Cystic fibrosis transmembrane conductance regulator activation by the solvent ethanol: implications for topical drug delivery.

BACKGROUND: Decreased cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride (Cl) secretion across mucosal surfaces contributes to the development of airway disease by depleting airway surface liquid, increasing mucus viscosity and adhesion, and consequently hindering mucociliary clearance. We serendipitously discovered during testing of drugs solubilized in low concentrations ethanol (0.25%, 43 mM) that the control vehicle produced robust activation of CFTR-mediated Cl(-) transport. The objective of the current study is to investigate low concentrations of ethanol for effects on Cl(-) secretion and ciliary beat frequency (CBF). METHODS: Wild-type (WT) and transgenic CFTR(-/-) primary murine nasoseptal epithelial (MNSE) cultures and WT and F508del/F508del human sinonasal epithelial (HSNE) cultures were subjected to transepithelial ion transport measurements using pharmacologic manipulation in Ussing chambers. CBF activation was also monitored. Murine nasal potential difference (NPD) was measured in vivo. RESULTS: Ussing chamber tracings revealed ethanol activated CFTR-mediated Cl transport in a dose-dependent fashion in WT MNSE (n = 4, p < 0.05) and HSNE (n = 4, p < 0.05). Ethanol also significantly increased CBF (fold change) in WT MNSE cultures in a dose-dependent fashion (phosphate-buffered saline [PBS], 1.33 ± 0.04; 0.25% ethanol, 1.37 ± 0.09; 0.5% ethanol, 1.53 ± 0.06 [p < 0.05]; 1% ethanol, 1.62 ± 0.1 [p < 0.05]). Lack of stimulation in CFTR(-/-) and F508del/F508del cultures indicated activity was dependent on the presence of intact functional CFTR. Ethanol perfusion (0.5%) resulted in a significant -3.5-mV mean NPD polarization when compared to control solution (p < 0.05). CONCLUSION: The observation that brief exposure of ethanol stimulated Cl(-) secretion via CFTR-mediated pathways indicates its possible use as topical aerosol delivered alone or in combination with other CFTR activators for diseases of dysfunctional mucociliary clearance (MCC) in chronic rhinosinusitis (CRS).

Endoscopic resection of anterolateral maxillary sinus inverted papillomas.

OBJECTIVES/HYPOTHESIS: Endoscopic medial maxillectomy (EMM) has become the surgical procedure of choice for resection of maxillary sinus inverted papillomas (IPs). Traditionally, IPs pedicled on the anterior and/or lateral walls of the maxillary sinus have required an adjuvant Caldwell-Luc approach due to decreased visualization with transnasal endoscopy in these locations. The objective of the current study is to evaluate outcomes following endoscopic resection of anterolateral maxillary sinus IPs. STUDY DESIGN: Prospective case series. SUBJECTS AND METHODS: Over 6 years, a total of 35 patients underwent EMM for maxillary sinus IPs located on the anterolateral maxillary wall. Demographics, operative technique, pathology, complications, recurrence, and postoperative follow-up were evaluated. RESULTS: The majority of patients were male (71%) with a mean age of 56 years (range 27-83). Most patients (71%) were referred for recurrence after previous attempts at surgical resection. Adequate visualization was obtained following EMM in the majority of patients with use of a 70-degree endoscope and angled instrumentation. The addition of transseptal surgical access was critical to the removal of IPs in 16 patients. No Caldwell-Luc approaches were required. Pathologic dysplasia was identified in nine patients, and three had carcinoma. There were no recurrences with a mean disease-free interval of 29 months (10-72 months). CONCLUSION: In the present study, EMM provided excellent surgical access to anterolateral maxillary sinus IPs. The transseptal approach allowed enhanced visualization to this challenging location, previously considered accessible only with external procedures.

Harmonic Scalpel versus electrocautery and surgical clips in head and neck free-flap harvesting.

