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Interested in ResearchThe Oral and Maxillofacial Surgery Research Reserve Fund, which is supported by a portion of our clinical income, continues to provide seed money for junior and senior faculty members to develop research projects.
Brian Bast
I maintain a clinical practice at both the Parnassus and San Francisco General Hospital sites. I have full time clinical responsibilities five days per week. On the Parnassus campus I am involved with facial and dental reconstruction. My practice is focused on orthognathic surgery, pathology , reconstruction, dental implants and dental alveolar surgery. At the San Francisco General Hospital my clinical practice is focused on facial trauma, pathology, head and neck infections and dental alveolar surgery.Current research projects: University of California, San Francisco. Department of Oral and Maxillofacial Surgery and Department of Psychiatry. ‘’Post Traumatic Stress after Facial Trauma.’’
Radhika Chigurupati
To date I have mainly conducted clinical research in the area of cleft and craniofacial anomalies and pediatric pathology. As part of my efforts to improve my research skills I have completed the clinical research design course in summer 2007 and I wish to enroll in the epidemiology and biostatistics course in following year to gain more skills in clinical research methodology.
Once the UCSF global health sciences program is established for faculty, I wish to enroll in this program to facilitate international collaborative programs. My passion is to improve health care and medical education in the developing regions of the world and I believe the Global health science institute at UCSF will provide an opportunity to develop my skills. As part of my health volunteer activities in the developing world, I would like to research the feasibility of Web based education to establish centers of surgical excellence in the developing world.
Maxillary Hypoplasia In Cleft Individuals: This review was conducted to determine the characteristics of cleft lip and palate individuals that develop severe maxillary hypoplasia and ultimately require surgical correction. The work was performed in collaboration with Dr. Oberoi and Dr. Vargervik craniofacial orthodontists, and was completed in May 2004. The abstract was presented at the Annual American Cleft Palate and Cranicofacial meeting and recently accepted for publication.
Volumetric assessment of alveolar cleft defects with three dimensional imaging techniques using cone-beam CT scan in collaboration with Dr. Oberoi. Research Students: Sylvania Yu and Pawandeep Gill. This outcome study is being conducted to evaluate the efficacy of surgical management of the alveolar cleft defects using 3-D cone beam CT technology. This work is in progress and abstracts have been presented at national and international cleft and orthodontic society meetings. In future we intend to study possibility of use of other materials such as BMP instead of autogenous bone to repair alveolar defects.
A review of pediatric head and neck pathology at UCSF Children’s Hospital was conducted to determine types and frequency of various head and neck lesions –tumors, cysts, developmental and infectious lesions in the different age groups in children. This work was conducted in collaboration with Dr. Richard Jordan and Grace Kim, department of Pathology and I also mentored a summer research student Sophie Yi.
To determine factors contributing to osteonecrosis of jaw bones in patients undergoing chemotherapy in collaboration with Dr. M. Hossaini. Research Student: Tony Li. This chart review was conducted to evaluate potential risk factors and co morbid factors contributing to chemotherapy induced osteonecrosis of the jaw. This project was completed by a summer research student and presented at the dental school research day in 2006.
Other areas of interest and work in progress includes role of Distraction Osteogenesis in Hemifacial Microsomia; Evaluation of jaw growth in non syndromic individuals with Pierre Robin Sequence; and Reconstruction of facial skeletal defects in children after tumor ablation.
Newton Gordon
Our studies on Factors Affecting Dental Postoperative Pain using the third molar (wisdom teeth) patient as the model, began in 1976 and have been funded continuously by the NIH since 1979. In 1994 we perceived that the NIDCR was changing its focus on research projects, and, consequently, switched our proposal to the NINH, which has provided funding since 1994. Our current program entitled “The Role of Gender and Sex Hormones in Opioid Analgesia” is funded until 01/31/07.
Since July 2000 we have published three (3) articles in refereed journals, while several submitted articles are being reviewed.
We are continuing to follow up on our discovery of a significant sex difference in analgesic response to the k-agonist/antagonist class of opioid analgesics. All three clinically available agents in this class (i.e. pentazocine, butorphanol, and nalbuphine) produce significantly greater analgesia in women than in men. In fact, nalbuphine (5 mg) produces greater pain than placebo in men, suggesting the existence of a novel anti-analgesic mechanism for nalbuphine and perhaps for k-agonists/antagonists in general. However, we found that the opioid antagonist naloxone abolished the sex difference and significantly enhanced analgesia in both women and men.
