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Macitentan Inhibits Oral Squamous Cell Carcinoma Growth and Invasion in Vitro and in Vivo
MORS Oral Abstracts Materials and Methods: A comparison of levels among 372 miRNAs in 12 non-tobacco, non-betel users with oral squamous cell carcinoma and 10 healthy controls was made using RT-PCR. Results: It revealed miR10b, miR-196a, miR-31, miR-187 and miR-503 were enriched in the tumor epithelium in oral squamous cell carcinoma (OSCC) of never tobacco users. A second study examining miRNA expression in tobacco or betel users revealed that the changes seen in miR187 and miR-503 were specific to OSCC epithelium in never users. Only one miRNA, miR-196a, was enriched in OSCCs in both smokers and never users but not in benign pathologies. It has already been shown to promote cell proliferation in squamous cell carcinoma cells. Conclusion: These results suggest that epithelial expression of miR-196a may be a key part of OSCC formation and/or progression. This miRNA, along with miR187 and miR503, serve as attractive targets in oral cancer diagnosis in never smokers. Exploration of the roles of miR187 and miR503 in OSCC in never smokers may shed light on the cellular changes specific to this OSCC subtype.
Oral Cancer Trends in Nova Scotia: 1987 to 2011 C. G. Robertson: Dalhousie University, N. Emanuele Current knowledge of oral cancer incidence and trends is very important in the development of appropriate research questions, preventive strategies, clinical examination and screening protocols, diagnostic procedures, approaches to treatment, surveillance requirements, educational programs and resource allocation. The purpose of this study was to characterize the burden of oral cancer in the province of Nova Scotia, Canada from 1987 to 2011 and to identify any trends in the incidence rates at specific anatomic locations or within specific age or gender groups over this 25 year period. This was an observational retrospective analysis conducted using data held by the Nova Scotia Cancer Registry, a registry of all cancers diagnosed in residents of the province, except for non-melanoma skin cancers. Non-aggregate, non-identifiable person level data was obtained from the registry for oral cancer in Nova Scotia between 1987 and 2011. Data obtained included the primary tumor site, gender, age at the time of diagnosis, and the year of diagnosis. Cases of cancer of the lip, lymphoma, and leukemia were excluded. Trends in the incidence rates of oral cancer over this time frame were also assessed. SEER*Stat software (http://seer.cancer.gov/seerstat/) was used to generate descriptive statistics related to incidence. JoinPoint Regression software (http://
AAOMS 2015
surveillance.cancer.gov/joinpoint/) was used for the analysis of trends in incidence rates using JoinPoint models. A total of 2206 cases of oral cancer were registered in Nova Scotia between 1987 and 2011. The most common site was the tongue (26.3%), followed by gum/other mouth (18.0%), tonsil (15.6%), hypopharynx (9.6%), salivary gland (9.5%), floor of mouth (7.6%), oropharynx (4.9%), nasopharynx (4.3%), and other oral cavity (4.2%). Statistically significant increases in annual percentage change were found in the base of tongue (3.77), tonsil (3.25), tongue (2.7), oral tongue (1.94), and oropharynx (1.67) over the study period. The only sites to demonstrate a statistically significant decrease in annual percentage change were the hypopharynx (-3.60), floor of mouth (-2.82), salivary gland (-2.54), and gum and other mouth (-1.77). The largest increases in annual percentage change were found in the base of tongue and tonsil, whereas decreases in annual percentage change were noted in other oral cavity sites such as the floor of mouth and gum/other mouth. These findings are consistent with trends reported in the literature of increasing incidence rates for oral squamous cell carcinoma at HPV associated sites in the oropharynx (base of tongue and tonsil) and decreasing rates of squamous cell carcinoma within the oral cavity in other western countries.
Macitentan Inhibits Oral Squamous Cell Carcinoma Growth and Invasion in Vitro and in Vivo C. T. Viet: Bluestone Center for Clinical Research, D. Dang, Y. Ye, B. L. Schmidt Purpose: Oral squamous cell carcinoma (SCC) invasion and metastasis result in treatment failure and correlate with increased pain. We have previously shown that the ‘‘endothelin axis,’’ consisting of endothelin A and B receptors (ETAR and ETBR), mediates oral SCC pain, and that inhibiting ETAR with macitentan alleviates pain. We now hypothesize that the endothelin axis also mediates oral SCC growth and metastasis. We explore the therapeutic effect of concurrent ETAR antagonism (with macitentan) and ETBR re-expression on oral SCC growth and invasion in vitro and in vivo. Methods: We quantified the effect of macitentan treatment and targeted ETBR re-expression on oral SCC cell invasion and proliferation, in vitro indices of metastasis and growth, using a Matrigel invasion chamber assay and the Real Time Cell Analyzer (RTCA). We then created an oral SCC mouse model to determine the effect of macitentan treatment on oral SCC growth.
