Jeffrey D. Suh

Liposome-Encapsulated Curcumin Suppresses Growth of Head and Neck Squamous Cell Carcinoma In vitro and in Xenografts through the Inhibition of Nuclear Factor κB by an AKT-Independent Pathway

Purpose: The purpose of this study was to determine whether a liposomal formulation of curcumin would suppress the growth of head and neck squamous cell carcinoma (HNSCC) cell lines CAL27 and UM-SCC1 in vitro and in vivo. Experimental Design: HNSCC cell lines were treated with liposomal curcumin at different doses and assayed for in vitro growth suppression using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. A reporter gene assay was done on cell lines to study the effect of liposomal curcumin on nuclear factor κB (NFκB) activation. Western blot analysis was done to determine the effect of curcumin on the expression of NFκB, phospho-IκBα, phospho-AKT (pAKT), phospho-S6 kinase, cyclin D1, cyclooxygenase-2, matrix metalloproteinase-9, Bcl-2, Bcl-xL, Mcl-1L, and Mcl-1S. Xenograft mouse tumors were grown and treated with intravenous liposomal curcumin. After 5 weeks, tumors were harvested and weighed. Immunohistochemistry and Western blot analyses were used to study the effect of liposomal curcumin on the expression of NFκB and pAKT. Results: The addition of liposomal curcumin resulted in a dose-dependent growth suppression of both cell lines. Liposomal curcumin treatment suppressed the activation of NFκB without affecting the expression of pAKT or its downstream target phospho-S6 kinase. Expression of cyclin D1, cyclooxygenase-2, matrix metalloproteinase-9, Bcl-2, Bcl-xL, Mcl-1L, and Mcl-1S were reduced, indicating the effect of curcumin on the NFκB pathway. Nude mice xenograft tumors were suppressed after 3.5 weeks of treatment with i.v. liposomal curcumin, and there was no demonstrable toxicity of liposomal curcumin upon autopsy. Immunohistochemistry and Western blot analysis on xenograft tumors showed the inhibition of NFκB without affecting the expression of pAKT. Conclusions: Liposomal curcumin suppresses HNSCC growth in vitro and in vivo. The results suggest that liposomal curcumin is a viable nontoxic therapeutic agent for HNSCC that may work via an AKT-independent pathway.

Curcumin Enhances the Effect of Cisplatin in Suppression of Head and Neck Squamous Cell Carcinoma via Inhibition of IKKβ Protein of the NFκB Pathway

Previous experiments have shown that curcumin or cisplatin treatment suppresses growth of head and neck squamous cell carcinoma (HNSCC). To study the potential cooperative effect of both agents, two HNSCC cell lines were treated with curcumin or cisplatin alone or in combination. In vivo studies consisted of intravenous tail vein injection of liposomal curcumin, with intraperitoneal cisplatin, into nude mice growing xenograft HNSCC tumors. Introduction of curcumin and suboptimal concentrations of cisplatin showed a significant suppressive effect compared with treatment with either agent alone. Reduced expression of cyclin D1, IκBα, phospho-IκBα, and IKKβ occurred in cisplatin- and curcumin-treated cell lines. Confocal microscopy showed expression of IKKβ in the nucleus of the cell lines. Chromatin immunoprecipitation assay on DNA isolated from IKKβ immunoprecipitated samples showed PCR amplification of interleukin-8 promoter sequences, a binding site of NFκB, indicating an interaction between IKKβ and NFκB. Curcumin inhibited IKKβ in the cytoplasm and nucleus, leading to reduced NFκB activity, with no effect on phospho-AKT. In vivo studies showed significant growth inhibition of xenograft tumors treated with a combination of liposomal curcumin and cisplatin. The suppressive effect of curcumin was mediated through inhibition of cytoplasmic and nuclear IKKβ, resulting in inhibition of NFκB activity. Cisplatin treatment led to cellular senescence, indicating an effect mediated by p53 activation. The mechanisms of the two agents through different growth signaling pathways suggest potential for the clinical use of subtherapeutic doses of cisplatin in combination with curcumin, which will allow effective suppression of tumor growth while minimizing the toxic side effects of cisplatin. Mol Cancer Ther; 9(10); 2665–75. ©2010 AACR.

Biofilms in chronic rhinosinusitis.