Currently, our studies are aimed at investigating the mechanism by which nalbuphine produces naloxone-sensitive anti-analgesia as well as analgesia. We hypothesize that its analgesic and anti-analgesic effects result from activation of distinct receptor subtypes and that the anti-analgesia receptors are more sensitive to naloxone than the analgesia receptors. The s-receptor is a strong candidate for the anti-analgesia receptor because k-opioids can act at this receptor and in doing so can inhibit their own analgesia or produce anti-analgesia. To test the hypothesis that s-receptors mediate nalbuphine anti-analgesia, we have initiated experiments in which haloperidol, a non-opioid s-receptor antagonist, is administered in combination with nalbuphine. Since haloperidol is also a dopamine D2-receptor antagonist, we will administer another D2-receptor antagonist as a control, chlorpromazine, which is devoid of antagonist properties at either opioid or s-receptors. Finally, in order to ascertain whether the anti-analgesic effect of nalbuphine is a general property of k-agonist/antagonists, we will substitute butorphanol for nalbuphine in some experiments to examine for parallel effects.
Mehran Hossaini
I am a member of the research team, as the primary or co-investigator, for three projects submitted to the Committee on Human Research. Two of these studies have received CHR approval. Additionally, I have been accepted in the Advanced Training in Clinical Research program for the academic year 2006-07. For the upcoming academic year I plan to propose two studies on facial reconstruction and collaborative simulation based learning environment. My continued goal is to increase my participation and effectiveness in the clinical research activities within my department and the university.
Janice Lee
My present clinical practice involves reconstruction of the craniofacial skeleton due to both congenital and acquired defects and deformities. Whether constructing the missing TM joint with a rib graft in a patient with hemifacial microsomia, using iliac crest bone marrow to unify a clefted maxilla (an alveolar cleft), or adding a bovine mineralized bone substitute to augment a sinus for future dental implants, skeletal defects of the craniofacial region require bone grafts and bone substitutes for augmentation. The body cannot naturally fill these bony defects. It is with these clinical problems in mind that my research has centered around bone regeneration. One of the primary areas that I am investigating is the body’s natural ability to form bone. There is only one site that can form bone consistently, that is the rib cage. Though it is well known among surgeons who routinely use this site as a source of bone grafting, it is poorly understood. There are personal accounts and case reports that indicate this consistent finding. One of my studies involves analysis of the bone marrow stem cells from rib grafts that are obtained from patients undergoing this procedure for reconstructive purposes (CHR #H42089-22594-04). The bone marrow stem cells are isolated and the differentiating capabilities are evaluated to determine potential factors that may influence this particular site’s ability to regenerate completely. These sites are also evaluated with quantitative CT over a 6-month period to confirm regeneration. Preliminary results are demonstrating variability of regeneration based on age; this will be correlated with the stem cell characteristics. Further understanding of this unique bone formation may provide opportunities to manipulate bone regeneration at other sites such as the craniofacial region. Most recently, stem cells have been isolated from human exfoliated deciduous teeth (SHED). These stem cells from the dental pulp have demonstrated a surprising ability to induce bone formation in nude mice (Miura et al, PNAS 2003). As noted above, there would be many applications for this unique, expendable source of osteogenic/osteoinductive stem cells. Prior to any therapeutic use, a large animal model will be needed to demonstrate the ability for these stem cells to form bone in clinically relevant defects. Based on my preliminary data demonstrating the same bone-forming ability by stem cells from porcine deciduous teeth transplanted into the nude mouse model, I will evaluate the ability for these stem cells to form bone in the mini-pig that is clinically sustainable and sufficient to be considered for patient application. I have initiated a pilot study involving mandibular defects in the minipig and have been awarded funding (AAOMS/OMSF grant) to pursue this area of research. I plan to submit an NIH grant. The long-term goal is to apply this to patients’ with craniofacial congenital anomalies. My clinical research projects include 3D imaging and analysis to guide skeletal reconstruction of the face, with particular emphasis on correcting facial asymmetry. This is one of the most difficult areas to correct since craniofacial growth is three dimensional. Facial asymmetry is not isolated to the unilateral face but often involves and influences the growth of the “normal” side. An extreme example of craniofacial asymmetry is seen in patients with hemifacial microsomia. Though this condition primarily involves the condyle, mandible, ear, soft tissue and CN VII on one side of the face, the skull base, maxilla, and contralateral mandible are also deformed and the extent of this is only truly appreciated on 3D imaging. Analysis with this new modality and technique will help to understand the condition and also provide better surgical treatment planning and reconstruction of the craniofacial skeleton. Within the area of facial reconstruction, I will also be initiating several studies on ethnic variations and influences on surgical management for ethnic minorities. With a clinical research team including a former resident of our program and current residents (one of whom has enrolled in the MS program for clinical research), we will begin evaluating the role of orthognathic surgery for Asian-Americans and Middle Eastern patients. There is currently very little in the literature regarding the appropriate management for these groups.