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MORS Oral Abstracts Results: Macitentan treatment or ETBR re-expression alone significantly inhibited oral SCC proliferation and invasion in a dose-dependent manner; macitentan combined with ETBR re-expression had the strongest inhibitory effect on cancer proliferation and invasion. In the oral SCC mouse model, macitentan treatment and ETBR re-expression had significant anti-proliferative and anti-metastatic effects compared to control treatment. Conclusion: Our strategy of targeting the endothelin axis inhibited cancer growth and invasion in vitro and in a preclinical model. These results establish the therapeutic potential of macitentan, an orally available ETAR antagonist, for oral SCC metastasis. References: 1. Viet CT et al., Pain. 2011 Oct;152(10):2323-32. 2. Pickering V et al., Oral Oncol. 2007 Jan;43(1):37-41.
The Incidental Finding of Recurrent Carcinoma in Osteoradionecrosis Resection Specimens: A Consecutive Case Series H. A. Marwan: Jackson Memorial Hospital/University of Miami, J. M. Green III, D. Hew, R. Tursun, R. E. Marx Purpose: Osteoradionecrosis (ORN) is a well known and usually late complication of radiation therapy in the treatment of head and neck cancer. Due to the hypoxic, hypovascular, and hypocellular nature of these wounds resection combined with pedicled or free tissue transfer is often required to achieved definitive cure.Statistically the mandible is the most commonly affected site1. In these resection specimens the incidental finding of malignancy has been documented but is somewhat rare. The aim of this review is to investigate the presence of recurrent carcinoma, sarcoma, or new primary malignancies in resection specimens previously diagnosed as ORN. Methods: A retrospective chart review was completed of 564 consecutive cases of ORN. Inclusion criteria included previous history of head and neck carcinoma treated with radiation of at least 6000 cGy, clinical diagnosis of ORN and surgical intervention with osseous resection for treatment of the ORN. A total of 564 patients were found to meet the inclusion criteria. The study endpoints measured include the microscopic evidence of malignancy in the osteoradionecrosis specimen and microscopic evidence of new primary in the foregut. This study has been reviewed and approved by the University of Miami-Miller School of Medicine institutional reviewed board.
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Results: Of the 564 patients, 14 patients had microscopic evidence of cancer in the specimen (2.48%) and 4 had a proven second primary malignancy in the foregut (one in the lung 0.18% and there in the oropharynx 0.53%). 1 of the 14 patients was diagnosed with a highgrade sarcoma and died within 1 year of diagnosis. Conclusion: Although an relatively rare finding (2.48% in this study) the oral and maxillofacial surgeon treating ORN should be cognizant about the potential of malignancy in this patient population and conduct their examinations and studies to investigate this potential. The differential diagnosis in osteoradionecrosis cases should include a loco-regional recurrence, radiation induced malignancies and a metachronous primary malignancy. The treatment of malignant disease is different than osteoradionecrosis and a multidisciplinary treatment approach specific to the newly discovered malignancy is recommended if a malignancy is diagnosed in an ORN patient.