Purpose of reviewRhinosinusitis is one of the most common medical complaints in the United States, affecting up to 16% of the population. It is associated with over 13 million physician visits per year and an estimated aggregated cost of over

Salvage surgery with free flap reconstruction: Factors affecting outcome after treatment of recurrent head and neck squamous carcinoma

6 billion annually. Patients with chronic rhinosinusitis (CRS) demonstrate worse quality-of-life scores than those suffering from chronic obstructive pulmonary disease, congestive heart failure, back pain, or angina. Despite the large societal impact and economic burden, the pathophysiology of CRS remains largely unsolved. One possible mechanism for the chronic nature of this disease is the involvement of bacterial biofilms, which represent a phenotypic change in bacteria that make them resistant to conventional treatment strategies. We will discuss these changes as well as emerging treatment options. Recent findingsNew research involving topical antimicrobials, surfactants, loop diuretics, and macrolide antibiotics can be used as adjuvant therapies to treat biofilm-associated CRS. All have shown some promise in laboratory or small patient studies, but all need further evaluation SummaryBacterial biofilms are highly organized structures composed of communities of bacteria encased within a protective extracellular matrix. If bacterial biofilms are the cause of certain cases of CRS, then the treatment paradigms will have to be changed. Novel nonantimicrobial therapies may have clinical applications to prevent and destabilize biofilms. We believe that ultimately methods to reduce sinonasal inflammation and protect cilia will be the first step in blocking the attachment and aggregation of bacteria that would otherwise start biofilm formation. Once more is known about the role of biofilms in CRS, new therapies will undoubtedly play a greater role and change our treatment paradigms.

Schneiderian papillomas: comparative review of exophytic, oncocytic, and inverted types.

Objective: To determine factors predicting the outcome after salvage surgery with microvascular flap reconstruction for recurrent squamous cell cancer (SCC) of the head and neck.

Disease relapse after segmental resection and free flap reconstruction for mandibular osteoradionecrosis

Background Sinonasal papillomas are benign epithelial neoplasms arising from Schneiderian mucosa. The three subtypes, exophytic, oncocytic, and inverted (inverted papilloma [IP]), should be distinguished from one another histopathologically. This study (1) highlight the histopathological and clinical differences between the Schneiderian papilloma subtypes and (2) identifies clinical features that potentially predict papilloma subtypes. Methods A retrospective review was performed of patients with Schneiderian papillomas over an 11-year period. Results Seventy patients with sinonasal papillomas who underwent sinus surgery were identified. There were 50 (71%) male and 20 (29%) female subjects diagnosed at an average age of 53 years (range, 13–80 years). Exophytic (n = 25), oncocytic (n = 9), and IP (n = 37) were identified. IP was associated with transformation into squamous cell carcinoma in three (8%) cases and dysplasia in three (8%) cases. Neither oncocytic nor exophytic subtypes were associated with dysplasia or malignancy. On multivariate analysis of potential predictors of papilloma subtype, history of chronic rhinosinusitis (CRS) and location of papilloma were significantly associated with papilloma subtype. Using classification and regression tree model, papilloma subtypes can be predicted based on presence or absence of CRS and papilloma location with nominal 82.4% accuracy. Conclusion The inverted and exophytic type are the most common sinonasal papillomas, with the inverted type having an 8% rate of malignant transformation in this study. In contrast, the oncocytic type was not associated with dysplasia or malignancy in our series despite reports in the literature indicating malignant potential. History of CRS and papilloma location can provide clues to the histological subtype, which is important for surgical planning and patient counseling.

Treatment Options for Chronic Rhinosinusitis

Objective: The objective of this study was to assess the outcomes, complications, and incidence of disease recurrence of mandibular osteoradionecrosis (ORN) after resection and microvascular free flap reconstruction. Study Design: Case series with chart review. Setting: Academic medical center. Subjects And Methods: Retrospective patient data review of 40 patients with mandibular ORN who were treated by segmental mandibulectomy and microvascular reconstruction between 1995 and 2009. All patients received radiation therapy for previous head and neck cancer, and 12 of 40 patients received concurrent chemotherapy. All patients failed to respond to conservative management. There were 26 males and 14 females, with a median age of 62 years. Median follow-up was 17.4 months. Results: There were no free flap failures. The incidence of wound-related complications was 55 percent. Median time to complication was 10.6 months. Ten (25%) patients developed symptoms of residual or recurrent ORN, with 70 percent of the recurrences arising in unresected condyles that were adjacent to the segmental mandibulectomy. Statistical analysis revealed that current smokers were at reduced risk to develop residual or recurrent ORN. Conclusion: This present study confirms that microvascular free flaps are reliable for treatment of advanced mandibular ORN. Nevertheless, there remains a 55 percent incidence of wound-healing complications. The lack of objective clinical criteria to judge the appropriate amount of mandible resection in patients with ORN remains an unresolved issue that resulted in the development of recurrent ORN in 25 percent of patients. Further investigations are needed to better understand the pathophysiology of ORN to prevent postoperative wound complications and disease recurrence.

