Faculty Bibliography

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

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

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

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

There are two promising herpes viral-based anticancer strategies: one involves replication-defective viruses to transfer therapeutic transgenes, and the other involves replication-conditional oncolytic viruses, which selectively infect and destroy cancer cells directly. This study examines a novel dual herpesvirus preparation, which combines the immunostimulatory effects of amplicon-mediated IL2 expression with direct viral-induced oncolysis. The oncolytic virus G207 was used as the helper virus to package a herpes simplex virus (HSV)-amplicon vector carrying the gene IL2 (HSV-IL2), yielding a single preparation with two complementary modes of action. In vivo comparison was carried out in a syngeneic squamous cell carcinoma flank tumor model. We directly injected established tumors with HSV-IL2, G207, G207 mixed with HSV-IL2, or G207-packaged HSV-amplicon carrying the IL2 transgene (G207[IL2]). Significant inhibition of tumor growth was seen at 2 weeks in the G207[IL2]-treated tumors relative to controls (0.57+/-0.44 cm(3) versus 39.45+/-5.13 cm(3), P<0.00001), HSV-IL2 (20.97+/-4.60 cm(3)), and the G207 group (7.71+/-2.10 cm(3)). This unique use of a replication-conditional, oncolytic virus to package a replication-incompetent amplicon vector demonstrates impressive efficacy in vitro and in vivo, and avoids the theoretical concerns of recombination with reversion to wild type

Herpes simplex type 2-defective infectious single-cycle (DISC) viruses are attenuated viruses that were originally produced as viral vaccines; however, these viruses are also efficient gene transfer vehicles. The main goals of this study were to examine determinants of the gene transfer by using DISC virus for squamous cancer and to evaluate the antitumoral efficacy of vaccination with tumor cells modified by DISC viruses carrying a combination of immunomodulatory genes (interleukin-2 (IL-2), granulocyte-macrophage colony-stimulating factor (GM-CSF), B7-1) in a model of squamous cell cancer (SCCVII) in C3H/HeJ mice. SCCVII cells transduced by DISC viruses (multiplicity of infection of 10) carrying the IL-2 or GM-CSF gene produced nanogram quantities of IL-2 or GM-CSF per 10(6) cells. Irradiated (5,000 cGy, 10,000 cGy) cells secreted levels of GM-CSF or IL-2 that were comparable with nonirradiated cells. In vivo vaccination using tumor cells transduced ex vivo with DISC-IL2 or DISC-GMCSF resulted in protection against subsequent tumor challenge (P < .01), with DISC-GMCSF-transduced, irradiated tumor cells showing the greatest effects (P < .001). Marked growth arrest also was noted in established tumors after direct injection of DISC-GMCSF (P < .001). These data demonstrate that (a) DISC virus is capable of efficient gene transfer, (b) GM-CSF-secreting genetically modified tumor vaccine protects against tumor cell challenge and suppresses tumor growth, and (c) intratumoral injection of DISC-GMCSF significantly suppresses the growth of established tumors. These results not only confirm clinically relevant gene transfer but also demonstrate that the gene transfer is an effective anti-cancer therapy

INTRODUCTION: Radiation therapy is an integral part of the treatment of head and neck cancer. Factors predicting radiation response are ill defined. The aim of this study was to identify genetic aberrations associated with radiation response in cell lines derived from head and neck squamous cell carcinomas (HNSCC) using comparative genomic hybridization (CGH) for genome-wide screening. METHODS: Five cell lines derived from HNSCC were subjected to a single course of radiation (400 cGy) in parallel with a similarly handled, untreated control. Cellular response to radiation was determined on posttreatment days 1, 2, 3, 4, and 5 using a cell viability assay (MTT assay). Radiation response was defined as 35% or greater decrease in cell survival relative to control. Tumor doubling time was determined by cell counts performed at day 0 and 1 for each cell line. All experiments were done in quadruplicate. CGH analysis was performed by differentially labeling DNA from tumor and normal tissue with fluorescent agents. The labeled DNAs were simultaneously hybridized to normal metaphase chromosomes. Image analysis for fluorescence intensity along the entire length of each metaphase chromosome allowed generation of a color ratio, which was used to detect copy number changes. RESULTS: Radioresistance was identified in two of five cell lines. The tumor doubling time was not a predictor of radiation response. CGH identified a complex pattern of aberrations, with gain of 3q common to all cell lines. The number of genetic aberration was higher in radiation-sensitive cell lines than in radiation-resistant ones. No recurrent aberrations were unique to the radiation-resistant cell lines. Recurrent gains at 7p and 17q and losses at 5q, 7q, and 18q were unique to the radiation-sensitive cell lines. CONCLUSIONS: The number of aberrations identified by CGH analysis may be a predictor of radiation response. A large study of primary tumors is warranted to confirm this association and identify specific genetic aberrations associated with radiation response

