Faculty Bibliography

Cancers often cause excruciating pain and rapid weight loss, severely reducing quality of life in cancer patients. Cancer-induced pain and cachexia are often studied and treated independently, although both symptoms are strongly linked with chronic inflammation and sustained production of proinflammatory cytokines. Because nerve growth factor (NGF) plays a cardinal role in inflammation and pain, and because it interacts with multiple proinflammatory cytokines, we hypothesized that NGF acts as a key endogenous molecule involved in the orchestration of cancer-related inflammation. NGF might be a molecule common to the mechanisms responsible for clinically distinctive cancer symptoms such as pain and cachexia as well as cancer progression. Here we reported that NGF was highly elevated in human oral squamous cell carcinoma tumors and cell cultures. Using two validated mouse cancer models, we further showed that NGF blockade decreased tumor proliferation, nociception, and weight loss by orchestrating proinflammatory cytokines and leptin production. NGF blockade also decreased expression levels of nociceptive receptors TRPV1, TRPA1, and PAR-2. Together, these results identified NGF as a common link among proliferation, pain, and cachexia in oral cancer. Anti-NGF could be an important mechanism-based therapy for oral cancer and its related symptoms

Contrary to a clinical aphorism that early head and neck cancer is painless, we show that patients who develop head and neck cancer experience significant pain at the time of initial diagnosis. We compared orofacial pain sensitivity in groups of patients with normal oral mucosa, oral precancer, and newly diagnosed oral cancer. The University of California San Francisco Oral Cancer Pain Questionnaire was administered to these patients at their initial visit, before being prescribed analgesics for pain and before any treatment. In contrast to those with biopsy-proven normal oral mucosa and oral precancer, only oral cancer patients reported significant levels of spontaneous pain and functional restriction from pain. Moreover, oral cancer patients experienced significantly higher function-related, rather than spontaneous, pain qualities. These findings suggest an important predictor for the transition from oral precancer to cancer may be the onset of orofacial pain that is exacerbated during function. Screening patients who have new-onset orofacial pain may lead to a diagnosis of early resectable head and neck cancer and may improve quality of life and survival for head and neck cancer patients. An important predictor for the transition from oral precancer to oral cancer may be the onset of orofacial pain that is exacerbated during function

BACKGROUND AND PURPOSE: Small oral cavity tumors are an imaging challenge. Intimate apposition of vestibular oral mucosa to the alveolar mucosa makes tumor assessment difficult. In CT imaging, the 'puffed cheek' method has been used to separate surfaces, though this is not feasible with long MR imaging sequences. We implemented placement of 2 x 2 inch (6.45 cm) gauze into the oral vestibule before the MR imaging examination, to determine whether this might improve tumor visualization. MATERIALS AND METHODS: MR imaging examinations of all T1 oral malignant tumors treated at University of California, San Francisco, by the Oral and Maxillofacial Department were reviewed by 2 neuroradiologists. Nine patients were included in the final analysis. Six patients were imaged by using a standard protocol. Three patients were imaged with gauze placement. The radiologists evaluated the MR images, assessing whether they could see the tumor and then fully delineate it and its thickness. RESULTS: Fisher exact analysis was performed on questions 1, 2, and 4 with the following results: P value = .048, Can you see the tumor? P value = .012, Can you fully delineate? P value of .012, How confident are you? MR imaging examinations with gauze clearly delineated the tumor with the tumor thickness measurable. MR imaging examinations without gauze did not clearly show the tumor or its thickness. Confidence of interpretation of the findings was also increased when gauze was used. CONCLUSIONS: A 2 x 2 inch (6.45 cm) rolled gauze in the oral vestibule significantly improved tumor localization and delineation at MR imaging. This technique is simple and provides superior preoperative imaging evaluation and treatment planning of small oral cavity tumors

