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tients undergoing extractions who also had concurrentdiagnoses of neutropenia, pancytopenia, aplastic ane-mia, or malignant neoplasms of the lymphatic and hema-topoietic tissues. Chart review was then performed toidentify patients who were neutropenic (� 1.5 � 109/L)t the time of dental extraction. Complications includingocal infection, delayed healing, bleeding, bacteremia,nd fever were recorded.Methods of Data Analysis: Preliminary chart re-

iews of 200 patients, who underwent extractions be-ween 2007 and 2010, revealed 27 patients that met fullnclusion for this study. Descriptive statistical analysis

as performed using JMP 8.0 software.Results of Investigation: Patient demographicsere: 14 males/13 females, mean age 53.7 years (range

-93). The mean absolute neutrophil count at the time ofxtractions was 0.633 � 109/L (range 0-1.48), and mean

platelet count was 94.9 (range 21-389). Clinical findingspre-extractions included: 63% of patients with radio-graphic caries, 74% with radiographic periapical radio-lucencies, 44% with radiographic evidence of local peri-odontal disease, 48% with clinical caries, 52% with painon percussion, 22% with clinical evidence of dentalabscess, and 56% with complaints of spontaneous oralpain. Mean number of teeth extracted per patient was2.96 (range 1-11) with 48% coded as simple extractions,44% as surgical extractions, and 7% as extractions ofimpacted teeth. Median post-operative follow up was163 days (range 4-1,404). Post-operative complicationswere found in 5/27 cases including 2 patients withdelayed healing (although both patients had a history ofBRONJ), 2 with pain after healing, and 1 with minortransient bleeding. No local infections were noted at theextraction sites. Three patients had pre-operative fever,of which two had resolution of fever within seven daysof extractions.

Conclusion: This retrospective study revealed nosignificant complications following dental extractionsin neutropenic patients. Specific antibiotic regimenswere not controlled for, although most patients re-ceived wide-spectrum antibiotics during the post-op-erative period as part of their medical management. Offive patients with post-operative complications, threeconsisted of pain or minor transient bleeding whilethe other two represented delayed healing in patientswith a BRONJ history. The lack of local post-operativeinfection in this study is notable. Although this pre-liminary review lacks sufficient sample size for defin-itive conclusions, it appears that the benefits associ-ated with extraction of indicated teeth in severelyneutropenic patients may outweigh the associatedrisks. A broader study, with larger sample size, isunderway to better characterize outcomes followingdental extractions in the severely neutropenic patient

population.

AAOMS • 2011

References:

Willford SK, Salisbury PL, Peacock JE, Cruz JM, Powell BL, Lyerly ES,apizzi RL. The safety of dental extractions in patients with hemato-

ogic malignancies. J Clin Onc 1989 7(6): 798-802.Overholser CD, Peterson DE, Bergman SA, Williams LT. Dental ex-

ractions in patients with acute nonlymphocytic leukemia. J Oral Surg982 (40): 296-298.

Predictors of BRONJ in High-RiskCancer PatientsS. K. Choyee: Oral & Maxillofacial Surgery, LAC�USCMedical Center, J. Uyanne, K. Akiyama, P.Sedghizadeh, D. Yamashita, R. Green, A. Garcia, S. Shi,A. Le

Statement of the Problem: Bisphosphonate-relatedosteonecrosis of the jaws (BRONJ) is an adverse effect ofbisphosphonate therapy, with highest incidence re-ported in the oncologic patients receiving intravenousnitrogen-containing bisphosphonates (BP). Our grouphas established a murine model of BRONJ-like diseasethat simulates major clinical, radiographic, and histolog-ical features of the human disease. We observed thatZolendronate (Zol), a potent nitrogen-containing BP,caused BRONJ-like disease in mice by suppressing theadaptive regulatory T cell, Tregs, and activating the in-flammatory T helper-producing interleukin 17 cells,Th17, thereby suppressing the ratio of Treg/Th17. In thisstudy, we will determine whether the altered immunehomeostasis elicited by bisphosphonate treatment, man-ifested as a suppressed ratio of Tregs and Th17 cells,renders the host susceptible to BRONJ, and thereforeserve as potential biomarkers in diagnosis of BRONJ inhigh-risk cancer patients.

Materials and Methods: We conducted an institu-tional review board (IRB)-approved cross-sectional studyusing a well-defined group of cancer patients with his-tory of chemotherapy and bisphosphonate treatment.The case-controlled study evaluated patients with clini-cal osteonecrosis of the jaws (ONJ). Age- and ethnicallymatched patients without ONJ were compared to theaffected patients. Patients were screened from the NorrisCancer Center, the Ostrow School of Dentistry of Uni-versity of Southern California (USC), and the LAC�USCmedical center. Treg and TH17 cells were determinedusing flow cytometric analysis. Bone serum markers (C-telopeptide, alkaline phosphatase) were measured usingELISA.

Results of Investigation: Data demonstrated astrong correlation between the suppressed ratio of Treg/Th17 cells and high-risk cancer patients with history ofchemotherapy with and without zoledronate, and thosewith active BRONJ lesion. The high-risk cancer patientsshowed a significantly higher level Th17 cells than con-trol. We also observed a nice correlation between a

suppressed Treg/Th17 ratio and disease severity, early,

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advanced, and late stage of BRONJ. The differential im-mune cells profile between control and high-risk BRONJgroups were more significant than the serum C-telopep-tide assay.

