MUSC research shines at cancer conferenceby Heather WoolwinePublic Relations Members of MUSC’s Head and Neck Tumor Program attended the Sixth Annual International Conference on Head and Neck Cancer, Aug. 7 through 11, and delivered an unprecedented 12 presentations on behalf of research conducted at MUSC. “The fact that there are so many presentations coming from MUSC speaks volumes about the university’s influence and research expertise in this area,” said Michael Rossi, M.D., a former MUSC student currently a resident in the Department of Otolaryngology, University of Pittsburgh. “It’s a testament to how excited Dr. Day got everyone about participating in the conference.” One of Terry Day’s studies involved a survey of oral and head and neck cancer knowledge among the U.S. public. Day, M.D., is associate professor and director of Head and Neck Oncology Surgery and vice chair for clinical affairs in the Department of Otolaryngology. “Among head and neck cancers, oral cancer represents the most common type, with laryngeal cancer second in prevalence in the United States,” he said. “Over the past several decades, head and neck cancers (HNC) have been diagnosed in advanced stages of disease, resulting in minimal improvement in survival … The objectives of this study were to assess the knowledge, opinions, and practices of Americans regarding HNC prevention and early detection and compare the high-risk groups (tobacco and alcohol users) to the general population in knowledge of HNC.” Researchers used a telephone survey to ask participants questions about self-perceived knowledge concerning early signs, symptoms, and risk factors for HNC. A total of 1,013 respondents were analyzed, and the results revealed that only 5 percent of the total respondents considered themselves extremely or very knowledgeable about these cancers. When asked about early symptoms of HNC (a red and white patch in the mouth that does not heal for oral cancer and hoarseness for laryngeal cancer), only 2 percent of the total respondents and even fewer of tobacco users (1 percent) responded accurately. “The general public is not knowledgeable about HNC, and high risk groups seem particularly uneducated about the risk factors and early signs and symptoms of these cancers,” Day said. “Future education programs should be directed toward educating the public at high risk for developing cancer of the oral cavity and larynx.” Looking at the Treatment of Head and Neck Cancer
Day presented the prelimanry results of the phase one study utilizing the agent in HNC. “Since the drug is given by direct intra-tumoral injection, HNC is a convenient target, as many lesions are visible and usually accessible for therapy,” Day said. “We sought to determine the maximum tolerated dose of M4N administered weekly and intralesionally to patients with inoperable but accessible HNC, refractory to radiation and/or chemotherapy. We were also interested in the feasibility of administering multiple doses of M4N, the toxicity of M4N, the pharmacokinetic parameters of M4N, and for signs of efficacy of the regimen.” A total of eight patients participated, with seven completing the study. M4N administration produced visible tumor necrosis in six of the seven patients who completed the study. And the maximum dose wasn’t directly associated with systemic side effects. (Adverse events in patients with advanced and recurrent head and neck cancer commonly occur making association with the drug difficult to assess.) In a third presentation by Day he explained that the treatment of HNC evolved to include an expanding role of chemotherapeutic agents, but the selection of an agent in recurrent HNC following prior surgery, radiation therapy, and/or chemotherapy remains difficult. “The identification of the sensitivity of an individual tumor to each chemotherapeutic prior to treatment would provide the advantage of directing the ideal agent at a specific tumor and potentially limiting more toxic agents deemed ineffective,” Day said. “This study was developed to see if HNC specimens could be analyzed in vitro against a variety of known chemotherapeutics. We also wanted to analyze the clinical response to standard chemotherapeutic agents compared to the chemosensitivity identified in vitro in the same patients with advanced, recurrent or metastatic primary HNC.” The investigations concluded that improved techniques of decontamination improved in vitro growth of HNC cells, chemosensitivity testing using the ChemoFx Assay can be successfully performed in the majority of cases of head and neck cancer, and clinical correlation of in vitro results with clinical outcomes will require further study. Anand Sharma, M.D., Radiation Oncology, discussed radiation treatment in patients with HNC. “Locally advanced HNC patients who achieve CR after definitive CCRT have better loco-regional control and survival,” he said. “However, patients with partial response, minor response or progressive disease at the end of definitive non-surgical therapy are likely to have poorer local control and survival after salvage surgery. If good responders can be objectively identified early during CCRT, poor responders or non-responders can be offered salvage treatment earlier with at least lower likelihood of surgical morbidity and possible improvement in outcome.” Studies in Ogretmen’s lab focused on uncovering the role of bioactive sphingolipids in the pathogenesis and treatment of HNC. Telomerase is an enzyme that regulates the proliferation of cancer cells and is not expressed in most normal cells, so compounds that target this enzyme may potentially be used as therapeutic agents for the treatment of HNC, with overall less toxicity. Rossi’s presentation demonstrated the roles of recently developed ceramide analogs in the inhibition of telomerase in HNC cells both in vitro and in vivo. Rossi said that these novel ceramide compounds are now under pre-clinical study and should be tested on humans in the future. Koybasi presented data that showed a role for a specific endogenous ceramide, a tumor suppressor lipid, in the inhibition of growth of human HNC cells. A defect in the generation of this specific ceramide exists in the tumor tissues of patients with HNC. Her data implicated that while altered generation of this ceramide might be involved in the pathogenesis/progression of