We sought to determine the safety and utility of Harmonic Scalpel-assisted free-flap harvesting as an alternative to a combined electrocautery and surgical clip technique. The medical records of 103 patients undergoing radial forearm free-flap reconstruction (105 free flaps) for head and neck surgical defects between 2006 and 2008 were reviewed. The use of bipolar electrocautery and surgical clips for division of small perforating vessels (n = 53) was compared to ultrasonic energy (Harmonic Scalpel; Ethicon Endo-Surgery, Inc., Cincinnati, Ohio) (n = 52) free-tissue harvesting techniques. Flap-harvesting time was reduced with the use of the Harmonic Scalpel when compared with electrocautery and surgical clip harvest (31.4 vs. 36.9 minutes, respectively; p = 0.06). Two patients who underwent flap harvest with electrocautery and surgical clips developed postoperative donor site hematomas, whereas no donor site complications were noted in the Harmonic Scalpel group. Recipient site complication rates for infection, fistula, and hematoma were similar for both harvesting techniques (p = 0.77). Two flap failures occurred in the clip-assisted radial forearm free-flap harvest group, and none in the Harmonic Scalpel group. Median length of hospitalization was significantly reduced for patients who underwent free-flap harvest with the Harmonic Scalpel when compared with the other technique (7 vs. 8 days; p = 0.01). The Harmonic Scalpel is safe, and its use is feasible for radial forearm free-flap harvest.

CD147 expression in advanced cutaneous squamous cell carcinoma.

BACKGROUND: CD147 is upregulated in multiple cancer types, but its expression in advanced cutaneous squamous cell carcinoma (SCC) is unknown. Our purpose was to evaluate the expression patterns of CD147 and related monocarboxylate transporters (MCT1, MCT4) to determine their correlation with survival. METHODS: This is a retrospective cohort study of patients with advanced stage cutaneous SCC of the head and neck who presented to a tertiary care center between 1998 and 2006 (n=50). CD147, MCT1 and MCT4 expression levels were assessed using immunofluorescence analysis of archived tumor samples and correlated with survival and clinicopathologic characteristics. RESULTS: The majority of patients (92%, n = 46) were diagnosed with stage III disease, with 46% (n = 23) having positive regional lymph node metastasis and 8% (n = 4) with distant metastasis. Primary malignancies had an overexpression of CD147 (78%; n = 35), MCT1 (23%; n = 10) and MCT4 (47%; n = 20). In addition, there was a significant relationship between the overexpression of CD147 and node positive disease (p = 0.048). Two- and five-year survival rates were 69 and 61%, respectively. There was a trend toward decreased survival in patients with overexpression of CD147 (p = 0.17), MCT1 (p = 0.11) and MCT4 (p = 0.15). CONCLUSION: CD147 may represent a biomarker or potential therapeutic target in advanced cutaneous SCC.

Use of recombinant bone morphogenetic protein 2 in free flap reconstruction for osteonecrosis of the mandible.

PURPOSE: Osteoradionecrosis of the mandible is a debilitating consequence of radiation therapy for head-and-neck malignancy. It can result in pain, bone exposure, fistula formation, and pathologic fracture. Recombinant human bone morphogenetic protein 2 (rhBMP-2) has shown promise in reconstruction of bone defects. The purpose of this study is to determine whether the addition of rhBMP-2 at the union of vascularized bone and native bone improves surgical outcomes in patients with osteonecrosis of the mandible. MATERIALS AND METHODS: This study was a retrospective analysis of patients who were treated between 2006 and 2010 for osteonecrosis of the mandible. Patients requiring definitive reconstruction after failure of a course of conservative management were included. Patients were divided into 2 cohorts depending on whether rhBMP-2 was used during the reconstruction. The primary outcome measure was defined as stable mandibular union. RESULTS: Seventeen patients were included. The development of malunion was similar in both groups (13% for rhBMP-2 group vs 11% for non-rhBMP-2 group). Infectious complications were similar between the groups (25% in rhBMP-2 group vs 56% in non-rhBMP-2 group, P = .33). The rates of hardware removal were similar for the 2 groups (33% in non-rhBMP-2 group vs 25% in rhBMP-2 group, P = .10). No cancer recurrences were observed in patients receiving rhBMP-2. CONCLUSIONS: The use of rhBMP-2 is safe in free flap reconstruction of the mandible, but its ability to significantly improve patient outcomes, as measured by rates of malunion, reoperation, or infection, is still unknown.