Jon Levine and Newton Gordon
Analgesic Treatment of Dental Postoperative Pain; Influence of Gender on Pain and Analgesia.
Acute orofacial pain that accompanies pathologic conditions in the teeth, gingival, face and associated structures is probably the most common pain experienced. Our research in this area is aimed at investigating the therapeutic potential of analgesic synergy in the treatment of acute pain, employing a model of postoperative dental pain. Based on current understanding of the actions of opiates of different classes, and of the interaction of elements of endogenous pain control circuits, we have chosen combinations of opiates with other agents that affect pain pathways interacting with endogenous control circuits.
The knowledge obtained from animal experiments on pain, analgesia and inflammation is employed to help design clinical studies of novel modalities for pain management. A well-established model of subacute postoperative dental pain after third molar extraction is used. The Oral and Maxillofacial Surgery model has been used both to understand neuroendocrine changes associated with trauma, stress and pain of surgery as well as to allow for the evaluation of new analgesic therapies in man. In these patients combinations of agents are investigated for analgesic synergy. We have demonstrated in a prospective study that the kappa-opioid class of analgesic (pentazocine, nalbuphine, and butorphanol) are much more effective in women than in men with dental postoperative pain and that nalbuphine is anti-analgesic effect of low dose nalbuphine, such that the combination produced potent analgesia in both men and women. Further experiments will investigate mechanisms underlying the sexual dimorphism in analgesic response.
Neural Mechanisms of Pain and Hyperalgesia.
It has been estimated that 80% of visits to physicians are motivated by either acute or chronic pain and chronic pain alone has been estimated to cost our society over $50 billion annually in time from lost work. Currently available therapies are still unable to manage symptoms in a relatively large percentage of patients with these conditions. To help address this problem, this ongoing research project is studying the mechanisms of pain and hyperalgesia (tenderness) with trauma and inflammation.
We study mechanisms involved in the mechanical sensitization of the rat primary afferent nociceptor. In particular, we evaluated the role of different second messenger pathways in inflammatory hyperalgesia and in rats with experimental diabetes. Two new second messenger pathways mediating pain in primary afferent nociceptors were discovered. Finally, models of neuropathic pain, associated with administration of the chemotherapeutic agents for AIDS and alcohol abuse, have been established and experiments initiated to elucidate underlying mechanisms.
