Purpose: Combined platinum-based chemoradiation therapy is frequently being used as therapy for head and neck cancer at multiple sites. These therapies are individually ototoxic, but little has been reported on their combined toxicity.Materials and methods: A retrospective investigation of 37 patients known to have undergone therapy with both agents, in combination, for head and neck malignancy was performed. Sixty percent of the patients had complaints of hearing loss subjectively. Reliable pretreatment and posttreatment audiograms were obtained on 15 of these patients. Audiograms were analyzed for sensorineural changes at 0.5, 1, 2, 4, and 8 kHz.Results: By paired t test analysis, there were significant changes in the patients with pretreatment and posttreatment audiograms at all frequencies. More than 50% of the patients had a change of 10 dB or greater in their pure-tone average. More than 85% of the patients experienced changes in their hearing at 4 and 8 kHz.Conclusions: We conclude that patients undergoing combined modality therapy for head and neck cancer experience hearing loss. We recommend that hearing assessment, including pretreatment and posttreatment audiometry, be performed in all patients undergoing combined platinum-based chemotherapy and radiation for the treatment of head and neck cancer. (c) 2006 Elsevier Inc. All rights reserved.

BACKGROUND: This study aimed to determine predictors for otolaryngology resident success using data available at the time candidates are interviewed (eg, medical school attended, letters of recommendation, test scores) and data that emerge during residency.STUDY DESIGN: We performed a retrospective cohort Study of 36 residents who entered our program between 1983 and 1993.RESULTS: Seventy percent of Alpha Omega Alpha (AOA) members and 13% of nonmembers were in the highest tertile based on faculty ranking (p < 0.01), and candidates with an exceptional trait were more likely than those without an exceptional trait to rank in the highest tertile (57% versus 10%, p < 0.01). AOA membership was also related to current academic appointment (p = 0.02). Significant correlations included United States Medical Licensing Examination (USMLE) I score, year 2 In-training score (0.48, p = 0.03), and years 3 and 4 in-training score and faculty ranking (minus 0.39, minus 0.50, respectively, p <= 0.01). Having more than one peer-reviewed publication was associated with higher USMLE I scores and being favored for selection by > 50% of the interviewers (p < 0.05 for both).CONCLUSIONS: In our program designed to train academic otolaryngologists, postresident success was strongly predicted by having an exceptional trait and AOA membership. Success during residency was predicted by interviewer's impression of the candidate and a USMLE I score > 570. Knowledge of these factors at the time of the resident interview could increase the likelihood of selecting the most appropriate candidates for academic otolaryngology. Resident success is a complex outcome, and other unmeasured and unexamined characteristics can provide additional insight into choosing successful residents.

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Adenoid cystic carcinoma (ACC) is a neoplasm with unpredictable behavior with frequent late relapses that lacks good prognostic indicators. c‐kit tyrosine kinase oncogene has recently been found to be expressed in ACC. The aim of this study is to correlate the expression of c‐kit in ACC with clinical follow‐up.

5509 Background: Concurrent cisplatin and radiation (RT) for locally-advanced larynx cancer provides higer organ preservation rates than either RT alone or sequential treatment. As local control ra...

Molecular studies of squamous cell carcinoma of the head and neck (HNSCC) have demonstrated multiple genetic abnormalities such as activation of various oncogenes (Ras, Myc, epidermal growth factor receptor, and cyclin D1), tumor suppressor gene inactivation (TP53 and p16), and loss of heterozygosity at numerous chromosomal locations. Despite these observations, accurate and reliable biomarkers that predict patients at highest risk for local recurrence have yet to be defined. In an effort to identify gene expression signatures that may serve as biomarkers, we studied 41 squamous cell carcinoma tumors (25 primary and 16 locally recurrent) from various anatomical sites and 13 normal oral mucosal biopsy samples from healthy volunteers with microarray analysis using Affymetrix U133A GeneChip arrays. Differentially expressed genes were identified by calculating generalized t tests (P < 0.001) and applying a series of filtering criteria to yield a highly discriminant list of 2890 genes. Hierarchical clustering and image generation using standard software were used to visualize gene expression signatures. Several gene expression signatures were readily identifiable in the HNSCC tumors, including signatures associated with proliferation, extracellular matrix production, cytokine/chemokine expression, and immune response. Of particular interest was the association of a gene expression signature enriched for genes involved in tumor invasion and metastasis with patients experiencing locally recurrent disease. Notably, these tumors also demonstrated a marked absence of an immune response signature suggesting that modulation of tumor-specific immune responses may play a role in local treatment failure. These data provide evidence for a new gene expression-based biomarker of local treatment failure in HNSCC.

