Levels of cyclooxygenase-2 are increased in the oral mucosa of smokers: evidence for the role of epidermal growth factor receptor and its ligands.

Cyclooxygenase-2 (COX-2) is a promising pharmacologic target for preventing aerodigestive malignancies. In this study, we investigated the effects of tobacco smoke on the expression of COX-2 in oral mucosa. An approximately 4-fold increase in amount of COX-2 mRNA was observed in the oral mucosa of active smokers versus never smokers. Thus, a series of in vitro studies were carried out to elucidate the mechanism by which tobacco smoke induced COX-2. Treatment of a nontumorigenic oral epithelial cell line (MSK-Leuk1) with a saline extract of tobacco smoke (TS) stimulated COX-2 transcription, resulting in increased amounts of COX-2 mRNA, COX-2 protein, and prostaglandin E(2) (PGE(2)) synthesis. Exposure of cells to TS also caused an increase in epidermal growth factor receptor (EGFR) tyrosine kinase activity. Both an inhibitor of EGFR tyrosine kinase activity and a neutralizing anti-EGFR antibody blocked TS-mediated induction of COX-2. To define the mechanism by which TS activated EGFR, the release of amphiregulin and transforming growth factor alpha, two ligands of the EGFR, was measured. Exposure to TS caused a rapid increase in the release of both ligands. TS also markedly induced the expression of mRNAs for amphiregulin and transforming growth factor alpha. Importantly, increased expression of both ligands was also detected in the oral mucosa of active smokers. Taken together, these results suggest that activation of EGFR signaling contributes to the elevated levels of COX-2 found in the oral mucosa of smokers. Moreover, these findings strengthen the rationale for determining whether inhibitors of COX-2 or EGFR tyrosine kinase activity can reduce the risk of tobacco smoke-related malignancies of the aerodigestive tract.

Combination of mutated herpes simplex virus type 1 (G207 virus) with radiation for the treatment of squamous cell carcinoma of the head and neck.

G207 is an oncolytic herpes simplex virus (HSV) with deletions at both gamma134.5 loci and a LacZ gene insertion inactivating the HSV ribonucleotide reductase gene. Ionising radiation induces the growth arrest-inducible gene, GADD34, and ribonucleotide reductase. GADD34 is a protein that correlates with apoptosis following radiation and has homology with the G207 gamma134.5 gene. We hypothesised that the combination of radiotherapy with G207 may have a potentiating effect on viral replication and anti-tumour efficacy. The purpose of this study was therefore to evaluate the combination of G207 with radiation therapy to treat head and neck tumours. The cytotoxicity of G207 was tested in six head and neck squamous carcinoma cell lines, in the presence or absence of irradiation. For in vivo experiments, flank tumours in C3H/HeJ mice or in nude mice were treated with direct injections of G207, with or without radiation. All head and neck squamous cancer cell lines tested demonstrated significantly increased antitumour effects with the combination of G207 virus and radiation therapy compared with each individual modality (P<0.01). Furthermore, the combination treatment effect was better than the expected additive effect of the two therapies in combination. Even the radiation-resistant cell lines (SCC25, MSKQLL2, SCCVII) were susceptible. The combination of direct G207 injection with radiation therapy suppressed human and murine squamous cell carcinoma growth significantly (P<0.05 and P<0.001) compared with controls or single modality therapy. G207 enhanced the effectiveness of radiation therapy and low-dose radiation potentiated the effectiveness of G207 viral therapy in head and neck cancer. These findings suggest a potential clinical application for this combined therapy as treatment for radiation-resistant head and neck cancers.

Management options for cerebrospinal fluid leak after vestibular schwannoma surgery and introduction of an innovative treatment.

OBJECTIVE: To review the management of cerebrospinal fluid leak after vestibular schwannoma removal reported in the literature and to present a novel approach to management of recalcitrant cases. DATA SOURCES: MEDLINE and PubMed literature search using the terms "cerebrospinal fluid leak" or "cerebrospinal fluid fistula" and "acoustic neuroma" or "vestibular schwannoma" covering the period from 1985 to present in English. A review of bibliographies of these studies was also performed. STUDY SELECTION: Criteria for inclusion in this meta-analysis consisted of the availability of extractable data from studies presenting a defined group of patients who had undergone primary vestibular schwannoma removal and for whom the presence and absence of cerebrospinal fluid leakage was reported. Studies reporting combined approaches were excluded. No duplications of patient populations were included. Twenty-five studies met the inclusion criteria. DATA EXTRACTION: Quality of the studies was determined by the design of each study and the ability to combine the data with the results of other studies. All of the studies were biased by their retrospective, nonrandomized nature. DATA SYNTHESIS: Significance (p < 0.05) was determined using the chi test. CONCLUSIONS: Incisional cerebrospinal fluid leakage responded well to local management and lumbar drainage. Rhinorrhea often necessitated surgical intervention. No specific reoperation techniques correlated exclusively with better reoperation outcomes. The transaural/transnasal approach presents an alternative for surgical management of cerebrospinal fluid rhinorrhea.

Hodgkin's disease of the head and neck in human immunodeficiency virus-infected patients.

INTRODUCTION: Hodgkin's disease can occur in immunocompromised patients. However, the head and neck manifestations of Hodgkin's disease in human immunodeficiency virus (HIV)-infected patients remain ill defined. The aim of this study was to describe Hodgkin's disease of the head and neck in HIV-infected patients and compare it with noninfected patients. MATERIALS AND RESULTS: Sixteen patients presented with Hodgkin's disease of the head and neck to the King's County Hospital Center, Brooklyn, New York, beginning in January of 1991. Five patients were infected with HIV. Hodgkin's disease involved the head and neck regions in 90.5% of cases, occurring in 100% of HIV-infected and in 81% of noninfected patients. Manifestations of Hodgkin's disease were isolated to the head and neck region in only 20% of HIV-infected and in 27% of noninfected patients. Lymphatic structures were involved in all cases with head and neck involvement. Systemic or group B symptoms (fever, night sweats, fatigue, and weight loss of more than 10% of normal body weight) were present in 40% of HIV-infected patients and in 27% of noninfected patients. Advanced stage disease (Stage III/IV) was diagnosed in 80% of HIV-infected patients compared with 45% of noninfected patients. The mixed cellularity subtype was most common in HIV-infected patients (75%), whereas the nodular sclerosis subtype predominated in noninfected patients (50%). CONCLUSIONS: The data combined with our report of the literature suggest that the course, presentation, and outcome of Hodgkin's disease is markedly altered in HIV-infected patients. An aggressive approach to the diagnosis and management is suggested in this patient population.