Mark J. Jameson

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. Mol Cancer Ther; 10(11); 2124–34. ©2011 AACR.

Anatomic risk factors for sinus disease: fact or fiction?

Background Sinonasal anatomic variants have been postulated as a risk factor for sinus disease. Therefore, a study was conducted to examine the correlation of sinus disease to septal deviation, concha bullosa, and infraorbital ethmoid cells. Methods Two hundred fifty consecutive sinus and orbital computed tomography scans were examined at the University of Virginia over a 2-year period. Coronal, sagittal, and axial views were examined for the presence and size of concha bullosa and infraorbital ethmoid cells. Septal deviations were measured by examining the width of the nasal cavity at the level of the maxillary sinus ostium. The severity of mucosal thickening in the maxillary, ethmoid, and frontal sinuses was recorded. The correlation between mucosal disease of the sinuses to the anatomic variants was then compared. Results Computed tomography images were reviewed in 250 consecutive studies (500 sides). Of the 500 sides, 67.2% of sides had some level of mucosal thickening. Concha bullosa and infraorbital ethmoid cells were both present in 27% of the sides. Concha bullosa was associated with maxillary sinus disease (p < 0.01). Infraorbital ethmoid cells were associated with both ethmoid (p < 0.05) and maxillary (p < 0.01) mucosal disease. Frontal sinus disease had no significant correlation with these anatomic variants (p > 0.05). For sinuses with infraorbital ethmoid cells or concha bullosa, there were a higher number of diseased sinuses with larger anatomic variants (p < 0.01). Narrow nasal cavities were associated with maxillary sinus disease (p < 0.01). Conclusion Septal deviations, concha bullosa, and infraorbital ethmoid cells, which contribute to the narrowing of the osteomeatal complex, are associated with mucosal disease.

Successful reconstruction of scalp and skull defects: Lessons learned from a large series†‡§¶

To provide a framework for the management of scalp and skull defects.

Intensity‐modulated radiotherapy outcomes for oropharyngeal squamous cell carcinoma patients stratified by p16 status

Patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with intensity‐modulated radiotherapy (IMRT) were stratified by p16 status, neck dissection, and chemotherapy to correlate these factors with outcomes.

Outcomes of Patients With Head-and-Neck Cancer of Unknown Primary Origin Treated With Intensity-Modulated Radiotherapy

PURPOSE To analyze survival, failure patterns, and toxicity in patients with head-and-neck carcinoma of unknown primary origin (HNCUP) treated with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS Records from 27 patients with HNCUP treated during the period 2002-2008 with IMRT were reviewed retrospectively. Nodal staging ranged from N1 to N3. The mean preoperative dose to gross or suspected disease, Waldeyers ring, and uninvolved bilateral cervical nodes was 59.4, 53.5, and 51.0 Gy, respectively. Sixteen patients underwent neck dissection after radiation and 4 patients before radiation. Eight patients with advanced nodal disease (N2b-c, N3) or extracapsular extension received chemotherapy. RESULTS With a median follow-up of 41.9 months (range, 25.3-93.9 months) for non deceased patients, the 5-year actuarial overall survival, disease-free survival, and nodal control rates were 70.9%, 85.2%, and 88.5%, respectively. Actuarial disease-free survival rates for N1, N2, and N3 disease were 100%, 94.1%, and 50.0%, respectively, at 5 years. When stratified by non advanced (N1, N2a nodal disease without extracapsular spread) vs. advanced nodal disease (N2b, N2c, N3), the 5-year actuarial disease-free survival rate for the non advanced nodal disease group was 100%, whereas for the advanced nodal disease group it was significantly lower at 66.7% (p = 0.017). Three nodal recurrences were observed: in 1 patient with bulky N2b disease and 2 in patients with N3 disease. No nodal failures occurred in patients with N1 or N2a disease who received only radiation and surgery. CONCLUSION Definitive IMRT to 50-56 Gy followed by neck dissection results in excellent nodal control and overall and disease-free survival, with acceptable toxicity for patients with T0N1 or non bulky T0N2a disease without extracapsular spread. Patients with extracapsular spread, advanced N2 disease, or N3 disease may benefit from concurrent chemotherapy, targeted therapeutic agents, or accelerated radiation regimens in addition to surgery.

Immediate postoperative extubation in patients undergoing free tissue transfer

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).

Nicotine enhances proliferation, migration, and radioresistance of human malignant glioma cells through EGFR activation

It has been suggested that continued tobacco use during radiation therapy contributes to maintenance of neoplastic growth despite treatment with radiation. Nicotine is a cigarette component that is an established risk factor for many diseases, neoplastic and otherwise. The hypothesis of this work is that nicotine promotes the proliferation, migration, and radioresistance of human malignant glioma cells. The effect of nicotine on cellular proliferation, migration, signaling, and radiation sensitivity were evaluated for malignant glioma U87 and GBM12 cells by use of the AlamarBlue, scratch healing, and clonogenic survival assays. Signal transduction was assessed by immunoblotting for activated EGFR, ERK, and AKT. At concentrations comparable with those found in chronic smokers, nicotine induced malignant glioma cell migration, growth, colony formation, and radioresistance. Nicotine increased phosphorylation of EGFRtyr992, AKTser473, and ERK. These molecular effects were reduced by pharmacological inhibitors of EGFR, PI3K, and MEK. It was therefore concluded that nicotine stimulates the malignant behavior of glioma cells in vitro by activation of the EGFR and downstream AKT and ERK pathways.