Performance Initiatives in Head and Neck Surgery: LSU Shreveport Oral and Maxillofacial Surgery Experience R. Smart: Lousiana State University Health Sciences Center, D. D. Kim Statement of the Problem: The aim of this study is to evaluate one institution’s performance based on published performance standards. Materials and Methods: This retrospective chart review utilizes data of patients treated July 2011 through March 2015. Inclusion criteria include: histopathological subtype of squamous cell carcinoma, adenoid cystic carcinoma, acinic cell carcinoma, melanoma, basal cell carcinoma, sarcoma, carcinoma ex pleomorphic adenoma, and adenocarcinoma. Lesion location includes oral cavity, lip, cutaneous lesions of the face, neck or scalp, and salivary gland. Recorded variables include tumor histology, T stage, margin status, transfusion, hospital length of stay, and documentation of adverse events. Microsoft Excel spreadsheets were used to collect and code data for statistical analysis. All patient identifiers were removed at the time of collection to avoid dissemination of sensitive medical information. Methods of Data Analysis: Descriptive statistics were calculated including: hospital length of stay, 30-day readmission, return to operating room within seven days of operation, 30 day mortality, use of blood products, surgical site infection, as well as margin status upon initial resection. Results: 123 records met inclusion criteria for the analysis. There were 71 males and 52 females (58% male). Average age at treatment is 64.5 years. Squamous cell carcinoma represents 82% of tumor histology. There is a
AAOMS 2015
Oral Cancer Trends in Nova Scotia: 1987 to 2011 C. G. Robertson: Dalhousie University, N. Emanuele Current knowledge of oral cancer incidence and trends is very important in the development of appropriate research questions, preventive strategies, clinical examination and screening protocols, diagnostic procedures, approaches to treatment, surveillance requirements, educational programs and resource allocation. The purpose of this study was to characterize the burden of oral cancer in the province of Nova Scotia, Canada from 1987 to 2011 and to identify any trends in the incidence rates at specific anatomic locations or within specific age or gender groups over this 25 year period. This was an observational retrospective analysis conducted using data held by the Nova Scotia Cancer Registry, a registry of all cancers diagnosed in residents of the province, except for non-melanoma skin cancers. Non-aggregate, non-identifiable person level data was obtained from the registry for oral cancer in Nova Scotia between 1987 and 2011. Data obtained included the primary tumor site, gender, age at the time of diagnosis, and the year of diagnosis. Cases of cancer of the lip, lymphoma, and leukemia were excluded. Trends in the incidence rates of oral cancer over this time frame were also assessed. SEER*Stat software (http://seer.cancer.gov/seerstat/) was used to generate descriptive statistics related to incidence. JoinPoint Regression software (http://
AAOMS 2015
surveillance.cancer.gov/joinpoint/) was used for the analysis of trends in incidence rates using JoinPoint models. A total of 2206 cases of oral cancer were registered in Nova Scotia between 1987 and 2011. The most common site was the tongue (26.3%), followed by gum/other mouth (18.0%), tonsil (15.6%), hypopharynx (9.6%), salivary gland (9.5%), floor of mouth (7.6%), oropharynx (4.9%), nasopharynx (4.3%), and other oral cavity (4.2%). Statistically significant increases in annual percentage change were found in the base of tongue (3.77), tonsil (3.25), tongue (2.7), oral tongue (1.94), and oropharynx (1.67) over the study period. The only sites to demonstrate a statistically significant decrease in annual percentage change were the hypopharynx (-3.60), floor of mouth (-2.82), salivary gland (-2.54), and gum and other mouth (-1.77). The largest increases in annual percentage change were found in the base of tongue and tonsil, whereas decreases in annual percentage change were noted in other oral cavity sites such as the floor of mouth and gum/other mouth. These findings are consistent with trends reported in the literature of increasing incidence rates for oral squamous cell carcinoma at HPV associated sites in the oropharynx (base of tongue and tonsil) and decreasing rates of squamous cell carcinoma within the oral cavity in other western countries.
Macitentan Inhibits Oral Squamous Cell Carcinoma Growth and Invasion in Vitro and in Vivo C. T. Viet: Bluestone Center for Clinical Research, D. Dang, Y. Ye, B. L. Schmidt Purpose: Oral squamous cell carcinoma (SCC) invasion and metastasis result in treatment failure and correlate with increased pain. We have previously shown that the ‘‘endothelin axis,’’ consisting of endothelin A and B receptors (ETAR and ETBR), mediates oral SCC pain, and that inhibiting ETAR with macitentan alleviates pain. We now hypothesize that the endothelin axis also mediates oral SCC growth and metastasis. We explore the therapeutic effect of concurrent ETAR antagonism (with macitentan) and ETBR re-expression on oral SCC growth and invasion in vitro and in vivo. Methods: We quantified the effect of macitentan treatment and targeted ETBR re-expression on oral SCC cell invasion and proliferation, in vitro indices of metastasis and growth, using a Matrigel invasion chamber assay and the Real Time Cell Analyzer (RTCA). We then created an oral SCC mouse model to determine the effect of macitentan treatment on oral SCC growth.