We investigated the effects of cannabinoid receptor agonists on (1) oral cancer cell viability in vitro and (2) oral cancer pain and tumor growth in a mouse cancer model. We utilized immunohistochemistry and Western blot to show that human oral cancer cells express CBr1 and CBr2. When treated with WIN55,212-2 (non-selective), ACEA (CBr1-selective) or AM1241 (CBr2-selective) agonists in vitro, oral cancer cell proliferation was significantly attenuated in a dose-dependent manner. In vivo, systemic administration (0.013M) of WIN55,212-2, ACEA, or AM1241 significantly attenuated cancer-induced mechanical allodynia. Tumor growth was also significantly attenuated with systemic AM1241 administration. Our findings suggest a direct role for cannabinoid mechanisms in oral cancer pain and proliferation. The systemic administration of cannabinoid receptor agonists may have important therapeutic implications wherein cannabinoid receptor agonists may reduce morbidity and mortality of oral cancer

BACKGROUND: Surgical resection of oral cancer can be associated with significant postoperative cardiovascular and respiratory complications that require more sensitive predictors. METHODS: All patients with oral squamous cell carcinoma treated from July 2005 to April 2008 were retrospectively reviewed. The Goldman Revised Cardiac Risk Index (GRCRI) was used to predict cardiovascular complications. Other evidence-based a priori predictors were applied in an h-fold cross-validation model. RESULTS: Operating room (OR) time was an independent predictor of cardiovascular complications (odds ratio = 1.54, p = .002, 95% confidence interval [CI] = 1.18-2.02) and respiratory complications (odds ratio = 1.3, p = .06, 95% CI = 0.99-1.64) after multivariate adjustment. OR time and estimated blood loss predicted cardiovascular complications with 73% sensitivity. The GRCRI achieved 37% sensitivity. OR time and tracheostomy predicted respiratory complications with 75% sensitivity. CONCLUSIONS: The GRCRI was not prognostic for cardiovascular complications in patients with oral cancer. The most sensitive predictors for cardiovascular complications were OR time and estimated blood loss; for respiratory complications they were OR time and tracheostomy

Completion of the human genome project approximately 15 years ago was followed closely by advancements in array technology. Investigators quickly applied this new powerful tool to the genomic and proteomic study of oral squamous cell carcinoma (OSCC). Resultant publications documented chromosome, gene, mRNA, and protein alterations that characterize oral cancer. In this review, we summarize how the genomic, proteomic, and epigenetic array studies have provided insight into the process of oral carcinogenesis. We discuss the significant limitations and requirement for validation of these array studies. We also review the manner in which state-of-the-art, high-throughput approaches are being used to search for salivary and serum oral cancer biomarkers

We previously reported that endothelin A (ET-A) receptor antagonism attenuates carcinoma-induced pain in a cancer pain mouse model. In this study, we investigated the mechanism of ET-A receptor-mediated antinociception and evaluated the role of endogenous opioid analgesia. Squamous cell carcinoma (SCC) cell culture treated with the ET-A receptor antagonist (BQ-123) at 10(-6) M and 10(-5) M significantly increased production and secretion of beta-endorphin and leu-enkephalin, respectively. Behavioral studies were performed by inducing tumors in the hind paw of female nude mice with local injection of cells derived from a human oral SCC. Significant pain, as indicated by reduction in withdrawal thresholds in response to mechanical stimulation, began at 4 days after SCC inoculation and lasted to 18 days, the last day of measurement. Local administration of either naloxone methiodide (500 microg/kg), selective antagonists for mu-opioid receptor (CTOP, 500 microg/kg), or delta-opioid receptor (naltrindole, 11 mg/kg) but not kappa-opioid receptor (nor-BNI, 2.5 mg/kg) significantly reversed antinociception observed from ET-A receptor antagonism (BQ-123, 92 mg/kg) in cancer animals. These results demonstrate that antagonism of peripheral ET-A receptor attenuates carcinoma pain by modulating release of endogenous opioids to act on opioid receptors in the cancer microenvironment. PERSPECTIVE: This article proposes a novel mechanism for ET-A receptor antagonist drugs in managing cancer-induced pain. An improved understanding of the role of innate opioid analgesia in ET-A receptor-mediated antinociception might provide novel alternatives to morphine therapy for the treatment of cancer pain