p16 Not a Prognostic Marker for Hypopharyngeal Squamous Cell Carcinoma

OBJECTIVE To investigate the prognostic significance of p16 in patients with hypopharyngeal squamous cell carcinoma (HPSCC) and to evaluate the relationship between p16 and human papillomavirus (HPV). Unlike in oropharyngeal SCC (OPSCC), the prognostic significance of p16 in HPSCC and its association with HPV is unclear. DESIGN Retrospective medical chart review. SETTING University tertiary referral center. PATIENTS A total of 27 patients with HPSCC treated with definitive radiation therapy between 2002 and 2011 whose tissue was available for immunohistochemical analysis. INTERVENTIONS Twenty-two patients were treated with chemoradiation, and 5 with radiation alone. All tumor biopsy specimens were analyzed for p16 and, when sufficient tissue was available, for HPV DNA. MAIN OUTCOME MEASURES Overall survival (OS), locoregional control (LRC), disease-free survival (DFS), and laryngoesophageal dysfunction-free survival (LEDFS) were analyzed according to p16 status. RESULTS Findings for p16 were positive in 9 tumors and negative in 18 tumors. Median follow-up was 29.3 months. There was no significant difference in OS, LRC, DFS, or LEDFS for patients with p16-positive vs p16-negative tumors. Only 1 of the 19 tumors tested for HPV was found to be HPV positive. When used as a test for HPV, p16 had a positive predictive value of 17%. CONCLUSIONS In contrast to OPSCC, p16 expression in patients with HPSCC had a low positive predictive value for HPV and did not predict improved OS, LRC, DFS, or LEDFS. Thus, for HPSCC, p16 is not a prognostic biomarker. Caution must be taken when extrapolating the prognostic significance of p16 in patients with OPSCC to patients with head and neck SCC of other subsites.

Predicting Residual Neck Disease in Patients With Oropharyngeal Squamous Cell Carcinoma Treated With Radiation Therapy: Utility of p16 Status

OBJECTIVE To identify factors that predict complete response of cervical nodal disease to radiation therapy (RT) in patients with oropharyngeal squamous cell carcinoma (OP-SCCA). DESIGN Histologic analysis of prospectively collected specimens and retrospective medical chart review. SETTING Tertiary referral center. SUBJECTS Sixty-nine patients with OP-SCCA treated from January 1, 2002, through June 1, 2008. INTERVENTION Definitive RT, with or without chemotherapy and with or without neck dissection (ND). MAIN OUTCOME MEASURE Presence of a viable tumor in post-RT ND specimen. RESULTS Tissue specimens from 69 patients with OP-SCCA treated primarily with RT, with or without chemotherapy, were evaluated. Of these, 47 (68.1%) were strongly and diffusely positive for p16 expression by immunohistochemical analysis, signifying human papillomavirus positivity. Patients with p16-positive and p16-negative tumors (hereinafter, p16+ and p16-, respectively) had similarly sized primary tumors on presentation, but p16+ primary tumors were associated with more advanced neck disease (nodal stages N2c-N3; 31.9% vs 4.5% for p16- tumors) and more contralateral nodes (27.7% vs 4.5% for p16- tumors). Forty-seven patients (59.0%) underwent planned posttreatment ND (a total of 55 NDs). The NDs performed for p16- tumors were significantly more likely to have viable tumor in the specimen (50.0% vs 18.0% for p16+ tumors; P = .02). In addition, p16+ necks with residual viable cancer were characterized by incomplete response on post-RT imaging, tobacco and alcohol use, and extracapsular spread on pretreatment imaging. CONCLUSIONS In conjunction with other clinical parameters, p16 status can help predict the need for post-RT ND in patients with OP-SCCA. Although close observation may be warranted in selected patients with p16+ tumors, patients with p16- tumors are at much higher risk for residual neck disease, even when initial nodal disease is less advanced.

Endoscopic management of extensive inverted papilloma.

Background Given the malignant potential and propensity for recurrence of inverted papilloma (IP) of the sinonasal cavity, complete excision is warranted. For disease extending to multiple sites, open surgical oncological procedures are associated with high morbidity and do not assure complete control of the tumor. The endoscopic approach provides excellent visualization, permits removal of diseased mucosa while preserving vital anatomic structures, and allows for excellent postoperative surveillance. Recurrences are identified early and endoscopic resection is repeated as necessary until there is no evidence of disease. Methods Data were prospectively collected and subsequently reviewed on 18 consecutive patients who underwent endoscopic management of extensive IP (present at more than one anatomic site) between 1999 and 2003. Results Fourteen men and four women with a mean age of 54 years (range, 36–74 years) were followed for an average of 29 months (range, 6–46 months) after initial endoscopic resection. Seventy-eight percent (14 patients) complained of nasal airway obstruction for more than 6 months and 22% (4 patients) were incidentally noted to have a nasal mass on endoscopy or computed tomography. Eleven patients had undergone therapeutic procedures on initial evaluation. The most common sites affected were maxillary sinus, lamina papyracea, and ethmoid sinus. Patients required an average of 1.6 endoscopic surgeries (range, 1–3 surgeries) to achieve local control; 10 patients (56%) required only one. All patients were symptomatically improved and complications were limited to one cerebrospinal fluid leak, which was repaired intraoperatively. Conclusion Extensive IP can be controlled using minimally invasive endoscopic procedures as long as close follow-up is maintained. Operative risk and postoperative morbidity are significantly less than observed with open procedures.