Faculty Bibliography

OBJECTIVE:This study aimed to quantify the adenoidal-nasopharyngeal ratio (ANR) in a cohort of healthy adults on cone beam computed tomography (CT) using the Fujioka method, which is a reproducible measure of adenoid size and nasopharyngeal patency. METHODS:Electronic health records and maxillofacial cone beam CT in 202 consecutive patients aged 16 years and older were retrospectively reviewed. Patients with a history of adenoidectomy, sinonasal disease, lymphoproliferative disorders, and cleft palate were excluded from the study. The midsagittal reconstructed cone beam CT image was used to determine the ANR. Statistical analysis was conducted using 1-way analysis of variance. RESULTS:Of the 202 subjects, 131 were female and 71 were male. The mean ± SD subject age was 45.43 ± 20.79 years (range, 16-91 years). The mean ± SD ANR in all subjects was 0.22 ± 0.13 (range, 0.03-0.75) and in each decade of adult life was as follows: younger than 21 years, 0.39 ± 0.12; 21 to 30 years, 0.29 ± 0.11; 31 to 40 years, 0.21 ± 0.09; 41 to 50 years, 0.20 ± 0.07; 51 to 60 years, 0.16 ± 0.10; 61 to 70 years, 0.13 ± 0.05; 71 to 80 years, 0.12 ± 0.05; 81 to 90 years, 0.11 ± 0.04; and 91 years or older, 0.10 ± 0. The differences in mean ANR among the age subgroups were statistically significant (P < 0.001). CONCLUSIONS:The mean ANR gradually decreased from 0.39 in the second decade of life to 0.16 in the sixth decade of life and plateaued at approximately 0.10 thereafter.

Metastasis reduces survival in oral cancer patients and pain is their greatest complaint. We have shown previously that oral cancer metastasis and pain are controlled by the endothelin axis, which is a pathway comprised of the endothelin A and B receptors (ET_AR and ET_BR). In this study we focus on individual genes of the pathway, demonstrating that the endothelin axis genes are methylated and dysregulated in cancer tissue. Based on these findings in patients, we hypothesize that ET_AR and ET_BR play dichotomous roles in oral carcinogenesis and pain, such that ET_AR activation and silenced ET_BR expression result in increased carcinogenesis and pain. We test a treatment strategy that targets the dichotomous functions of the two receptors by inhibiting ET_AR with macitentan, an ET_AR antagonist approved for treatment of pulmonary hypertension, and re-expressing the ET_BR gene with adenovirus transduction, and determine the treatment effect on cancer invasion (i.e., metastasis), proliferation and pain in vitro and in vivo. We demonstrate that combination treatment of macitentan and ET_BR gene therapy inhibits invasion, but not proliferation, in cell culture and in a mouse model of tongue cancer. Furthermore, the treatment combination produces an antinociceptive effect through inhibition of endothelin-1 mediated neuronal activation, revealing the analgesic potential of macitentan. Our treatment approach targets a pathway shown to be dysregulated in oral cancer patients, using gene therapy and repurposing an available drug to effectively treat both oral cancer metastasis and pain in a preclinical model.

Synthetic host defense peptides (HDP) are a new class of promising therapeutic agents with potential application in a variety of diseases. RP-182 is a 10mer synthetic HDP design, which selectively reduces M2-like tumor associated macrophages via engagement with the cell surface lectin receptor MRC1/CD206 and is currently being developed as an innate immune defense regulator to improve anti-tumor immunity in immunologically cold tumors. Herein, we describe a sensitive and specific liquid chromatography (LC) coupled to quadrupole electron spray tandem mass spectrometry method to measure positively charged HDPs and HDP peptide fragments in complex biological matrices. Carboxylic acid magnetic beads were used as an affinity-capturing agent to extract the positively charged RP-182 from both mouse plasma and tissue homogenates. Beads were eluted with 0.1% (v/v) formic acid and chromatographic separation was achieved on a Waters 2.1 × 100 mm, 3.5 μm XSelect Peptide CSH C18 column with a Vanguard pre-column of the same phase. MS/MS was performed on a Thermo TSQ Quantiva triple quadrupole mass spectrometer operating in Selected Reaction Monitoring (SRM) mode fragmenting the plus three parent ion 458.9⁺³ and monitoring ions 624.0⁺², 550.5⁺², and 597.3⁺¹ for RP-182 and 462.4⁺³ > 629.1⁺², 555.5⁺², and 607.3⁺¹ for isotopic RP-182 standard. The assay had good linearity ranging from 1 ng to 1000 ng in mouse plasma with the lower limit of detection for RP-182 at 1 ng in mouse plasma with good intra- and inter-sample precision and accuracy. Recovery ranged from 66% to 77% with minimum matrix effects. The method was successfully applied to an abbreviated pharmacokinetic study in mice after single IP injection of RP-182. The method was successfully tested on a second HDP, the 17mer D4E1, and the cationic human peptide hormone ghrelin suggesting that it might be a general sensitive method applicable to quantifying HDP peptides that are difficult to extract.

PURPOSE/OBJECTIVE:Lifestyle factors associated with personal behavior can alter tumor-associated biological pathways and thereby increase cancer risk, growth, and disease recurrence. Advanced glycation end products (AGEs) are reactive metabolites produced endogenously as a by-product of normal metabolism. A Western lifestyle also promotes AGE accumulation in the body which is associated with disease phenotypes through modification of the genome, protein crosslinking/dysfunction, and aberrant cell signaling. Given the links between lifestyle, AGEs, and disease, we examined the association between dietary-AGEs and breast cancer. METHODS:We evaluated AGE levels in bio-specimens from estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer patients, examined their role in therapy resistance, and assessed the ability of lifestyle intervention to reduce circulating AGE levels in ER+ breast cancer survivors. RESULTS:An association between ER status and AGE levels was observed in tumor and serum samples. AGE treatment of ER+ breast cancer cells altered ERα phosphorylation and promoted resistance to tamoxifen therapy. In a proof of concept study, physical activity and dietary intervention was shown to be viable options for reducing circulating AGE levels in breast cancer survivors. CONCLUSIONS:There is a potential prognostic and therapeutic role for lifestyle derived AGEs in breast cancer. Given the potential benefits of lifestyle intervention on incidence and mortality, opportunities exist for the development of community health and nutritional programs aimed at reducing AGE exposure in order to improve breast cancer prevention and treatment outcomes.