OBJECTIVE. We sought to review the current and proposed management, as well as bring about discussion, of managing the patient with distal tracheal and pulmonary parenchymal involvement by recurrent respiratory papillomatosis (RRP).DESIGN, SETTING, AND PATIENTS., We conducted a review of 6 patients with pulmonary metastasis from RRP at 3 academic tertiary care hospitals. Interventions included surgical and medical management with antiviral, chemotherapeutic, and/or immune-modulating agents.RESULTS: Although treatment with alpha-2-beta interferon, isotretinoin, and methotrexate have not proved to eradicate pulmonary involvement by RRP, possible epithelial stabilization and slowing of disease progression are noted.CONCLUSIONS: The rates of distal tracheal and pulmonary metastasis as seen in our cohort were higher than previously reported. Approximately 12% of our patients with RRP have distal tracheal spread and as many as 7% of all patients with RRP at our institutions have pulmonary dissemination. Also, high suspicion for malignant conversion to squamous carcinoma in the patient with pulmonary spread should be maintained. In addition, aggressive treatment, although not proved to eradicate the pulmonary disease, should be undertaken due to the high morbidity and mortality associated with pulmonary dissemination of RRP in our cohort.

Objective: Streptococcus pneumoniae is the most common pathogen in otitis media. Infection of the middle ear with S. pneumoniae potentiates development of thick effusion in the middle ear which frequently causes hearing loss and communication disorders in children. What has changed immediately in the middle ear cleft following pneumococcal infection is extensively studied and characterized but what has changed ever after remains elusive. The purpose of this study is to explore the cellular and molecular basis that remains on a longer time after acute pneumococcal middle ear infection and potentiates development of thick effusion in the middle ear. Methods: 12 rats were intrabullarly inoculated with pneumococcus at 2.5x10(6) CFU/ear and profiles of gene expression in the middle ear were examined by cDNA microarrays in combination with reverse transcription-polymer chain reaction (RT-PCR) 6 weeks after infection while the morphologic changes in middle ear were simultaneously characterized by histopathologic techniques. Twelve rats receiving phosphate-buffered saline (PBS) served as controls. Results: it demonstrated that pneumococcus infected ears had the expression of the following genes at a high level compared to the controls: mitogenic signaling proteins (mitogen-activated protein kinase [MEK1 and MEK2], helix-loop-helix transcriptional regulators (Id3 and Id1), ion channels (sodium channel beta 1 and sodium channel 2), and mucin glycoproteins (Muc2 and Muc5). The morphology demonstrated a thickened mucosa and submucosa with increased expression of macroglycoconjugates compared to the controls. Conclusion. the expression of several genes remains high even after the acute episode of pneumococcal otitis media has been resolved. The up-regulated expression of these genes may serve as the basis for the development of thick effusion and mucous cell metaplasia/hyperplasia once it is complicated with other factors such as dysfunction of the Eustachian tube. (C) 2002 Published by Elsevier Science Ireland Ltd.

PURPOSE:To determine dose-response effects and the activity of paclitaxel combined with cisplatin in patients with incurable squamous cell carcinoma of the head and neck.PATIENTS AND METHODS:Two hundred ten patients with locally advanced, recurrent, or metastatic disease were randomly placed in either Arm A, paclitaxel 200 mg/m(2) (24-hour infusion) + cisplatin 75mg/m(2) + granulocyte colony-stimulating factor, or Arm B, paclitaxel 135 mg/m(2) (24-hour infusion) + cisplatin 75 mg/m(2). Cycles were repeated every 3 weeks until progression or a total of 12 cycles for complete responses. Primary outcomes were event-free and overall survival.RESULTS:No significant differences in outcomes were observed between the high- and low-dose paclitaxel regimens. The estimated median survival was 7.3 months (95% confidence interval, 6.0 to 8.6). The 1-year survival rate was 29%, and event-free survival was 4.0 months. The objective response rate (complete response plus partial response) was 35% for the high-dose patients and 36% for the low-dose patients. Myelosuppression was the most frequent toxicity: grade 3 or 4 granulocytopenia, 70% of patients in Arm A and 78% in Arm B; febrile neutropenia, 27% of patients in Arm A and 39% in Arm B. Grade 5 toxicities occurred in 22 patients (10.5%). Treatment was terminated early in 31% because of excessive toxicity or patient refusal.CONCLUSION:This phase III multicenter trial showed (1) no advantage for high-dose paclitaxel and (2) excessive hematologic toxicity associated with both regimens. Therefore, neither of the paclitaxel regimens evaluated in this trial can be recommended.