tumors, enhancing its generation could thus inhibit tumor growth in patients with HNC. “We have developed a very strong team which includes excellent clinical and basic scientists working together for the development of mechanism-based therapeutic approaches for the treatment of HNC,” Ogretmen said. “Our primary goal is to take this mechanistic knowledge and use it in clinics as efficiently as possible. I think we’re on the right track.” Part of learning how to better treat HNC is learning how tumors and the blood vessels that fuel them operate and disable the immune system. “Our research studies conducted in a mouse tumor model demonstrate that tumors produce factors that selectively alter the immune cells recruited into the tumor,” Lathers said. “The cells recruited are less effective against the tumors. This work is important basic research as it investigates one mechanism tumors use to subvert immune responses.” Young’s studies sought to determine how tumors direct the differentiation of progenitor cells into peripheral blood and tumor tissue. Using the Lewis lung carcinoma model, in vitro studies showed that tumor cells chemo-attract progenitor cells through production of VEGF. In vivo studies showed that infusion of progenitor cells into tumor-bearing mice resulted in the accumulation of progenitor cells within the tumor mass. “These studies demonstrate the capacity of a tumor to attract progenitor cells to the tumor site and to then direct the differentiation of these cells into endothelial cells that can become a component of the tumor vasculature,” Young said. “The implication of these results is that tumor treatment approaches to block tumor vascularization need to target vasculogenesis, not only angiogenesis.” HNC, Breathing and Swallowing
With these patterns defined, other investigators can compare them to different disease populations known to have swallowing problems as a serious consequence of their disease or treatments, like HNC patients. “HNC treatments have the potential for and often do cause serious swallowing problems that lead to poor nutrition, aspiration of food/liquid into the lungs, and may be life threatening,” Martin-Harris said. “Breathing and swallowing patterns differ in these patients, and we studied the relative contribution of the aberrant breathing and swallowing patterns to their overall swallowing impairment and functional outcome. We also studied if some cancer treatments (chemotherapy plus radiation) cause more or less aberration than the other standard of care (surgery followed by radiation). An apneic period (cessation of breathing) occurs during swallowing and is necessary to protect the airway from aspiration of food and liquid. Aspiration is a common sequela in treated head and neck cancer patients. The results of our preliminary experiments show that patients treated for head and neck cancer sustain apnea for nearly twice as long as normal age-matched controls. It may be that we can train patients to modulate their breathing and swallowing coordination, thus effecting a more safe and efficient swallow.” “This finding suggests coordination of breathing and swallowing may be habituated and capable of being unlearned or relearned, a finding that challenges the involvement of the central nervous system,” Brodsky said. “If this is the case, therapists would be able to develop strategies to teach patients to form a more normal pattern of breathing and swallowing. We hope that with larger studies we’ll be able to determine the characteristics of this change in pattern to determine the best time for intervention.” Martin-Harris’ goals for ongoing research at the MUSC and Saint Joseph’s Hospital Evelyn Trammell Institutes for Voice and Swallowing include better prediction of which patients will achieve functional recovery based on their respiratory phase/swallowing impairment profile, to develop a standardized tool for the assessment of swallowing impairment, and to develop swallowing therapy techniques directed toward improving impairment profiles, maximizing oral intake status, patient nutrition, safety, and quality of life. “MUSC is well-equipped to handle patients with head and neck cancer,” Brodsky said. “We have an excellent staff of physicians, nurses, and researchers in the Department of Otolaryngology-Head and Neck Surgery working in collaboration with speech-language pathologists in the Department of Speech Pathology and with the physicians, nurses, and researchers in Hollings Cancer Center. This team approach affords the patient the best possible care.” Human Saliva and Oral Cancer
“The fluorescence technique is important because it will probably be used in the upcoming case-control study of oral cancer,” she said. “The hydrolyses of dietary flavonoids in the oral cavity may be significant because some hydrolyzed flavonoids are oral cancer cell suppressive. A hypothesis of ours was that the oral microflora may be an important factor in the rates of hydrolyses of dietary flavonoids in the oral cavity.” Program participants and research team members: Terry Day, M.D.,
associate professor and director of Head and Neck Oncology Surgery and
vice chair for clinical affairs in Otolaryngology; Bonnie Martin-Harris,
Ph.D., MUSC Evelyn Trammell Institute for Voice and Swallowing director
and Otolaryngology-Head and Neck Surgery associate professor; Anand Sharma,
M.D., Radiation Oncology; Rita Young, Ph.D., associate chief of staff for
research at the Charleston Veterans Administration Medical Center (VA)
and Medicine and Otolaryngology professor; Deanne Lathers, Ph.D., Charleston
Veterans Administration Medical Center research health scientist and Otolaryngology
assistant professor; Martin Brodsky, Otolaryngology-Head and Neck Surgery
clinical instructor; Sue Reed, College of Dental Medicine/Stomatology;
Betsy Davis, M.D., Maxiofacialprosthodontics director; M. Boyd Gillespie,
M.D., Otolaryngology—Head and Neck Surgery assistant professor; and a group
from Besim Ogretmen’s, Ph.D., Biochemistry and Molecular Biology professor,
lab including Serap Koybasi, M.D. (currently at Abnat Izzet Baysal University,
Department of Otolaryngology, Turkey), and Michael Rossi, M.D., former
MUSC student (currently at the Department of Otolaryngology, University
of Pittsburgh).
Friday, Aug. 20, 2004
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