Faculty Bibliography

The endogenous peptide endothelin-1 (ET-1), originally identified as a potent vasoconstrictor, plays a role in a number of painful conditions. In this review article we discuss the mechanisms that are essential for local sensitization by subcutaneously administered ET-1, and report evidence of ET-1's ability to sensitize distant regions of the body, through the central nervous system and, likely, coupling through the spinal cord. In addition, we will review the latest information on the role of ET-1 in cancerous and non-cancerous conditions. Cancer pain has indeed been shown to be attenuated by antagonists of endothelin receptors, and ET-1 is known to be secreted by cancer cells of many different histologic types. Furthermore, a growing body of evidence links increased expression and secretion of ET-1 to the occurrence of non-cancer related pain syndromes, such as inflammatory and neuropathic pain syndromes.

Hedgehog signaling is often activated in tumors, yet it remains unclear how GLI2, a transcription factor activated by this pathway, acts as an oncogene. We show that GLI2 is a pleiotropic oncogene. The overexpression induces genomic instability and blocks differentiation, likely mediated in part by enhanced expression of the stem cell gene SOX2. GLI2 also induces transforming growth factor (TGF)B1-dependent transdifferentiation of foreskin and tongue, but not gingival fibroblasts into myofibroblasts, creating an environment permissive for invasion by keratinocytes, which are in various stages of differentiation having downregulated GLI2. Thus, upregulated GLI2 expression is sufficient to induce a number of the acquired characteristics of tumor cells; however, the stroma, in a tissue-specific manner, determines whether certain GLI2 oncogenic traits are expressed

BACKGROUND: Hyalinizing clear cell carcinoma (HCCC) is an uncommon malignant salivary gland tumor that was characterized only recently as a distinct entity. Because of its histologic similarity to several other primary and metastatic tumors and its purported favorable clinical outcome after local resection, it is important to recognize the features of this unusual tumor. METHODS: The authors present 8 new, fully characterized cases of HCCC and systematically reviewed 44 other cases of HCCC reported in the English language literature from 1980 to 2008. Historic cases were reviewed, and available data regarding morphology, special stains, demographics, clinical presentation, radiographic findings, management, and outcomes were extracted. Data from the current series were compared with the earlier published literature. RESULTS: To the best of the authors' knowledge, this was the largest reviewed series of HCCC and included a total of 52 cases. The findings, which included key histologic features, clinical presentation, and outcome, generally were consistent with what was reported previously. However, the current review revealed that 25% of patients reported in the literature had metastatases at initial presentation, including 10 of 44 patients who had metastases to regional lymph nodes and 1 patient who had metastasis to the lung. The authors were unable to identify any specific histologic features that would predict this behavior. CONCLUSIONS: The current results indicated that HCCC is less indolent than was believed previously; therefore, regional lymph node dissection should be considered in conjunction with wide local excision for patients with HCC

BACKGROUND: Tumors involving the parapharyngeal space present a challenge of surgical access. METHODS: We reviewed all parapharyngeal space tumors resected at the University of California, San Francisco, between 2003 and 2006 and identified 14 patients who had a mandibular osteotomy to enhance surgical access to the parapharyngeal space. RESULTS: The surgical approach for the 14 patients who had a mandibulotomy was accomplished via either 1 or 2 mandibular osteotomies. A single paramedian osteotomy between the canine and the first premolar was used in 4 cases, whereas a combination of a horizontal osteotomy above the lingula and a paramedian osteotomy between the canine and first premolar was employed in 8 cases. A lingual dental splint and rigid fixation were used to achieve mandibular stabilization and fixation. CONCLUSION: We found that the single and double mandibular osteotomies provided excellent surgical access allowing for total tumor removal with few sequelae

PURPOSE: To perform methylation array analysis of 807 cancer-associated genes using tissue and saliva of oral squamous cell carcinoma (OSCC) patients with the objective of identifying highly methylated gene loci that hold diagnostic and predictive value as a biomarker. Experimental Design: We did the methylation array on DNA extracted from preoperative saliva, postoperative saliva, and tissue of 13 patients with OSCC, and saliva of 10 normal subjects. We identified sites that were highly methylated in the tissue and preoperative saliva samples but not methylated in the postoperative saliva samples or in normal subjects. RESULTS: High quality DNA was obtained and the methylation array was successfully run on all samples. We identified significant differences in methylation patterns between the preoperative and postoperative saliva from cancer patients. We established a gene classifier consisting of 41 gene loci from 34 genes that showed methylation in preoperative saliva and tissue but were not methylated in postoperative saliva or normal subjects. Gene panels of 4 to 10 genes were constructed from genes in the classifier. The panels had a sensitivity of 62% to 77% and a specificity of 83% to 100% for OSCC. CONCLUSIONS: We report methylation array analysis of 807 cancer-associated genes in the saliva of oral cancer patients before and after oral cancer resection. Our methylation biomarker approach shows the proof of principle that methylation array analysis of saliva can produce a set of cancer-related genes that are specific and can be used as a composite biomarker for the early detection of oral cancer

BACKGROUND: Oral cancer continues to be diagnosed and treated at a late stage, which has a negative effect on outcomes. This study identified and quantified delays in diagnosis and treatment. METHODS: The authors conducted a study that included all new patients seen in the Department of Oral and Maxillofacial Surgery, University of California, San Francisco, between 2003 and 2007 who had a diagnosis of squamous cell carcinoma of the oral cavity. They identified the time intervals for six stages, beginning with the time at which patients first became aware of symptoms and ending with the time at which definitive treatment began. RESULTS: The total time from patients' first sign or symptoms to commencement of treatment was a mean of 205.9 days (range, 52-786 days). The longest delay was from the time symptoms first appeared to the initial visit to a health care professional (mean time, 104.7 days; range, 0-730 days). CONCLUSIONS: Health care professionals need to place greater emphasis on patient education to encourage early self-referrals. CLINICAL IMPLICATIONS: Patients should be encouraged to visit a health care professional when signs or symptoms of oral cancer first develop