EGFR expression in advanced head and neck cutaneous squamous cell carcinoma.

BACKGROUND: The significance of epidermal growth factor receptor (EGFR) expression in advanced cutaneous squamous cell carcinoma (SCC) of the head and neck remains poorly understood. METHODS: We performed a retrospective review of patients with advanced-stage (stage III or stage IV) cutaneous SCC of the head and neck (n = 56). RESULTS: The majority of patients (91%) had stage III disease, with 54% having regional metastasis and 9% with distant metastasis. Two-year survival was 64% and the 5-year survival was 56%. EGFR was found to be overexpressed in 56% of primary tumors and 58% of regional metastatic disease. Overall survival did not correlate with EGFR (p = .47) expression in primary lesions, nor was it associated with an increase in regional (p = .74) or distant metastasis (p = .56). Furthermore, there was no correlation between clinicopathologic characteristics and EGFR expression CONCLUSIONS: These data do not suggest upregulation of EGFR is associated with poor survival or aggressive disease.

Free tissue transfer for head and neck reconstruction in solid organ transplant patients.

BACKGROUND: Patients with head and neck malignancies who have had solid organ transplant and require free tissue transfer are a unique population. This study was performed to evaluate the effect of immunosuppression on the rate of perioperative complications and the success of free tissue transfer in the head and neck. METHODS: Complications in solid organ transplant patients undergoing free tissue transfer for reconstruction of head and neck malignancies from 1998 to 2010 were evaluated. RESULTS: A total of 22 flaps in 17 patients were performed. Eight patients (11 of 22 flaps) had complications. The median hospital stay was 6 days (range, 4-26 days). The median length of follow-up was 13.5 months (range, 3.5-49.9 months). CONCLUSIONS: Solid organ transplant patients are at an increased risk of de novo malignancies due to chronic immunosuppression. This study demonstrates that free tissue transfer is a viable option in transplant patients with morbidity similar to nontransplant patients.

Free flap reconstruction of lateral mandibular defects: indications and outcomes.

OBJECTIVE: To compare outcomes following osteocutaneous radial forearm and fibula free flap reconstruction of lateral mandibular defects. STUDY DESIGN: Retrospective case-controlled study. SETTING: Historical cohort study. SUBJECTS AND METHODS: All patients who underwent free flap reconstruction of lateral mandibular defects from 1999 to 2010 were included in this study. Patients were classified into 2 groups based on type of reconstruction: (1) osteocutaneous radial forearm (n = 73) and (2) fibula free flap reconstruction (n = 51). Patient characteristics, length of hospital stay, recipient and donor site complications, and long-term outcomes including postoperative diet were evaluated. RESULTS: Most patients were male (68%) and presented with advanced T-stage (71%) squamous cell carcinoma (94%) involving the alveolus (21%), retromolar trigone (23%), or oral tongue (21%). Median length of hospital stay was 8 days (range, 4-22 days). The recipient site complication rate approached 27% and included infection (n = 11), mandibular malunion (n = 9), exposed bone or mandibular plates (n = 9), and flap failure (n = 5). Most patients demonstrated little to no trismus following reconstruction (94%) and were able to resume a regular or edentulous diet (73%). No difference in complication rates or postoperative outcomes was seen between osteocutaneous radial forearm and fibula free flap groups (P > .05). One patient underwent dental implantation following osteocutaneous radial forearm free flap reconstruction. No patients from the fibula free flap group underwent dental implantation. CONCLUSION: The osteocutaneous radial forearm and fibula free flap provide equivalent wound healing and functional outcomes in patients undergoing lateral mandibular defect reconstruction.

Utility of CT surveillance for primary site recurrence of squamous cell carcinoma of the head and neck.