Jon Levine
My laboratory employs a multidisciplinary approach: molecular, biochemical, in vitro and in vivo electrophysiological and behavioral techniques are employed to evaluate mechanisms underlying pain, analgesia and inflammatory states. I am investigating signal transduction mechanisms for mechanical, thermal and chemical stimulus-induced activation of sensory neurons and mechanisms underlying sensitization of responses to these stimuli. We have described novel transducer mechanisms for thermal stimuli. We have also described a second messenger pathway mediating sensitization. We have demonstrated recently, using knockout mice, a novel role for the epsilon isoform of PKC in mediating nociception. We have also recently developed the first in vitro model for study of mechanical transduction in somatosensory neurons. We are in the process of developing a model for the development of a propensity for a chronic inflammatory pain state after a period of resolved acute inflammation. I also investigate circuits that mediate analgesia and have described a novel analgesia circuit involving limbic pathways. Recently we demonstrated that a sufficiently intense painful stimulus results in a prolonged period of heterosegmental antinociception that depends on mechanisms of the mesolimbic dopaminergic reward pathway. The modulation of transduction in the periphery, by opioids, is also being investigated, including the mechanisms underlying opioid tolerance and dependence for peripheral antinociception. I am investigating neural and endocrine contributions to inflammation and to the immune response. We have elucidated a physiological mechanism consisting of a negative feedback inhibition of the inflammatory response, involving neural and endocrine circuits. Shedding of the neutrophil adhesion molecule L-selectin plays a critical role in this feedback inhibition as well as action locally of annexin. We have also recently investigated effects of nicotine on inflammation, at very low dose, relevant to both smokers and individuals exposed to secondhand smoke. In a recent study we demonstrated that stress, when introduced chronically, intermittently, is be a potent modulator of inflammatory response. The roles of the individual stress axes (HPA, sympathoadrenal and sympathetic) are investigated. Our laboratory has an emerging interest in developing and understanding mechanistically, animal models relevant to the major neuropathies experienced in clinical medicine. We have demonstrated alterations in electrophysiological and cellular second messenger response in models of diabetes and chemotherapy-induced neuropathy. We are presently embarking on the establishment of a model for painful alcoholic neuropathy. We also have had a longstanding interest in the roles of the different adrenergic receptors in sympathetically-maintained pain models. Finally, we have, in both experimental and clinical studies demonstrated a profound role of gender and often sex hormones in nociception and anti-nociception, including that mediated by opioids of different receptor class. We also have demonstrated marked effects of gender for the influence of vagal afferent activity on processing of nociceptive stimuli, both acutely and tonically.
Charles McNeill
Dr. McNeill continues as the Course Director for the Dental Sciences 128 course on neuromuscular function and dysfunction for the second year dental students. The 40 hour course includes the anatomy, physiology and pathology of the stomatognathic system including orofacial pain emphasizing temporomandibular and cervical disorders. Also, he lectures in the Patient Centered Care courses on occlusion, intraoral appliances and neuropathic pain. He continues to give presentations at National and International symposia and various other meetings and congresses. Dr. McNeill was recently recognized by the American Academy of Oral Medicine as a Honorary Member for his role in applying the medical model to the management of Orofacial Pain.
Dr. McNeill is the co-editor of the recently published TMJ Atlas by eHuman on a virtual 3-D anatomical imaging and animation of the TM Joint and surrounding structures including the muscles of the head and neck with mandibular movements and the dental occlusion. It is a NIH funded grant with Stanford University’s Department of Anatomy; Project #5 - R44 DE014944-04 Brown (PI), dates 7/1/04-6/31/2007. Source: NIH/National Institute of Dental & Craniofacial Research (Budget- $877,798 Title: A 3-D Interactive Atlas of the Maxilla, Mandible and TMJ C McNeill, C Goodacre, P Brown, E Herbranson).
Lastly, Dr. McNeill is collaborating with Dr. Rudd and Dr. Miller on a retrospective two year chart review (July 2005 to June 2007) to assess the prevalence of cervical signs and symptoms in patients only evaluated by him seeking treatment in an orofacial pain center. The study is also comparing the treatment outcomes of the various management protocols. The second aim of the study is to assess patient self-reported neck pain outcomes after treatment in an orofacial pain center. The funding source for the physical therapy arm is the existing Eugene Dyer Memorial Fund (R4408).
My research is currently mainly clinical and translational in nature and covers both clinical trials and evaluation of surgical treatments. Among my current research interests which have led to publications in peer-reviewed journals are:
Areas of expertise include
Patricia Rudd
Ms. Rudd provide rehabilitation for orofacial pain patients in the Center for Orofacial Pain. She also co-directs the orofacial pain course DS 128 for 2nd year dental students. She teaches residents at UCSF and practicing dentists nationally and internationally on the subject of orofacial pain, rehabilitation and cervical spine influences. In May 2008, she completed the doctor of physical therapy at Pacific University. She is a founding board member for the international Physical Therapy Board of Craniofacial and Cervical Therapeutics (PTBCCT). Her research areas include the prevalence of cervical disorders in the orofacial pain population at UCSF. Preliminary findings show 85% of these patients presented with significant cervical muscle tenderness. Furthermore, the patients with primary complaints of jaw pain were three times more likely to have cervical muscle tenderness as compared to other head and neck complaint groups. Future investigation is looking at specific and combined treatment efficacies for individual diagnostic groups in the orofacial pain population.
