Brandon G. Bentz

The Yin and Yang of nitric oxide: Reflections on the physiology and pathophysiology of NO·

Nitric oxide (NO·) is an arginine‐derived nitrogen‐based radical that is rapidly becoming one of the most important molecular species to be discovered. Over the past decade, an explosion of evidence has revealed the extreme complexity of function of this seemingly simple inorganic molecule. It is now evident that NO· demonstrates a functional dualism, playing a pivotal role in numerous physiologic and pathophysiologic processes. Whether this molecule is beneficial or detrimental is dependent upon the tissue of generation, the level of production, the oxidative/reductive (redox) environment in which this radical is generated, and the presence or absence of NO· transduction elements. Nitric oxide is generated by three independent isoenzymes that resemble the p‐450 enzyme superfamily in both form and function. It ultimately alters enzymatic function through covalent modification, redox interactions, and interactions with metallic functional centers. This radical is a key figure in a number of pathophysiologic processes by means of similar yet uncoordinated interactions. In consideration of the already broad spectrum of roles attributed to NO·, it seems highly likely that this molecule will be implicated in an ever widening variety of functions relative to the practice of otolaryngology–head and neck surgery. This article reviews the enzymology, signal transduction mechanisms, physiology, and pathophysiology of NO· as it pertains to head and neck cancer.

Nitric Oxide Synthase Type 3 is Increased in Squamous Hyperplasia, Dysplasia, and Squamous Cell Carcinoma of the Head and Neck

The implication of nitric oxide (NO) in the multistep process of carcinogenesis prompted us to examine the expression of endothelial constitutive nitric oxide synthase (NOS3) in head and neck squamous cell carcinoma (HNSCCa). Eleven paraffin-embedded samples of normal oral mucosa, 3 reactive oral lesions, 13 samples of squamous dysplasia, and 120 specimens of HNSCCa were immunostained with an anti-NOS3 monoclonal antibody and graded on a 0 to 4+ scale of intensity. Normal squamous mucosa demonstrated very little NOS3 expression. Areas of normal mucosa, reactive mucosa, and dysplastic lesions associated with inflammation tended to demonstrate regional expression of NOS3. Reactive mucosal lesions, squamous dysplasia, and HNSCCa demonstrated a significant (p < .0001) increase in global expression of NOS3. Therefore, NOS3 is expressed very little in histologically normal squamous mucosa, while squamous hyperplasia, dysplasia, and HNSCCa express significantly more NOS3. Regional variation in NOS3 expression appears to be associated with perilesional inflammation.

Endothelial constitutive nitric oxide synthase (ecNOS) localization in normal and neoplastic salivary tissue

Nitric oxide (NO·) has been implicated in the process of carcinogenesis in various organs. This study was designed to investigate the expression of endothelial constitutive nitric oxide synthase (ecNOS) in normal and neoplastic salivary tissues.

Glutathione S‐Transferase π in Squamous Cell Carcinoma of the Head and Neck

Objectives/Hypothesis Oxidative/reductive (redox) DNA damage from radical species such as nitric oxide (NO·) are increasingly being implicated in the development of cancer. Moreover, redox‐protective cellular mechanisms, such as glutathione S‐transferase, may determine cellular susceptibility to this redox‐mediated damage.

Expression of glutathione S-transferase II in benign mucosa, Barrett's metaplasia, and adenocarcinoma of the esophagus

Glutathione s‐transferase π (GSTπ) is an enzyme that provides cellular protection against redox‐mediated damage by free radicals, which have been implicated in carcinogenesis.