BACKGROUND: The literature directly comparing the utility of clinical examination (CE) to that of CT in detecting recurrence of squamous cell carcinoma (SCC) for primary site recurrences is lacking. METHODS: Patients who received both CT scans and CEs after primary treatment for SCC of the upper aerodigestive tract (oropharynx, hypopharynx, and larynx) were identified. Individual CT scans and CEs were evaluated for their ability to detect recurrence status. RESULTS: One hundred thirty-one patients underwent a total of 886 CEs and 346 CT scans during the follow-up period. The sensitivity for CE and CT was 84.0% and 66.7%, respectively; for specificity, 98.7% and 90.7%, respectively; for positive predictive value, 65.6% and 31.8%, respectively; and for negative predictive value the values were 99.5% and 97.7%, respectively. CONCLUSION: Due to the low sensitivity and positive predictive value of CT scans compared to physical examination in evaluating primary site tumor recurrences, the utility of CT for surveillance may be limited.

Assessment of tissue autofluorescence and reflectance for oral cavity cancer screening.

OBJECTIVE: Although approved by the US Food and Drug Administration for clinical use, the utility of handheld tissue reflectance and autofluorescence devices for screening head and neck cancer patients is poorly defined. There is limited published evidence regarding the efficacy of these devices. The authors investigated the sensitivity and specificity of these modalities compared with standard examination. STUDY DESIGN: Prospective, cross-sectional analysis. SETTING: Tertiary care medical center. SUBJECTS AND METHODS: Patients who were treated previously for head and neck cancer (n = 88) between 2009 and 2010 were included. Patients were screened using white light visualization (standard of care) and compared with tissue reflectance and autofluorescence visualization. Screening results were compared with biopsy or long-term follow-up. RESULTS: Autofluorescence visualization had a specificity of 81% and a sensitivity of 50% for detecting oral cavity cancer, whereas white light visualization had a specificity of 98% and a sensitivity of 50%. Tissue reflectance visualization had low sensitivity (0%) and good specificity (86%). The power of this study was insufficient to compare the positive and negative predictive values of standard white light examination (50% and 98%, respectively) to tissue autofluorescence (11% and 97%) or reflectance (0% and 95%). In addition, stratification by previous radiation therapy found no statistically significant difference in screening results. CONCLUSION: Standard clinical lighting has a higher specificity than tissue reflectance and autofluorescence visualization for detection of disease in patients with a history of head and neck cancer. This study does not support the added costs associated with these devices.

Outcomes of recurrent head and neck cutaneous squamous cell carcinoma.

Recurrent, advanced stage cutaneous squamous cell carcinoma (cSCC) is uncommon with limited publications on patient outcomes. A retrospective study including patients who underwent surgical resection for recurrent, advanced stage cSCC of the head and neck was performed (n = 72). Data regarding tumor site, stage, treatment, parotid involvement, perineural invasion, positive margins, metastasis, and disease-free survival was analyzed. The majority of patients were male (85%) and presented with recurrent stage III (89%) cSCC. Two-year disease-free survival was 62% and decreased to 47% at 5 years. Parotid involvement, positive margins, nodal metastasis, or the presence of perineural invasion did not correlate with decreased survival (P > .05). Distant metastasis was a strong indicator of poor overall survival (P < .001). Adjuvant postoperative radiotherapy did not improve overall survival (P = .42). Overall survival was poor for patients with advanced recurrent cSCC despite the combined treatment with surgery and radiotherapy.

Free flap reconstruction of self-inflicted submental gunshot wounds.

In this study, we review outcomes for 15 patients with self-inflicted submental gunshot wounds requiring free flap reconstruction. Patients presented to two tertiary care centers over a 7-year period. Mean age was 46 years (range, 16 to 76 years), 67% (n = 10) had a psychiatric history, and four were known to abuse illicit substances. Patients with oromandibular involvement required on average a total of 2.8 procedures, and those with midface (3.7) or combined defects (6) required more total procedures (p = 0.21). Donor sites included osteocutaneous radial forearm (n = 8), fibula (n = 4), fasciocutaneous radial forearm (n = 5), and anterior lateral thigh (n = 1). Median length of hospitalization was 8 days. Overall complication rate was 33% (n = 5), and included hematoma (n = 1), fistula (n = 1), and mandibular malunion (n = 2). Most patients were able to tolerate a regular or soft diet (92%), maintain oral competency (58%), and demonstrate intelligible speech (92%) at a median time to follow-up of 12 months. Despite the devastating nature of this injury, free flap reconstruction of self-inflicted submental gunshot wounds results in acceptable functional results for the majority of patients.

