULTS: Patients with tumors that were strongly positive for cyclin D1 and FADD had reduced overall (OS; P = .003 and P < .001), disease-specific (DSS; P = .039 and P < .001), and disease-free (DFS; P = .026 and P < .001) survival, respectively. Together, the 2 markers effectively stratified OS (P < .001), DSS (P < .001), and DFS (P = .002). Strong FADD staining correlated with greater alcohol consumption and varied significantly with primary tumor site: 56% of hypopharynx tumors expressed high levels of FADD but only 7% of glottis tumors. Using Cox regression analysis, FADD and N stage were significant independent predictors of DSS and DFS, whereas cyclin D1, FADD, and N stage were independently significant for OS. CONCLUSION: Cyclin D1 and FADD may have utility as predictors of long-term outcomes for patients with HNSCC. Further study is needed to determine if these proteins predict response to different treatment approaches or assist in selecting patients for multimodality therapy.

Activation of the insulin-like growth factor-1 receptor induces resistance to epidermal growth factor receptor antagonism in head and neck squamous carcinoma cells.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have poor efficacy in head and neck squamous carcinoma cells (HNSCC). Because the IGF-1 receptor (IGF1R) generates potent prosurvival signals and has been implicated in therapeutic resistance, its ability to induce resistance to EGFR-TKIs was studied in vitro. Five HNSCC cell lines showed reduced sensitivity to the EGFR-TKI gefitinib when the IGF1R was activated. In SCC-25 and Cal27 cells, gefitinib inhibited basal and EGF-stimulated EGFR, extracellular signal-regulated kinase (Erk), and Akt phosphorylation and reduced cell number. This correlated with initiation of apoptosis based on a 4-fold increase in PARP cleavage and a 2.5-fold increase in Annexin V positivity. The apoptotic response and reduction in cell number were blocked by IGF1R activation, which resulted in phosphorylation of both Erk and Akt. In both the cell lines, IGF1R-induced Erk, but not Akt, activation was eliminated by gefitinib. IGF1R-induced gefitinib resistance was unaffected by MAP/Erk kinase inhibition with U0126 but was partially impaired by inhibition of phosphoinositide-3-kinase with LY294002. The IGF1R-TKI PQ401 inhibited growth of SCC-25 and Cal27 cells alone and also acted synergistically with gefitinib. Thus, the IGF1R can make HNSCC cells resistant to EGFR-TKI treatment via a prosurvival mechanism. Of the 8 HNSCC tumor samples studied, all samples expressed the IGF1R and 5 showed detectable IGF1R phosphorylation, suggesting that this receptor may be relevant in vivo, and thus, combined EGFR/IGF1R inhibition may be necessary in some patients for effective targeted molecular therapy.

Timing for repair of mandible fractures.

OBJECTIVES/HYPOTHESIS: Timing for repair of mandible fractures is a significant factor with regard to the rate of complication. STUDY DESIGN: Retrospective chart review of the previous 5 years (January 2005-January 2010). METHODS: All patients undergoing mandible fracture fixation performed in the study period and having complete records were analyzed (n = 83). Patients were stratified by time to fixation following initial injury. Subjects were then separated by the presence or absence of any of the following complications: infection, malunion, and nonunion. Logistical regression was then performed. RESULTS: Out of 83 patients there were 4 patients with six complications including malunion (n = 4) and infection (n = 2). There were no cases of nonunion. Delay in surgical intervention did not influence the complication rate. CONCLUSIONS: Complications from repair of mandible fractures are rare; it is difficult to detect significant variables that may impact outcomes. We found no relationship between complications and timing to repair.

Immediate postoperative extubation in patients undergoing free tissue transfer.

OBJECTIVES/HYPOTHESIS: Extubation (cessation of ventilatory support) is often delayed in free flap patients to protect the microvascular anastomosis, presumably by reducing emergence-related agitation. We sought to determine if immediate extubation in the operating room (OR) would improve the postoperative course compared to delayed extubation in the intensive care unit (ICU). STUDY DESIGN: Retrospective chart review. METHODS: Medical records of all patients undergoing free tissue transfer for head and neck reconstruction between January 2009 and July 2010 were reviewed (n = 52). Patients extubated immediately postoperatively in the OR (immediate group, n = 26) were compared to patients extubated in the ICU (delayed group, n = 26). RESULTS: Tobacco use, alcohol use, pulmonary history, case length, and free flap type were not significantly different between the two groups. Although the average ICU stay for the immediate group was significantly shorter than the delayed group (2.0 days vs. 3.4 days; P = .008), the reduction in overall hospital stay for the immediate group did not achieve statistical significance (8.2 days vs. 9.5 days; P = .21). Use of treatment for agitation (27% vs. 65%) and physical restraints (8% vs. 69%) were significantly lower in the immediate versus delayed group (P = .01 and P < .001, respectively). Although flap-related, surgical, and medical complication rates were not significantly different between the two groups, the delayed extubation group had a significantly higher incidence of pneumonia (15% vs. 0%; P = .05). CONCLUSIONS: Immediate postoperative extubation in the OR following head and neck microvascular free tissue transfer reduces ICU stay, anxiolytic use, restraint use, and incidence of pneumonia without an increase in flap- or wound-related complications.

Mechanism of dynamic visual acuity recovery with vestibular rehabilitation.

OBJECTIVE: To determine why dynamic visual acuity (DVA) improves after vestibular rehabilitation in people with vestibular hypofunction. DESIGN: Combined descriptive and intervention study. SETTING: Outpatient department in an academic medical institution. PARTICIPANTS: Five patients (age, 42-66 y) and 4 age-matched controls (age, 39-67 y) were studied. Patients had vestibular hypofunction (mean duration, 177+/-188 d) identified by clinical (positive head thrust test, abnormal DVA), physiologic (reduced angular vestibulo-ocular reflex [aVOR] gain during passive head thrust testing), and imaging examinations (absence of tumor in the internal auditory canals or cerebellopontine angle). INTERVENTION: Vestibular rehabilitation focused on gaze and gait stabilization (mean, 5.0+/-1.4 visits; mean, 66+/-24 d). The control group did not receive any intervention. MAIN OUTCOME MEASURES: aVOR gain (eye velocity/head velocity) during DVA testing (active head rotation) and horizontal head thrust testing (passive head rotation) to control for spontaneous recovery. RESULTS: For all patients, DVA improved (mean, 51%+/-25%; range, 21%-81%). aVOR gain during the active DVA test increased in each of the patients (mean range, 0.7+/-0.2 to 0.9+/-0.2 [35%]). aVOR gain during passive head thrust did not improve in 3 patients and improved only partially in the other 2. For control subjects, aVOR gain during DVA was near 1. CONCLUSIONS: Our data suggest that vestibular rehabilitation increases aVOR gain during active head rotation independent of peripheral aVOR gain recovery.