Faculty Bibliography

Study purposes were to determine the prevalence of persistent pain in the breast; characterize distinct persistent pain classes using growth mixture modeling; and evaluate for differences among these pain classes in demographic, preoperative, intraoperative, and postoperative characteristics. In addition, differences in the severity of common symptoms and quality of life outcomes measured prior to surgery, among the pain classes, were evaluated. Patients (n = 398) were recruited prior to surgery and followed for 6 months. Using growth mixture modeling, patients were classified into no (31.7%), mild (43.4%), moderate (13.3%), and severe (11.6%) pain groups based on ratings of worst breast pain. Differences in a number of demographic, preoperative, intraoperative, and postoperative characteristics differentiated among the pain classes. In addition, patients in the moderate and severe pain classes reported higher preoperative levels of depression, anxiety, and sleep disturbance than the no pain class. Findings suggest that approximately 25% of women experience significant and persistent levels of breast pain in the first 6 months following breast cancer surgery. PERSPECTIVE: Persistent pain is a significant problem for 25% of women following surgery for breast cancer. Severe breast pain is associated with clinically meaningful decrements in functional status and quality of life.

Targeted therapy to prevent the progression from acute to chronic pain in cancer patients remains elusive. We developed three novel cancer models in mice that together recapitulate the anatomical, temporal, and functional characteristics of acute and chronic head and neck cancer pain in humans. Using pharmacologic and genetic approaches in these novel cancer models, we identified the interaction between protease-activated receptor 2 (PAR2) and serine proteases to be of central importance. We show that serine proteases such as trypsin induce acute cancer pain in a PAR2-dependent manner. Chronic cancer pain is associated with elevated serine proteases in the cancer microenvironment and PAR2 upregulation in peripheral nerves. Serine protease inhibition greatly reduces the severity of persistent cancer pain in wild-type mice, but most strikingly, the development of chronic cancer pain is prevented in PAR2-deficient mice. Our results demonstrate a direct role for PAR2 in acute cancer pain and suggest that PAR2 upregulation may favor the development and maintenance of chronic cancer pain. Targeting the PAR2-serine protease interaction is a promising approach to the treatment of acute cancer pain and prevention of chronic cancer pain.

Approximately half of head and neck carcinomas arise from the oral cavity. Imaging plays an essential role in the preoperative evaluation of oral cavity carcinomas. MR imaging is particularly advantageous in the evaluation of the oral cavity, with better depiction of the anatomy in this region and reduction of dental artifacts compared with CT. MR is also the preferred imaging modality for the evaluation of bone marrow invasion and perineural tumor spread, which are findings critical for treatment planning. Advanced MR imaging techniques may potentially better delineate true tumor extent, determine lymph node metastases, and predict treatment response.

PURPOSE: To compare vascularity and angiogenic activity in aggressive and nonaggressive giant cell lesions (GCLs) of the jaws. MATERIALS AND METHODS: This is a retrospective study of 14 GCLs treated at the University of California, San Francisco. Immunohistochemistry was used to determine of the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), CD34, and CD31. VEGF and bFGF expression in giant cells (GCs) and surrounding mononuclear stroma was classified into 1) high immunoreactivity (>50% staining) and 2) low immunoreactivity (<50% staining). CD31- and CD34-stained vessels were counted at 200x magnification. Clinical and radiographic records were reviewed to classify lesions as aggressive or nonaggressive. RESULTS: Of the lesions, 8 were aggressive and 6 were nonaggressive. High VEGF expression was found within the GCs in 4 of 8 aggressive lesions compared with 1 of 6 nonaggressive lesions. The stroma in both groups had low staining. High staining of the GCs for bFGF was found in 6 of 8 aggressive lesions compared with 3 of 6 nonaggressive lesions. The stroma of all aggressive cases showed high expression of bFGF compared with 3 of 6 nonaggressive cases. The aggressive group had a mean of 20.1 +/- 5.4 vessels/high-powered field (hpf) stained for CD31 compared with 11.5 +/- 5.6 vessels/hpf in the nonaggressive group. The aggressive group had 24.6 +/- 7.0 vessels/hpf stained with CD34 compared with 18.5 +/- 4.0 vessels/hpf in the nonaggressive group. CONCLUSIONS: The vascularity and level of angiogenesis within aggressive GCLs are higher than those in nonaggressive lesions.