e-3
MORS Oral Abstracts Results: Macitentan treatment or ETBR re-expression alone significantly inhibited oral SCC proliferation and invasion in a dose-dependent manner; macitentan combined with ETBR re-expression had the strongest inhibitory effect on cancer proliferation and invasion. In the oral SCC mouse model, macitentan treatment and ETBR re-expression had significant anti-proliferative and anti-metastatic effects compared to control treatment. Conclusion: Our strategy of targeting the endothelin axis inhibited cancer growth and invasion in vitro and in a preclinical model. These results establish the therapeutic potential of macitentan, an orally available ETAR antagonist, for oral SCC metastasis. References: 1. Viet CT et al., Pain. 2011 Oct;152(10):2323-32. 2. Pickering V et al., Oral Oncol. 2007 Jan;43(1):37-41.
The Incidental Finding of Recurrent Carcinoma in Osteoradionecrosis Resection Specimens: A Consecutive Case Series H. A. Marwan: Jackson Memorial Hospital/University of Miami, J. M. Green III, D. Hew, R. Tursun, R. E. Marx Purpose: Osteoradionecrosis (ORN) is a well known and usually late complication of radiation therapy in the treatment of head and neck cancer. Due to the hypoxic, hypovascular, and hypocellular nature of these wounds resection combined with pedicled or free tissue transfer is often required to achieved definitive cure.Statistically the mandible is the most commonly affected site1. In these resection specimens the incidental finding of malignancy has been documented but is somewhat rare. The aim of this review is to investigate the presence of recurrent carcinoma, sarcoma, or new primary malignancies in resection specimens previously diagnosed as ORN. Methods: A retrospective chart review was completed of 564 consecutive cases of ORN. Inclusion criteria included previous history of head and neck carcinoma treated with radiation of at least 6000 cGy, clinical diagnosis of ORN and surgical intervention with osseous resection for treatment of the ORN. A total of 564 patients were found to meet the inclusion criteria. The study endpoints measured include the microscopic evidence of malignancy in the osteoradionecrosis specimen and microscopic evidence of new primary in the foregut. This study has been reviewed and approved by the University of Miami-Miller School of Medicine institutional reviewed board.
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Results: Of the 564 patients, 14 patients had microscopic evidence of cancer in the specimen (2.48%) and 4 had a proven second primary malignancy in the foregut (one in the lung 0.18% and there in the oropharynx 0.53%). 1 of the 14 patients was diagnosed with a highgrade sarcoma and died within 1 year of diagnosis. Conclusion: Although an relatively rare finding (2.48% in this study) the oral and maxillofacial surgeon treating ORN should be cognizant about the potential of malignancy in this patient population and conduct their examinations and studies to investigate this potential. The differential diagnosis in osteoradionecrosis cases should include a loco-regional recurrence, radiation induced malignancies and a metachronous primary malignancy. The treatment of malignant disease is different than osteoradionecrosis and a multidisciplinary treatment approach specific to the newly discovered malignancy is recommended if a malignancy is diagnosed in an ORN patient.
Performance Initiatives in Head and Neck Surgery: LSU Shreveport Oral and Maxillofacial Surgery Experience R. Smart: Lousiana State University Health Sciences Center, D. D. Kim Statement of the Problem: The aim of this study is to evaluate one institution’s performance based on published performance standards. Materials and Methods: This retrospective chart review utilizes data of patients treated July 2011 through March 2015. Inclusion criteria include: histopathological subtype of squamous cell carcinoma, adenoid cystic carcinoma, acinic cell carcinoma, melanoma, basal cell carcinoma, sarcoma, carcinoma ex pleomorphic adenoma, and adenocarcinoma. Lesion location includes oral cavity, lip, cutaneous lesions of the face, neck or scalp, and salivary gland. Recorded variables include tumor histology, T stage, margin status, transfusion, hospital length of stay, and documentation of adverse events. Microsoft Excel spreadsheets were used to collect and code data for statistical analysis. All patient identifiers were removed at the time of collection to avoid dissemination of sensitive medical information. Methods of Data Analysis: Descriptive statistics were calculated including: hospital length of stay, 30-day readmission, return to operating room within seven days of operation, 30 day mortality, use of blood products, surgical site infection, as well as margin status upon initial resection. Results: 123 records met inclusion criteria for the analysis. There were 71 males and 52 females (58% male). Average age at treatment is 64.5 years. Squamous cell carcinoma represents 82% of tumor histology. There is a
AAOMS 2015