Outcomes and Complications of Endoscopic Approaches for Malignancies of the Paranasal Sinuses and Anterior Skull Base

Chronic rhinosinusitis (CRS) is defined as persistent symptomatic inflammation of the nasal and sinus mucosa. Although insights into the pathophysiology of CRS have largely expanded over the last 2 decades, the exact etiology is still unknown and is likely due to multiple host and environmental factors. Treatments are aimed at reducing mucosal inflammation, controlling infection, and restoring mucociliary clearance within the sinuses. The principal goal of this article is to outline a rational approach to the treatment of chronic sinus disease on the basis of currently available diagnostic and therapeutic techniques. Emphasis will be placed on the management, therapeutic response, and objective evaluation of therapeutic efficiency.

Diagnosis and endoscopic management of sinonasal schwannomas.

Objectives: Malignant tumors of the paranasal sinuses are traditionally approached by a variety of external incisions. Recent advances in endoscopic endonasal surgery have allowed for some of these tumors to be treated endoscopically. The purpose of this study was to assess the outcomes and complications of the endoscopic approach in a series of patients with paranasal sinus malignancies. Methods: A retrospective chart review was performed of patients with sinonasal or skull base malignancies treated with endoscopic or endoscopic-assisted resections at a tertiary care institution from 2002 to 2010. Patient data were collected on symptoms, tumor type, operative technique, and postoperative course. Baseline risk factors, overall and disease-free survival data, and surgical outcomes were compared between the two groups. Results: Of the total 49 patients, 36 (73%) underwent an endoscopic approach and 13 (27%) underwent endoscopicassisted approaches. Sarcomas (9 cases) were the most common tumor type, followed by squamous cell carcinoma (8), adenocarcinoma (8), and melanoma (7). The mean follow-up time for all patients was 3.58 years (range, 1.1 to 8.8 years). Surgical complications were more frequent with open approaches than with endoscopic approaches (23.1% versus 5.6%; p = 0.11). Medical complications were significantly more common with open approaches (38.5% versus 8.3%; p = 0.02). The disease-specific mortality rate was 8% (4 of 49). The local tumor recurrence rate was 16% (8 of 49). The 3-year disease-free survival rates were 86.8% in the endoscopic group and 67.7% in the open group (p = 0.047); however, the patients in the endoscopic group had lower T stages (p = 0.0068) and lower ASA scores (p = 0.03). Conclusions: Endoscopic approaches to the sinuses and skull base have become progressively more sophisticated with advances in skull base reconstruction, advances in surgical technique, and improvements in technology. This study demonstrates the relative safety and utility of the endoscopic approach for sinonasal and skull base malignancies. In carefully selected patients, endoscopic approaches demonstrate survival rates comparable to those of traditional surgery, and fewer perioperative complications. With appropriate planning and careful surgical decision-making, endoscopic surgery shows promise as a minimally invasive alternative in the treatment of sinonasal malignancies. Recent advances in endoscopic endonasal surgery have allowed for some of these tumors to be treated endoscopically. The purpose of this study was to assess the outcomes and complications of the endoscopic approach in a series of patients with paranasal sinus malignancies.

Animal model of radiogenic bone damage to study mandibular osteoradionecrosis.

Aims: Survey the clinical symptoms, radiological features, management, and long-term outcomes of sinonasal and anterior skull base schwannomas. Patients and Methods: Retrospective review of patients with sinonasal schwannomas treated from June 2001 through January 2010 at two academic institutions. Results: There were 4 women and 3 men in this study. The mean age was 46 years (range 17–68). The mean tumor size was 2.4 cm (range 1.4–3.8 cm). Tumor locations included ethmoid sinuses (3), nasal cavity (2) and pterygopalatine fossa (2). Six patients had endoscopic resections, while 1 was approached and resected via a lateral rhinotomy. The mean follow-up was 2.8 years. There were no tumor recurrences during the study period. Conclusions: Schwannomas of the paranasal sinuses and nasal cavity are uncommon tumors that can usually present with vague and nonspecific symptoms. Magnetic resonance imaging can suggest the diagnosis; however, a definitive diagnosis is made by correlation with histopathological findings. Treatment is complete surgical resection. This study illustrates the effectiveness of the endoscopic endonasal approach in the treatment of these benign tumors.