Cancer patients often suffer from pain and most will be prescribed mu-opioids. mu-opioids are not satisfactory in treating cancer pain and are associated with multiple debilitating side effects. Recent studies show that mu and delta opioid receptors are separately expressed on IB4 (-) and IB4 (+) neurons, which control thermal and mechanical pain, respectively. In this study we investigated IB4 (+) and IB4 (-) neurons in mechanical and thermal hypersensitivity in an orthotopic mouse oral cancer model. We used a delta opioid receptor agonist and a P2X(3) antagonist to target IB4 (+) neurons and to demonstrate that this subset plays a key role in cancer-induced mechanical allodynia, but not in thermal hyperalgesia. Moreover, selective removal of IB4 (+) neurons using IB4-saporin impacts cancer-induced mechanical but not thermal hypersensitivity. Our results demonstrate that peripherally administered pharmacological agents targeting IB4 (+) neurons, such as a selective delta-opioid receptor agonist or P2X(3) antagonist, might be useful in treating oral cancer pain. PERSPECTIVE: To clarify the mechanisms of oral cancer pain, we examined the differential role of IB4 (+) and IB4 (-) neurons. Characterization of these 2 subsets of putative nociceptors is important for further development of effective clinical cancer pain relief.

The purposes of this study were to determine the occurrence rate for preoperative breast pain; describe the characteristics of this pain; evaluate for differences in demographic and clinical characteristics; and evaluate for variations in pro- and anti-inflammatory cytokine genes between women who did and did not report pain. Patients (n = 398) were recruited prior to surgery and completed self-report questionnaires on a number of pain characteristics. Genotyping was done using a custom genotyping array. Women (28.2%) who reported breast pain were significantly younger (P < .001); more likely to be nonwhite (P = .032); reported significantly lower Karnofsky Performance Status scores (P = .008); were less likely to be postmenopausal (P = .012); and had undergone significantly more biopsies (P = .006). Carriers of the minor allele for a single nucleotide polymorphism in interleukin (IL)1-receptor 1 (IL1R1) (rs2110726) were less likely to report breast pain prior to surgery (P = .007). Carriers of the minor allele for a single nucleotide polymorphism in IL13 (rs1295686) were more likely to report breast pain prior to surgery (P = .019). Findings suggest that breast pain occurs in over a quarter of women who are about to undergo breast cancer surgery. Based on phenotypic and genotypic characteristics found, inflammatory mechanisms contribute to preoperative breast pain. PERSPECTIVE: In women with breast cancer, preoperative pain may be associated with increases in inflammatory responses associated with an increased number of biopsies. In addition, differences in cytokine genes may contribute to this preoperative breast pain.

BACKGROUND: Mandibular osteoradionecrosis is the most devastating complication after radiation therapy for head and neck malignancies. Quality of life (QOL) after surgical treatment is unclear. METHODS: A retrospective cohort analysis (1997-2007) was conducted of all patients treated at our institution for stage II and III mandibular osteoradionecrosis. Nineteen of 35 patients responded to a modified University of Washington QOL questionnaire. Twenty had undergone reconstruction using free flaps, and the remainder with plates, plates and local flaps, or debridement alone. RESULTS: Complications included 3 infections, 5 with hardware, 5 flap-specific, and 1 nonunion. Four patients had recurrent squamous cell carcinoma (SCC). The factors of greatest concern to patients were appearance, swallowing, and chewing. Average overall QOL was good to very good, and very good compared to preoperative. CONCLUSION: Despite a 37% complication rate, a multidisciplinary team approach with adequate debridement, resection, and reconstruction can greatly improve QOL. (c) 2011 Wiley Periodicals, Inc. Head Neck, 2012.

Cancer pain is an ever-present public health concern. With innovations in treatment, cancer patients are surviving longer, but uncontrollable pain creates a poor quality of life for these patients. Oral cancer is unique in that it causes intense pain at the primary site and significantly impairs speech, swallowing, and masticatory functions. We propose that oral cancer pain has underlying biologic mechanisms that are generated within the cancer microenvironment. A comprehensive understanding of key mediators that control cross-talk between the cancer and peripheral nervous system, and possible interventions, underlies effective cancer pain management. The purpose of this review is to explore the current studies on oral cancer pain and their implications in clinical management for cancer pain in general. Furthermore, we will explore the endogenous opioid systems and novel cancer pain therapeutics that target these systems, which could solve the issue of opiate tolerance and improve quality of life in oral cancer patients.

Posterior tongue defects present a unique reconstructive challenge. The various reconstructive options available for treating the defect created by a posterior hemiglossectomy frequently result in a distorted tongue and functional impairment. This paper describes a novel sliding anterior hemitongue flap to allow reconstruction of moderate resection defects (i.e. for T1-T2 tongue squamous cell carcinomas) of the posterior tongue. By mobilizing the anterior tongue, near normal mobility and tongue length are maintained. This surgical technique may be performed alone intraorally or in combination with a neck dissection.