Brian Schmidt
My clinical practice is focused on the surgical management of patients with oral squamous cell carcinoma. My research and clinical programs are closely integrated and my research addresses the two clinical challenges I face in the management of these patients. I have had a long standing interest in the neurologic basis and treatment of cancer pain. Since my recruitment to UC San Francisco in 2002, I have gained experience in the area of cancer genomics and expanded my long term research program to include development of molecular diagnostics for use in the treatment of oral cancer patients.
Oral Cancer Biomarkers
Oral cancer is well known for its capricious clinical behavior. Oral squamous cell carcinoma remains a significant health problem. The 5-year survival rate, at 40%, is among the worst of all sites in the body and has not improved over the past 40 years. In the USA more people die from oral cancer than melanoma, cervical or ovarian cancer. The two issues affecting outcome and survival are delay in diagnosis and metastasis. We have been using a genomic approach to identify genomic markers that could be used to understand progression of premalignant lesions and predict metastasis. We have employed array comparative genomic hybridization to analyze oral squamous cell carcinoma specimens for characteristic genetic gains and losses. Array comparative genomic hybridization detects and maps DNA sequence copy number variation throughout the entire genome. The advantage of this approach is that in addition to providing entire genome coverage, the analysis can be performed on formalin fixed specimens.
The first step we took in discovering new key steps in oral carcinogenesis, as well as identifying genomic markers for metastasis was to analyze 89 oral cavity squamous cell carcinoma specimens with array comparative genomic hybridization. This work required two years and culminated in a 2005 Oncogene publication and it is the largest series of oral squamous cell carcinomas using array comparative genomic hybridization.
This genomic work has provided me and other investigators with insight into oral carcinogenesis and pointed the way to potentially fruitful avenues for further investigation. However, the primary directive with my genomic work has been to identify markers that can be used in predicting metastasis and guiding treatment. Neck metastasis is the most significant clinical factor responsible for death from oral squamous cell carcinoma. The metastatic behavior of oral squamous cell carcinoma is highly variable and there is not a clinical, histologic or molecular method to determine which oral squamous cell carcinomas will metastasize. Because of its unpredictable nature many patients with oral cancer are either under- or over-treated with a neck dissection and radiation therapy.
I am proposing to find molecular markers in oral squamous cell carcinoma that could be used to predict metastasis. I have developed a comprehensive step-wise approach designed to converge on a small set of informative markers that discriminate between oral squamous cell carcinomas with and without metastatic potential. These steps will provide a better understanding of the genetics of oral squamous cell carcinoma and will result in a composite molecular marker for assessing metastatic potential of oral squamous cell carcinomas. I am the principal investigator for this project which has been funded through the NIH/NCI (1R01CA113833-01A2). If the approach outlined here is successful, then this project provides the foundation for a larger study in a prospective cohort of patients that may allow for routine implementation of the composite molecular marker in clinical practice to distinguish between non-metastatic and metastatic oral squamous cell carcinomas. Because the marker developed in this study will be based on genetic changes the study will also provide functional insight into oral carcinogenesis and metastasis.