Objective: The importance of nitric oxide (NO) in the development of mucoid middle ear effusion (MMEE) has been reported, but the mechanism regulating NO release is unclear. We hypothesized that middle ear epithelial cells (MEEC) are an important source of NO and that cytokines may be responsible for inducible nitric oxide synthase (iNOS) mRNA expression in middle ear epithelial cells. This study aims to identify and localize iNOS in middle ear epithelium, and to characterize the effects of cytokines IL-1 beta and TNF-alpha on the expression and regulation of iNOS in rat middle ear epithelial cells. Methods: In vitro study: 40 Healthy adult Sprague-Dawley rats weighing 200-250 g were used as donors of MEEC. Cultured MEEC were exposed to IL-1 beta (10 ng/ml), TNF-alpha (5 ng/ml) or PBS (negative control) stimulation for 16 h. In vivo study: A total of 45 healthy adult Sprague-Dawley rats weighing 200-250 grams were used For this study. The tympanic bullae were exposed bilaterally by a submandibular approach. Animals were equally divided into three groups and inoculated with either 250 ng of IL-1 beta, 250 ng of TNF-alpha or PBS. A PBS group served as control. Expression of iNOS mRNA in MEEC from both in vivo and in vitro studies was determined by RT-PCR using specific primers. Expression of iNOS protein in MEEC was determined by immunocytochemistry and Western blot using specific anti-iNOS antibody. Results: Primary culture of rat MEEC was positively stained by cytokeratin antibody, but not by vimentin, indicating the epithelial origin of the cultured cells. RT-PCR revealed that cultured MEEC without treatment of IL-1 beta or TNF-alpha did not express iNOS mRNA whereas cultured MEEC treated with IL-1 beta or TNF-alpha for 16 h expressed iNOS mRNA. Both immunocytochemistry and Western blot demonstrated the expression of iNOS protein in the majority of cultured MEEC treated with IL-1 beta or TNF-alpha for 16 h, whereas the expression of iNOS protein was not detectable in MEEC without treatment. Expression of iNOS protein in vivo was observed in middle ear mucosa treated with IL-1 beta and TNF-alpha by immunohistochemistry. Conclusion: Expression of iNOS mRNA and iNOS protein is induced in MEEC following the treatment of cytokines IL-1 beta or TNF-alpha both in vivo and in vitro. The results of the present study demonstrate that rat MEEC possess the capacity to express iNOS after IL-1 beta and TNF-alpha stimulation. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

CK2 is a messenger-independent protein serine/threonine kinase that has been implicated in cell growth and proliferation. Our recent analysis of squamous cell carcinomas of the head and neck (SCCHN) revealed a significant elevation in CK2 activity in these tumor cells relative to normal mucosa of the upper aerodigestive tract and suggested a correlation with aggressive tumor behavior and poor clinical outcome. In order to further define the distribution of CK2 in these tissues, we have examined the immunohistochemical staining pattern of surgical specimens of both SCCHN tumors and normal upper aerodigestive tract mucosa using a monoclonal antibody directed against the catalytic subunit CK2-α of the kinase, and have compared these data with the subcellular distribution of CK2 activity in these same tissues. These measurements showed that CK2 is predominantly localized to the nuclei of the tumor cells, which agreed closely with the immunohistochemical staining pattern of CK2-α in tumor cells. The chiefly nuclear distribution of CK2-α immunostaining found consistently in SCCHN tumor cells and tumor-infiltrating lymphocytes contrasted with a relatively more predominant cytosolic staining pattern exhibited by various cellular constituents of normal oropharyngeal mucosa. The immunostaining pattern of CK2-α revealed that staining was observed in the cells stained for the proliferation-marker Ki-67; however, strong distinct immunostaining for CK2-α was also observed in large numbers of other cells in these same tumors, suggesting that CK2 elevation in these tumors is not a reflection of proliferative activity alone, but may also relate to the pathobiological behavior of the tumor.

