Reconstruction of the pedicled nasoseptal flap donor site with a contralateral reverse rotation flap: technical modifications and outcomes.

OBJECTIVES/HYPOTHESIS: A pedicled nasoseptal flap is our preferred reconstructive technique after endoscopic endonasal skull base surgery. Its harvesting implies that the donor site (septal cartilage) is left bare. Secondary healing leads to crusting at the donor site that negatively affects the patient's quality of life and requires multiple outpatient debridements. A nasoseptal reverse rotation flap was designed to eliminate this problem; however, its outcomes have not been reported. STUDY DESIGN: Retrospective review. METHODS: We retrospectively reviewed the clinical charts of patients who underwent endoscopic endonasal skull base surgery at the Wexner Medical Center at The Ohio State University from November 2010 to September 2012, and in whom a reverse flap was used. We analyzed patients' demographics, pathology, and outcomes regarding the reverse flap. RESULTS: Forty-nine patients with various pathologies were included (11 meningiomas, seven craniopharyngiomas, five pituitary macroadenomas, five chondrosarcomas, five meningoencephaloceles, three chordomas, 11 malignant tumors, two other lesions). There were two patients lost to follow-up. Mean follow-up time was 11 weeks (range = 1-39 weeks). A follow-up examination 1 to 2 weeks after surgery revealed a complete re-epithelialization in 46 of 47 patients (97.87%). Adverse events included granuloma (n = 1), anterior dehiscence (n = 1), and excoriated mucosa (n = 1). Factors such as underlying disease, prior chemoradiotherapy, and postoperative chemoradiotherapy did not seem to affect the healing of the reverse flap. CONCLUSIONS: The reverse flap provides complete remucosalization of the denuded donor septum, decreasing septal crusting within the first 1 to 2 postoperative weeks, and adds minimal morbidity.

Inhibitor of differentiation 1 contributes to head and neck squamous cell carcinoma survival via the NF-kappaB/survivin and phosphoinositide 3-kinase/Akt signaling pathways.

PURPOSE: A key issue in cancer is apoptosis resistance. However, little is known about the transcription factors that contribute to cellular survival of head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN: Three batches (54, 64, and 38) of HNSCC specimens were used for cellular and molecular analyses to determine the major molecular signaling pathways for cellular survival in HNSCC. Animal models (cell culture and xenografts) were used to verify the importance of apoptosis resistance in HNSCC. RESULTS: Inhibitor of differentiation (Id) family member, Id1, was significantly upregulated in clinical HNSCC specimens and acted to protect keratinocytes from apoptosis. Transfection of HNSCC cells with Id1 in vitro induced the phosphorylation of Akt (p-Akt) via phosphoinositide 3-kinase and increased the expression of survivin via NF-kappaB. Blockage of both pathways by specific inhibitors (LY294002 and IkappaBalphaM, respectively) abrogated Id1-induced cell survival of keratinocytes. In vivo studies showed that increased expression of Id1 allowed nontumorigenic keratinocytes (Rhek-1A) to become tumorigenic in nude mice by increased expression of survival genes such as p-Akt and survivin. More importantly, short interfering RNA for Id1 significantly reduced HNSCC tumor volume of HNSCC in xenograft studies. Analysis of clinical data verified the importance of the Id1 downstream molecule, survivin, in the prognosis of HNSCC patients. CONCLUSIONS: The above data, taken together, suggest that Id1 and its downstream effectors are potential targets for treatment of HNSCC because of their contribution to apoptosis resistance.

Efficacy of an osmotic pump delivered, GM-CSF-based tumor vaccine in the treatment of upper aerodigestive squamous cell carcinoma in rats.

PURPOSE: Upper aerodigestive tract (UADT) cancer has not experienced significant overall survival improvement for over 20 years, and no successful treatments for systemic disease exist. Most patients with UADT cancer experience immune suppression, therefore immune restorative therapies may offer promise for these patients. We presently tested the efficacy of granulocyte macrophage-colony stimulating factor (GM-CSF) delivered via 28-day continuous infusion pump, in combination with irradiated tumor cells, in a flank model of UADT cancer. METHODS: Five groups of rats were inoculated with syngeneic mucosally derived squamous carcinoma cells (FAT-7). Osmotic minipumps were implanted in the contralateral flank to deliver GM-CSF at 0 (PBS), 0.1, 1, 10, or 100 ng/day (n = 6 per group) for 28 days; 10(6) irradiated FAT-7 cells (ITC) were injected at the site of the GM-CSF infusion on days 0, 3, 7, 14, and 21 immune infiltrates in tumors were analyzed. RESULTS: Rats that received 10 or 100 ng/day GM-CSF/ITC had a significantly slower tumor growth rate compared to those who received 0, 0.1, or 1 ng/day (ANOVA, P < 0.01). There were increased CD 4+, CD 8+, and CD 68+ cells in tumors of GM-CSF/ITC treated animals over controls. CONCLUSION: GM-CSF (10 or 100 ng/day) delivered locally via osmotic pump with ITC slows the growth rate of mucosally derived squamous cell carcinoma in rats while improving immune cell infiltrates. The efficacy of locally delivered GM-CSF immunotherapy in this model may be a first step toward this immunotherapy strategy for humans.

Pseudomonas aeruginosa lipopolysaccharide induction of keratinocyte proliferation, NF-kappa B, and cyclin D1 is inhibited by indomethacin.

NF-kappaB is activated during acute inflammatory states as well as in other injury response disease states. Several pathologic states in squamous tissue injury response are characterized by increased squamous proliferation. This study was performed to investigate the hypothesis that Pseudomonas aeruginosa LPS is able to activate a proliferative phenotype in squamous cells via NF-kappaB induction and that this NF-kappaB-mediated response may be abrogated with the classic anti-inflammatory agent indomethacin. EMSA, luciferase reporter gene experiments, Western blots, and cellular proliferation assays were performed in normal and transformed human keratinocytes after stimulation with P. aeruginosa LPS. EMSA and luciferase reporter gene assays showed a 3- to 5-fold induction of active NF-kappaB in human keratinocyte cell lines after stimulation with P. aeruginosa LPS. The stimulation correlated with significantly increased cellular proliferation. As one potential mechanism for this increase in proliferation, an NF-kappaB-specific activation of cyclin D1 was observed. Both the NF-kappaB induction and proliferation response were inhibited with indomethacin and in dominant negative stable transfection clones. P. aeruginosa LPS activates proliferation of human keratinocytes, potentially through the induction of NF-kappaB and cyclin D1. These findings suggest that bacterial components can contribute to proliferative disease states in squamous epithelium through NF-kappaB activation.