The laboratory has been aggressively pursing a salivary biomarker that could be used for the early diagnosis of oral cancer. Oral health care professionals could drastically improve quality of life for patients with potentially malignant oral lesions by using a non-invasive test that could be used to detect cancer using saliva. We have been investigating protein markers as well as epigenetic events that could be detected in the saliva of oral cancer patients. We published a pilot study demonstrating that endothelin levels are significantly increased in the saliva of oral cancer patients (Pickering V, Jordan RCK, Schmidt BL. Elevated salivary endothelin levels in oral cancer patients – a pilot study. Oral Oncology 43:37-41, 2007). To further explore endothelin as a potential biomarker we have been awarded a $55,000 Research Support Grant through the Oral and Maxillofacial Surgery Foundation. We have also been looking at gene promoter methylation levels in the saliva of oral cancer patients. Promoter DNA hypermethylation is a critical step in oral carcinogenesis. In fact, epigenetic silencing events (i.e. promoter hypermethylation) are more frequent mechanisms of gene silencing than genetic changes making it a more attractive diagnostic marker than detecting a genetic mutation or measuring gene expression. The loss of gene expression is a negative biologic event. For a diagnostic test to be implemented clinically the test must detect a positive event. We were the first to quantitatively measure promoter methylation levels in the saliva of oral cancer and dysplasia patients. This pilot study was published in the Journal of the California Dental Association in December, 2007. We next used the Illumina Methylation Array to analyze the saliva of oral cancer patients before and after cancer resection. We were the second group in the country to use this array and the first to use it on oral cancer specimens. This work was funded by a $75,000 Research Support Grant through the Oral and Maxillofacial Surgery Foundation. The manuscript describing this work was published in Cancer Epidemiology, Biomarkers and Prevention.
Oral Cancer Pain
For head and neck cancer patients, pain is the primary determinant of a poor quality of life, and is rated by 35-40% of oral cancer patients as the worst symptom. Quality of life studies have demonstrated the significant impact oral cancer pain has on mood, interpersonal relations and oral function. More specifically, in the final period of life, pain is their most common problem and is reported in 85% of this group. While pain is one of the primary concerns for oral cancer patients, there has almost been no research conducted to specifically address the underlying etiology of oral cancer pain or to develop a model that could be used to study the etiology and therapeutic approaches for oral cancer pain. The goal of this portion of my research program is to identify the source of oral cancer pain and to develop therapeutic strategies aimed at improving the quality of life for patients with oral cancer.
The overall strategy that I have developed to investigate, understand and treat oral cancer pain integrates my clinical practice and laboratory research program. This strategy is based on the following steps:
I have spent the last four years since my recruitment to UCSF developing each phase of this approach. As of 2004 there was not an instrument or questionnaire available to quantify pain in patients with oral cancer pain. Therefore, I developed, tested and published the UCSF Oral Cancer Pain Questionnaire (Connelly ST, Schmidt BL. The evaluation of pain in patients with oral squamous cell carcinoma. Journal of Pain, 5:505-510, 2004). The questionnaire consists of 8 items on a visual analogue scale, with a scale 0-100 mm, rated by the patient. The design of the questions is aimed at targeting function-related and spontaneous pain experienced by oral cancer patients and addressing the nature and quality of pain. The functional restrictions of eating, drinking and swallowing are also evaluated. The questionnaire is designed to be short and easily self-administered. We have now validated the questionnaire (Kolokythas A, Connelly ST, Schmidt BL. Validation of the University of California San Francisco Oral Cancer Pain Questionnaire. Journal of Pain, 2007.) As part of the second phase I have analyzed resected cancer specimens from my patients and attempted to discover pain-producing proteins and correlate those levels with pain. I have used this approach to demonstrate that inducible nitric oxide synthase (iNOS) is a likely protein contributing to cancer pain (Connelly ST, Macabeo-Ong M, Dekker N, Jordan RCK, Schmidt BL. Increased nitric oxide levels and iNOS over-expression in oral squamous cell carcinomas. Oral Oncology 41:261-7, 2005). Cancer pain is most likely generated by mediators that are produced and then secreted into the extracellular environment where they sensitize or activate peripheral sensory fibers. I have been concerned that the traditional approach of analyzing resected specimens I might be missing a key mediator. To address this potential problem I have recently developed a technique where I perform intraoperative, in vivo microdialysis within the oral cancer specimen to identify potential pain producing mediators that are secreted by the cancer. Most patients with oral cancer require a neck dissection in addition to resection of the oral cancer. At the beginning of my operations for oral cancer patients I place a microdialysis probe into the cancerous lesion as I complete the neck dissection which typically requires 4-5 hours. During this time I am collecting the extracellular fluid in the cancer microenvironment. This approach to analyzing proteins produced by cancer has not been previously published. The advantages to this approach are numerous and will provide for the first time real-time, in vivo, in situ measurement of secreted proteins. I then use HPLC and mass spectrometry to identify and measure protein levels and attempt to correlate with patients’ reported pain levels. I have received a $40,000 Pilot Award in Clinical and Translational Research by the UCSF Clinical and Translational Science Institute-Strategic Opportunities Support Center to further explore this approach for identifying pain producing mediators in the tumor microenvironment.