Objective/Hypothesis: To determine the value of preoperative balloon occlusion in predicting the safety of carotid artery resection in advanced recurrent head and neck squamous cell carcinoma. Study Design: Retrospective chart review of all cases undergoing planned carotid artery resection for recurrent disease at a major university hospital. Methods: If the carotid artery was encased, a nonemergent carotid artery balloon test occlusion was performed for 30 minutes. If the patient tolerated this, he or she underwent permanent carotid artery occlusion, Results: Twenty-three patients were prospectively evaluated for resection, Three underwent emergent carotid artery ligation, Twenty others underwent nonemergent carotid artery test occlusion, Of these, 5 patients failed preoperative carotid artery balloon occlusion and 15 patients successfully underwent permanent carotid balloon occlusion, Although eight of these patients died of recurrent disease in less than 1 year, seven patients survived more than 1 year with two patients surviving more than 2 years. Conclusions: Preoperative carotid balloon occlusion predicted patients who could tolerate permanent occlusion, All patients eventually developed recurrent disease, but in 14 of the 15 patients, no hemorrhages occurred.

Various cytokines are presently known to be associated with the regulation of inflammatory responses. In pediatric otitis media, cytokines that correlate with various degrees of inflammation are present in middle ear effusions as inflammatory mediators. The present study was undertaken to examine the potential role of the early-response cytokines, interleukin-1beta and tumor necrosis factor-alpha, in adult otitis media. Fifty-nine adults with otitis media underwent tympanocentesis, and the effusion specimens were analyzed for the presence of both cytokines by enzyme-linked immunosorbent assay methods. Eighty-eight percent of the effusions were serous in nature. Sixty-seven percent of the patients had a known history of head and neck malignancy and radiation to the temporal bone. Twelve percent of the effusions were positive for interleukin-1beta expression, compared with 85% of effusions in children with otitis media. Eight percent of the effusions contained tumor necrosis factor-alpha, compared with 85% of those collected in pediatric otitis media. All of the specimens that contained tumor necrosis factor-alpha also contained interleukin-1beta. In the present study, there was no correlation with head and neck malignancy/radiation or the clinical degree of inflammation with the presence of either cytokine. We conclude that adult otitis media is associated with lower expression of an acute inflammatory response, as judged by the levels of interleukin-1beta and tumor necrosis factor-alpha in the effusions. Additionally, adult otitis probably represents a less severe and more chronic inflammatory state in comparison with pediatric otitis media. Further analysis of inflammatory mediators in adult otitis media is necessary to evaluate the contribution of cytokines in relation to various etiologic factors.

Indomethacin has been shown clinically to inhibit growth of SCCHN (Panje, 1981). This inhibition appears to be due to augmentation of cellular immunity. The inhibitory effect of indomethacin may act by limiting tumor associated prostaglandin E2 production, thereby allowing return of costimulatory cytokines by antigen presenting cells. This would have the net result of relief from host unresponsiveness and promotion of B-cell and CTL differentiation, allowing the individual to mount an effective response. The enhancement of tumor infiltrating lymphocytes in SCCHN seen with indomethacin administration could presumably be further augmented when given in combination with cytokine therapy. Future investigation may allow the biochemical staging of an individuals' tumor to determine the optimal combination of cytokine therapy and prostaglandin inhibition through selective use of NSAID's. The effect of NSAID manipulation of prostaglandin and leukotriene metabolism on prevention of metastatic disease in SCCHN has yet to be studied. Given that a preselected, potentially responsive subset of immunocytes exists within the tumor tissue and lymph nodes, the development of the LAK phenomenon in TIL's and tumor draining lymph nodes from surgical specimens is a viable and exceedingly interesting area for future investigations in autologous LAK immunotherapy. The potential exists to harvest a preselected population of tumor infiltrating (Boscia, 1988) or tumor draining immunocytes (McKinnon, 1990). These can then potentially be returned to a state of antigen responsiveness with a combination of cytokine exposure (e.g. rIL-2) and systemic cytokine therapy. With subsequent inhibition of tumor associated prostaglandin synthesis by the systemic administration of prostaglandin synthesis inhibitors, it may be possible to successfully alter the host response to tumor.