Conclusion: The Treg/Th17 ratio appears to corre-late with BRONJ disease severity and potentially servesan immune biomarker for prediction of BRONJ in cancerpatients on IV bisphosphonate and chemotherapy.

References:

Cell-Based Immunotherapy with Mesenchymal Stem Cells Cures Bi-phophonate-Related Osteonecrosis of the Jaw-like Disease in MiceKikuiri 2010)

American Association of Oral and Maxillofacial Surgeons Positionaper on Bisphosphonate-Related Osteonecrosis of the Jaws (2007)

Mucoadhesive Patch for Local IntraoralDelivery of the ChemopreventiveCompound Fenretinide: In VivoPharmacokineticsM. Phelps: Division of Oral and Maxillofacial Surgery,Pathology, and Anesthesiology, The Ohio StateUniversity, Columbus, OH, A. Holpuch, K. Desai,W. Chen, B. Han, Z. Liu, S. Schwendeman, H. Fields,P. Larsen, S. Mallery

Statement of the Problem: The prognosis for per-sons diagnosed with oral squamous cell carcinoma(OSCC) remains one of the lowest for solid cancers. Eventhose individuals fortunate enough to be cured faceextensive surgery resulting in loss of structures vital foresthetics and function. Clearly, identification of non-toxic, effective compounds to prevent progression ofpremalignant oral lesions to overt OSCC represents apromising chemopreventive strategy. Vitamin A-likecompounds, like fenretinide, have demonstrated desir-able anti-cancer effects in vitro. Human clinical trials,however, have been unsuccessful due to dose-limitingtoxicities and potential sub-therapeutic concentrationsin target tissues, i.e., oral epithelium. By contrast, localdelivery of fenretinide is hypothesized to provide a phar-macological advantage by sustaining therapeutically rel-evant concentrations in oral epithelium while minimiz-ing systemic exposure.

Materials and Methods: Eight female New ZealandWhite rabbits were treated daily with mucoadhesivefenretinide patches (right buccal mucosa) and blankpatches (left buccal mucosa) for 30 minutes for 10 con-secutive days. Blood was drawn prior to and 30 minutesafter patch placement, and saliva was collected follow-ing patch removal. On day 10, rabbits were sacrificedand tissue samples collected for LC-MS/MS, immunohis-tochemistry and Western blot analyses. Saliva, patch-treated oral mucosa (fenretinide- and blank-treated), andplasma are being analyzed via LC-MS/MS for quantifica-

tion of fenretinide and its metabolites. Saliva samples, C

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which have been quantified, were normalized relative toprotein quantity (Bradford protein assay). Tissues forimmunohistochemistry staining and Western blots wereprepared by standard methods and analyzed for cellproliferation (Ki-67) and fenretinide-relevant metabolicenzymes (cytochrome P450 isoform 3A4 [CYP3A4],UDP-glucuronosyltransferase isoform 1A1 [UGT1A1],and indolethylamine-N-methyltransferase [INMT]).Translational studies will be conducted on normal hu-man oral mucosal tissues (n�8) to characterize the fen-retinide-relevant human metabolic enzyme profile.

Methods of Data Analysis: Evaluative parametersinclude intra- and inter-animal comparisons and longitu-dinal analyses. For the sample size estimation analysis,significance (a) was established at the 0.05 level and thebeta error at 0.10. Using a conservative estimate, i.e.requisite sample size if the difference between themeans of control versus treated tissues was 1/3 thedifference obtained from our previously conducted ani-mal local delivery pharmacokinetic analyses, an n�8 wasdetermined. If the data display a normal distribution andhomogeneity of variance, the data will be analyzed usingparametric tests such as the One Way ANOVA, followedby a Scheffe post hoc comparison. If the data are notnormally distributed, either log conversion or corre-sponding nonparametric analyses such as a Kruskal-Wal-lis with post hoc z test will be used. Depending upon thedata distribution, two compartment comparisons willentail either a Student t test (normal distribution) or aMann Whitney U test or �2 analyses.

Results of Investigation: Daily saliva concentrationsf fenretinide significantly correlated with saliva proteinoncentrations (r�0.7577, P � .0001), and demonstratedustained therapeutic levels over the 10-day study, i.e.,reater than 6 �M. H&E and Ki-67 data indicate minimal

adverse histopathological effects of fenretinide treatmentrelative to blank patch treatment. Preliminary metabolicprofiling of fenretinide-relevant enzymes in rabbit oral tis-sues indicate the presence of CYP3A4 (required for metab-olism of fenretinide to the active metabolite, 4-oxo-4-hy-droxyphenylretinamide) and induced expression of INMTin fenretinide-treated vs. blank-treated oral mucosa (re-quired for metabolism of fenretinide to the inactive metab-olite, 4-methoxyphenylretinamide).

Conclusion: These data suggest successful delivery oftherapeutically-relevant levels of fenretinide to the rabbitbuccal mucosa. Characterization of the human oral epi-thelial metabolic enzyme profile will provide a founda-tion for translational application of these rabbit studiesto humans.

References:

Hail N Jr, et al. Mechanisms of fenretinide-induced apoptosis. Apo-tosis. 11:1677-1694 (2006)William WN Jr, et al. High-dose fenretinide in oral leukoplakia.

ancer Prev Res. 2(1):22-26 (2009)

AAOMS • 2011