In the third phase of this approach I use a mouse model of cancer pain that I have developed to test the role of the mediators identified to test for analgesic therapies. Using the mouse model we have demonstrated and published for the first time that endothelin, a vasoactive peptide, acts peripherally in the tumor microenvironment to produce cancer pain rather than at the central nervous system. We were also the first to demonstrate that endothelin contributes to oral cancer pain and that cancer pain can be significantly attenuated with an endothelin antagonist. In my laboratory we work with many types of cancer besides oral cancer including breast, prostate, ovarian and melanoma; therefore, we are gaining information on cancer pain in general, as well as, head and neck cancer pain. This work has been funded for the last four years through the Tobacco Related Disease Research Program (12 KT-0166).
The animal model that we have used to date is a well-established, validated rodent paw withdrawal model that we have modified to measure cancer pain. While this model is appropriate for studying peripheral mechanisms of cancer pain we are also interested in understanding how pain disrupts oral function. We and others have shown that oral cancer patients have significant debilitation of chewing and oral function secondary to pain. Because half of all head and neck cancers are incurable and many patients suffer from intractable cancer pain for extended periods, there is a critical need for an oral assay to investigate the etiology and impact of cancer pain on oral functioning. We have designed, custom built and pilot tested a novel device that objectively quantifies oral function in rodents. Studies on patients with chronic orofacial pain have demonstrated that the duration of chewing is critical for determining the amount of pain that patients experience. Current orofacial pain assays for rodents do not parallel the oral functions that elicit pain in patients with chronic orofacial pain. To parallel the human condition we have carefully designed the device to measure the duration of gnawing required to complete a discrete task. The apparatus is called a dolognawmeter (dolor for pain; gnawmeter for the measurement of gnawing). Animals that are placed into the device perform a masticatory function analogous to the behavior that elicits pain in chronic orofacial pain patients. We are currently validating the device for the study of head and neck cancer pain. We also submitted a grant proposal based on this device to the NIH to specifically address the major goals of the NIH/NIDCR RFA-DE-07-007. We have been awarded this grant and I will be serving as principal investigator (NIH/NIDCR R21 DE018561). The patent application for this device has been filed.
The above strategy is designed to provide a method for the investigation of analgesic strategies that would subsequently be tested in human clinical trials. Pharmacologic testing in animal models that demonstrates functional improvement will set the stage for human clinical trials evaluating novel therapeutic approaches in patients with cancer pain.
Rebeka G. Silva
As Chief of the Dental Service and Chief of the Oral and Maxillofacial Surgery Section at the VA Medical Center, Dr. Silva works closely with OMS residents. In the past, she participated in large scale VA Cooperative Studies in Dental Implants and Oral Cancer and residents regularly participated in the evaluation and treatment of study patients. She also published a study based on over 500 patients entitled "Prevalence of Malocclusion Among Latino Adolescents" in the American Journal of Orthodontics and Dentofacial Orthopedics. Dr. Silva was also part of a group of investigators that had a poster entitled "Awareness of Premalignant Oral Lesions Among U.S. Veterans" presented at the 2002 meeting of the International Association of Dental Research/American Association of Dental Research, San Diego, CA. Presently, she is co-PI with the Palo Alto VAMC in a study entitled “Advanced Visuohaptic Planning for Trauma Surgery”. The research goal is the development and evaluation of a computational software tool for planning of interventions for reconstructive trauma surgery. The research is pending final ERB approval at this time. Future projects will also include testing of new bio-adhesive products in oral surgery applications, including the prevention of dry sockets. For VA Quality Improvement projects, Dr. Silva designed a performance improvement project evaluating patient waiting time at the VA for oral surgery consultations and procedures in order to identify the reasons for delayed care. The VA’s on-going extensive experience with the placement and restoration dental implants will lead to improvements in the existing database. Future research regarding implant outcomes is anticipated.
Richard A. Smith
Clinical Study Implant Stability Evaluation Using Resonance Frequency Analysis with the Ostell Mentor and custom transducer; co-Principal Investigator
Quality Assurance/Improvement Studies
Research and Development
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