OBJECTIVE AND IMPORTANCE: Delayed epistaxis resulting from trauma to branches of the external carotid artery is an infrequent but potentially serious complication of transsphenoidal surgery. We report two cases of severe, delayed epistaxis in patients who had undergone transsphenoidal surgery. In both cases, noninvasive treatment failed, necessitating endovascular intervention. CLINICAL PRESENTATION: The first patient, a 52-year-old woman with a prolactinoma, underwent a second transsphenoidal resection 18 months after the first surgery. She was readmitted on postoperative Day 15 with massive epistaxis. The second patient, a 40-year-old woman, had undergone two transsphenoidal surgeries, 14 years apart, for an adrenocorticotropic hormone-secreting adenoma. She was readmitted with massive epistaxis on postoperative Day 17. INTERVENTION: Both patients were initially treated with nasal balloon packing but experienced recurrent hemorrhage when the balloon was deflated, necessitating referral to the interventional radiology department for embolization. At arteriography, the first patient was found to have a pseudoaneurysm of the medial branch of the left internal maxillary artery, which was subsequently embolized. Arteriography in the second patient revealed an abnormally dilated midline branch of the right internal maxillary artery in the nasal septum; this vessel was occluded at arteriography. CONCLUSION: Delayed massive epistaxis is a rare but significant complication of transsphenoidal surgery. Injury to branches of the external carotid artery, along with injury to the internal carotid artery, should be suspected in patients who present with delayed epistaxis after transsphenoidal surgery. Angiography performed in patients with refractory bleeding should include selective external carotid injections. Epistaxis that is refractory to anterior and posterior nasal packing may be effectively treated with endovascular embolization

BACKGROUND: This study was performed to assess the relationship between Hashimoto's thyroiditis and the development, presentation, management, and outcome of papillary thyroid carcinoma. METHODS: Two complementary analytic methods were used. The clinical study was a retrospective case-control study, including patients seen with papillary thyroid carcinoma presenting during a 12-year period. We also used a systematic literature review to identify suitable reports and meta-analysis to statistically combine published results. RESULTS: The prevalence of Hashimoto's thyroiditis is significantly higher in patients with papillary thyroid cancer (odds ratio, 1.89; 95% CI, 1.02-3.50). These patients typically have a dominant nodule, 44% of which are discovered incidentally on routine examinations. Fine-needle aspiration has a sensitivity of 91% for the identification of papillary cancer. The prognostic variables at the time of a diagnosis of papillary cancer and the approach to management are not altered by the presence of coexistent Hashimoto's thyroiditis. In addition, the rate of surgical complications was not higher in patients with coexistent Hashimoto's disease. Meta-analysis suggested a positive correlation between Hashimoto's disease and disease-free survival (r = 0.09; 95% CI, 0.05-0.12) and overall survival (r = 0.11; 95% CI, 0.07-0.15). CONCLUSIONS: There is an increased prevalence of Hashimoto's thyroiditis in patients with papillary thyroid carcinoma. The presence of coexistent Hashimoto's thyroiditis does not affect the diagnostic evaluation or management of papillary thyroid cancers. The survival of patients who have papillary thyroid cancers may be superior in coexistent Hashimoto's thyroiditis