Expression of Nitric Oxide Synthase Type 3 in Reflux-Induced Esophageal Lesions

BACKGROUND: The expression of endothelial constitutive nitric oxide synthase (NOS3) by squamous dysplasia and carcinomas of the head and neck has previously been described. We sought to compare NOS3 expression in squamous mucosa, glandular metaplasia, and adenocarcinoma of the esophagus. METHODS: Forty paraffin-embedded specimens from 20 patients with adenocarcinoma were stained with anti-NOS3 monoclonal antibody. The percentage of cells stained and the intensity of staining were determined for squamous epithelium, metaplasia, and adenocarcinoma. Staining characteristics were statistically analyzed according to clinical variables. RESULTS: NOS3 expression was significantly higher in adenocarcinoma and squamous epithelium compared with glandular metaplasia. Among the carcinomas, larger tumor size (T3/4), nodal positivity, and advanced TNM stage (III/IV) significantly correlated with increased NOS3 expression. CONCLUSIONS: NOS3 is expressed in refluxinduced lesions of the esophagus. Glandular metaplasia shows basal levels of NOS3 that significantly increase with malignant transformation and tumor progression. The role of free radicals in carcinogenesis is being actively studied.

Black thyroid resulting from short-term doxycycline use: case report, review of the literature, and discussion of implications.

Black thyroid pigmentation has been considered pathognomonic for chronic minocycline ingestion for more than 30 years. Although never conclusively linked to overt disease, evidence clearly exists that minocycline is a competitive inhibitor of thyroid peroxidase in metabolically active thyroid tissue. This offers a potential mechanism of pigment accumulation, which can account for the occasional finding of hypopigmentation in thyroid carcinomas. To our knowledge, an association with tetracycline derivatives other than minocycline has not been documented.

Large Vestibular Aqueduct Syndrome Presenting with Mixed Hearing Loss and an Intact Mobile Ossicular Chain

The majority of patients with large vestibular aqueduct syndrome (LVAS) present with progressive sensorineural hearing loss. Some patients with LVAS also have a mixed hearing loss with conduction components ranging from 15 to 40 dB. In this paper, we report a child with LVAS who presented with a moderate mixed hearing loss which appeared following a head trauma. Exploration of the middle ear revealed an intact and mobile ossicular chain. Opening of the inner ear showed a moderate gusher. Aspects of the issue that LVAS might present with a combined sensorineural and conductive hearing loss are discussed.

Glutathione S-Transferase ?? in Squamous Cell Carcinoma of the Head and Neck

Objectives/Hypothesis Oxidative/reductive (redox) DNA damage from radical species such as nitric oxide (NO·) are increasingly being implicated in the development of cancer. Moreover, redox‐protective cellular mechanisms, such as glutathione S‐transferase, may determine cellular susceptibility to this redox‐mediated damage.

Expression of the adenocarcinoma-related antigen recognized by monoclonal antibody 44-3A6 in salivary gland neoplasias

The monoclonal antibody 44-3A6 detects a cell-surface protein that has been shown to be a useful marker in distinguishing adenocarcinomas from other histologic tumor types in a variety of tissues. The objective of this study was to determine whether 44-3A6 could be used as a tool in the classification of salivary gland neoplasms. These complex tumors share overlapping pathologic features but distinct clinical outcomes. This study used 44-3A6 to immunohistochemically describe the pattern and frequency of this antigen in salivary gland neoplasms. Formalin-fixed, paraffin-embedded tissue sections of 22 benign and 26 malignant salivary tumors were evaluated. The patient population consisted of 25 (52.1%) women and 23 (47.9%) men selected from archival pathology files to reflect a range of salivary gland diseases. Normal surrounding salivary glands were found to have intense focal staining almost exclusively localized to ductal luminal cells. There was little staining of either myoepithelial or acinar cells. A wide spectrum of expression was found between and within tumor types, but a trend toward more expression of this antigen with decreasing differentiation was seen. A significant increase in staining was also seen in those tumors with ductal differentiation (n = 41) as opposed to those with predominantly acinar (i.e., acinic cell carcinoma) or myoepithelial (i.e., myoepithelioma; n = 8) differentiation (2.6 vs. 1.3, p < 0.05). No correlation was found between staining intensity and facial paralysis, pain, skin involvement, TNM stage, residual disease, or disease-free or total survival. Therefore this antigen appears to designate a duct luminal phenotype in normal and neoplastic salivary tissues.