Outcomes following temporal bone resection.

OBJECTIVES/HYPOTHESIS: To evaluate survival outcomes in patients undergoing temporal bone resection. STUDY DESIGN: Retrospective review. METHODS: From 2002 to 2009 a total of 65 patients underwent temporal bone resection for epithelial (n = 47) and salivary (n = 18) skull base malignancies. Tumor characteristics, defect reconstruction, and postoperative course were assessed. Outcomes measured included disease-free survival and cancer recurrence. RESULTS: The majority of patients presented with recurrent (65%), advanced stage (94%), cutaneous (72%), and squamous cell carcinoma (57%). Thirty-nine patients had perineural invasion (60%) and required facial nerve resection; 16 (25%) had intracranial extension. Local (n = 6), regional (n = 2), or free flap (n = 46) reconstruction was required in 80% of patients. Free flap donor sites included the anterolateral thigh (31%), radial forearm free flap (19%), rectus (35%), and latissimus (4%). The average hospital stay was 4.9 days (range, 1-28 days). The overall complication rate was 15% and included stroke (n = 4), cerebrospinal fluid leak (n = 2), hematoma formation (n = 1), infection (n = 1), flap loss (n = 1), and postoperative myocardial infarction (n = 1). A total of 22 patients (34%) developed cancer recurrence during the follow-up period (median, 10 months), 17 (77%) of whom presented with recurrent disease at the time of temporal bone resection. Two-year disease-free survival was 68%, and 5-year disease-free survival was 50%. CONCLUSIONS: Aggressive surgical resection and reconstruction is recommended for primary and recurrent skull base malignancies with acceptable morbidity and improved disease-free survival.

Optical imaging predicts tumor response to anti-EGFR therapy.

To evaluate cetuximab treatment in head and neck squamous cell carcinoma xenografts and cell lines, we investigated a preclinical model of head and neck squamous cell carcinoma. Head and neck squamous cell carcinoma cell lines SCC-1, FaDu, CAL27, UM-SCC-5 and UM-SCC-22A were used to generate subcutaneous flank xenografts in SCID mice. Mice were divided into control and cetuximab treatment groups, mice in the latter group received 250 µg cetuximab once weekly for four weeks. After completion of therapy, SCC-1 (p < 0.001), UM-SCC-5 (p < 0.001), UM-SCC-22A (p = 0.016) and FaDu (p = 0.007) tumors were significantly smaller than control, while CAL27 tumors were not different from controls (p = 0.90). Mice were systemically injected with 50 µg of the Cy5.5-cetuximab bioconjugate and imaged by stereomicroscopy to determine if tumor fluorescence predicted tumor response. Intact tumor fluorescence did not predict response. Tissue was harvested from untreated xenografts to evaluate ex vivo imaging. Cell lines were then evaluated in vitro for fluorescence imaging after Cy5.5-cetuximab bioconjugate labeling. The location of fluorescence observed in labeled cells was significantly different for cell lines that responded to treatment, relative to unresponsive cells. Tumors from cell lines that showed low internalized signal in vitro responded best to treatment with cetuximab. This preclinical model may aid in determining which cancer patients are best suited for cetuximab therapy.

Robotic-assisted surgery for primary or recurrent oropharyngeal carcinoma.