OBJECTIVETo test the hypothesis that transformation of normal upper aerodigestive mucosa to squamous cell carcinoma of the head and neck (SCCHN) is associated with specific changes in nuclear matrix (NM) proteins.DESIGNRetrospective, nonrandomized investigation using a cellular fractionation sequence followed by 2-dimensional gel electrophoresis analysis of NM proteins.SUBJECTSNuclear matrix proteins were extracted from a cohort of 12 pathologic SCCHN specimens and 5 normal specimens of oropharyngeal mucosa.RESULTSAll SCCHN specimens examined expressed 11 NM proteins that were not detected in normal mucosa. Conversely, at least 4 NM proteins that were expressed by all specimens of normal mucosa were absent from all SCCHN tumors. Seven NM proteins were common to carcinomas and normal specimens. Spindle cell histological variants of squamous cell carcinoma had distinct NM patterns.CONCLUSIONSMalignant transformation of normal upper aerodigestive mucosa to SCCHN is associated with specific changes in NM composition. These data suggest that different NM proteins might serve as specific tumor markers.

Inhibition or attenuation of mucous hypersecretion in middle ear epithelium is a key step toward resolution of mucoid otitis media. Mucous hypersecretion induced by platelet-activating factor (PAF) in cultured Chinchilla middle ear epithelial cells is dependent on arachidonic acid metabolites via PAF receptors, suggestive of the role of phospholipase A2 (PLA2) in mucous glycoprotein (MGP) secretion. In this study, dexamethasone added to cultured Chinchilla middle ear epithelial cells inhibited baseline and PAF-induced MGP secretion in a concentration-dependent manner. A definite time lag (16 h) was observed between administration of dexamethasone and MGP inhibition. This inhibition was reversed by the addition of exogenous PLA2 (the rate-limiting enzyme of arachidonic acid metabolism) and actinomycin D (an inhibitor of mRNA synthesis). This suggests that dexamethasone inhibits baseline and PAF-induced MGP secretion via a PLA2-dependent mechanism.

There is considerable information available about the modulation of DNA synthesis in normal and neoplastic cells with eicosanoids (1–5). It is difficult to formulate general statements about these processes because a variety of eicosanoids can contribute to cell growth, and no commonly accepted mechanisms of action for these processes have yet emerged. Previously, our work has shown that leukotriene C4 was able to partially restore growth to lipoxygenase inhibited U937 cells. Additionally, the cells were able to synthesize leukotriene C4, and its production was inhibited by ETYA, the inhibitor employed in several experiments (6).

Head and neck tumors are known to synthesize arachidonic acid metabolites. The authors have postulated that these substances may confer growth advantage to cancer cells, and by interfering with arachidonic acid metabolism squamous cancer growth may be altered. The tongue derived squamous carcinoma cell line, SCC-25, was treated with three leukotriene synthesis inhibitors and indomethacin. A dose-dependent decrease in DNA synthesis occurred with leukotriene inhibition, but not prostaglandin inhibition. All leukotriene synthesis inhibitors produced a dramatic and immediate effect ( > 70% inhibition by 4 hours) without cytotoxicity ( > 90% trypan blue exclusion). Cell populations at 96 hours were decreased when compared to control populations. In conclusion, leukotrienes or other lipoxygenase products may play a role as growth factors for squamous cell carcinoma, and arachidonic acid inhibition may be a novel target for chemotherapeutic intervention.

We hypothesized that malignant transformation of normal mucosa of the upper aerodigestive tract to squamous cell carcinoma of the head and neck (SCCHN) might be associated with altered CK2 activity in the chromatin compartment of these tumors. We measured CK2 activity in the cytosol and chromatin of 7 surgical specimens of SCCHN, and 5 specimens of normal oropharyngeal mucosa from non-smokers/non-drinkers. CK2 activity in SCCHN tumors was significantly elevated in both the nuclear chromatin (P < 0.0005) and cytosolic (P < 0.04) compartments relative to normal mucosa. These data suggest that activation or dysregulation of the chromatin-associated CK2 signal may play a role in the pathobiology of SCCHN.