OBJECTIVE: To determine the feasibility of robotic-assisted salvage surgery for oropharyngeal cancer. DESIGN: Retrospective case-controlled study. SETTING: Academic, tertiary referral center. PATIENTS: Patients who underwent surgical resection for T1 and T2 oropharyngeal cancer between 2001 and 2008 were classified into the following 3 groups based on type of resection: (1) robotic-assisted surgery for primary neoplasms (robotic primary) (n = 15), (2) robotic-assisted salvage surgery for recurrent disease (robotic salvage) (n = 7), and (3) open salvage resection for recurrent disease (n = 14). MAIN OUTCOME MEASURES: Data regarding tumor subsite, stage, and prior treatment were evaluated as well as margin status, nodal disease, length of hospital stay, diet, and tracheotomy tube dependence. RESULTS: The median length of stay in the open salvage group was longer (8.2 days) than robotic salvage (5.0 days) (P = .14) and robotic primary (1.5 days) resection groups (P < .001). There was no difference in postoperative diet between robotic primary and robotic salvage surgery groups. However, a greater proportion of patients who underwent open salvage procedures were gastrostomy tube dependent 6 months following treatment (43%) compared with robotic salvage resection (0%) (P = .06). A greater proportion of patients who underwent open salvage procedures also remained tracheotomy tube dependent after 6 months (7%) compared with robotic salvage or robotic primary patients (0%) (P = .48). No complications were reported in the robotic salvage group. Two patients who underwent open salvage resection developed postoperative hematomas and 2 developed wound infections. CONCLUSION: When feasible, robotic-assisted surgery is an acceptable procedure for resection of both primary and recurrent oropharyngeal tumors. Trial Registration clinicaltrials.gov Identifier: NCT00473564.

Outcomes of static and dynamic facial nerve repair in head and neck cancer.

OBJECTIVES/HYPOTHESIS: Determine outcomes associated with nerve grafting versus static repair following facial nerve resection. STUDY DESIGN: Retrospective chart review. METHODS: Charts from 105 patients who underwent facial nerve reconstruction between January 1999 and January 2009 were reviewed. The majority had parotid malignancy (78.1%), most commonly squamous cell carcinoma (50.5%). Patients underwent static (n = 72) or dynamic (n = 33) reconstruction with nerve grafting. Facial nerve function was measured using the House-Brackmann (H-B) scale. RESULTS: Patients receiving static reconstruction were on average 10.3 years older (P = .002). Mean overall survival for tumor cases was 61.9 months; parotid squamous cell carcinoma was associated with worse prognosis (P = .10). Median follow-up was 16.1 months (range, 4-96.1 months). Most (97%) patients receiving a nerve graft had some return of function at a median of 6.2 months postoperatively (range, 4-9 months) and the majority (63.6%) had good function (H-B score 6 cm), and prolonged preoperative dysfunction.

Anti-EMMPRIN monoclonal antibody as a novel agent for therapy of head and neck cancer.

PURPOSE: Extracellular matrix metalloprotease inducer (EMMPRIN) is a tumor surface protein that promotes growth and is overexpressed in head and neck cancer. These features make it a potential therapeutic target for monoclonal antibody (mAb)-based therapy. Because molecular therapy is considered more effective when delivered with conventional cytotoxic agents, anti-EMMPRIN therapy was assessed alone and in combination with external beam radiation. EXPERIMENTAL DESIGN: Using a murine flank model, loss of EMMPRIN function was achieved by transfection with a small interfering RNA against EMMPRIN or treatment with a chimeric anti-EMMPRIN blocking mAb. Cytokine expression was assessed for xenografts, tumor cells, fibroblasts, and endothelial cells. RESULTS: Animals treated with anti-EMMPRIN mAb had delayed tumor growth compared with untreated controls, whereas treatment with combination radiation and anti-EMMPRIN mAb showed the greatest reduction in tumor growth (P = 0.001). Radiation-treated EMMPRIN knockdown xenografts showed a reduction in tumor growth compared with untreated knockdown controls (P = 0.01), whereas radiation-treated EMMPRIN-expressing xenografts did not show a delay in tumor growth. Immunohistochemical evaluation for Ki67 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) resulted in a reduction in proliferation (P = 0.007) and increased apoptosis in anti-EMMPRIN mAb-treated xenografts compared with untreated controls (P = 0.087). In addition, we provide evidence that EMMPRIN suppression results in decreased interleukin 1beta (IL-1beta), IL-6, and IL-8 cytokine production, in vitro and in vivo. CONCLUSIONS: These data suggest that anti-EMMPRIN antibody inhibits tumor cell proliferation in vivo and may represent a novel targeted treatment option in head and neck squamous cell carcinoma.