BACKGROUND AND PURPOSE:Periventricular white matter injury is the common cause of spastic cerebral palsy. However, the early diagnosis of spastic cerebral palsy still remains a challenge. Our aim was to investigate whether infants with periventricular white matter injury with bilateral spastic cerebral palsy have unique lesions different from those in infants without cerebral palsy and to evaluate the efficiency of DTI in the early diagnosis of spastic cerebral palsy. MATERIALS AND METHODS:Infants with periventricular white matter injury and controls underwent MR imaging at 6-18 months of age. Fractional anisotropy was calculated from DTI. Cerebral palsy was diagnosed by 24-30 months of age. Subjects were divided into 3 groups: infants with periventricular white matter injury with bilateral spastic cerebral palsy, infants with periventricular white matter injury without cerebral palsy, and controls. Tract-Based Spatial Statistics and Automated Fiber Quantification were used to investigate intergroup differences. Receiver operating characteristic curves were used to assess the diagnostic accuracy of spastic cerebral palsy. Correlations between motor function scores and fractional anisotropy were evaluated along white matter tracts. RESULTS:There were 20, 19, and 33 subjects in periventricular white matter injury with spastic cerebral palsy, periventricular white matter injury without cerebral palsy, and control groups, respectively. Decreased fractional anisotropy in the corticospinal tract was only observed in infants with periventricular white matter injury with spastic cerebral palsy, whereas decreased fractional anisotropy in the posterior thalamic radiation and genu and splenium of the corpus callosum was seen in both periventricular white matter injury subgroups. Fractional anisotropy in the corticospinal tract at the internal capsule level was effective in differentiating infants with periventricular white matter injury with spastic cerebral palsy from those without cerebral palsy by a threshold of 0.53, and it had strong correlations with motor function scores. CONCLUSIONS:Corticospinal tract lesions play a crucial role in motor impairment related to spastic cerebral palsy in infants with periventricular white matter injury. Fractional anisotropy in the corticospinal tract at the internal capsule level could aid in the early diagnosis of spastic cerebral palsy with high diagnostic accuracy.

OBJECTIVES: While dental development is important to life history investigations, data from wild known-aged great apes are scarce. We report on the first radiographic examination of dental development in wild Virunga mountain gorillas, using known-age skeletal samples recovered in Rwanda. MATERIALS AND METHODS: In 43 individuals (0.0-14.94 years), we collected radiographs of mandibular molars, and where possible, cone beam CT scans. Molar crown and root calcification status was assessed using two established staging systems, and age prediction equations generated using polynomial regression. Results were compared to available data from known-age captive and wild chimpanzees. RESULTS: Mountain gorillas generally fell within reported captive chimpanzee distributions or exceeded them, exhibiting older ages at equivalent radiographic stages of development. Differences reflect delayed initiation and/or an extended duration of second molar crown development, and extended first and second molar root development, in mountain gorillas compared to captive chimpanzees. However, differences in the duration of molar root development were less evident compared to wild chimpanzees. DISCUSSION: Despite sample limitations, our findings extend the known range of variation in radiographic estimates of molar formation timing in great apes, and provide a new age prediction technique based on wild specimens. However, mountain gorillas do not appear accelerated in radiographic assessment of molar formation compared to chimpanzees, as they are for other life history traits. Future studies should aim to resolve the influence of species differences, wild versus captive environments, and/or sampling phenomena on patterns observed here, and more generally, how they relate to variation in tooth size, eruption timing, and developmental life history.

OBJECTIVES: Changes to the radiographic appearance of the jaws after head and neck radiotherapy have not been thoroughly characterized. This retrospective study examines changes to the appearance of the mandible on panoramic images following intensity-modulated radiotherapy (IMRT) and relates these changes to medical co-morbidities and radiation dose. STUDY DESIGN: The medical and dental charts, and panoramic images of 126 patients who received IMRT at the Princess Margaret Hospital between January 1, 2005, and December 31, 2008, were analyzed independently by three observers. RESULTS: Of the 126 patients, 75 (60%) had post-IMRT changes, as seen on panoramic images; most, 66 (88%), consisted of widened periodontal ligament space (WPLS). The median time to WPLS was 29 months after IMRT. Female gender and radiation dose correlated with decreased time to WPLS. CONCLUSIONS: These results indicate that WPLS is a common radiographic sequela after head and neck radiotherapy, underscoring its clinical significance as a reliable marker of irradiated bone. Furthermore, this type of WPLS needs to be differentiated from odontogenic inflammatory disease and cancer recurrence to avoid unnecessary treatment that may precipitate osteoradionecrosis.

PURPOSE: There is considerable controversy over the treatment of medication-related osteonecrosis of the jaw (MRONJ) and growing interest and debate related to the timing, type, technique, and goals of surgical intervention. The specific aim was to evaluate the predictive value of fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT) on healing outcomes in patients undergoing surgery for MRONJ of the mandible. MATERIALS AND METHODS: A retrospective cohort study of 31 patients with 33 MRONJ lesions of the mandible who had undergone surgery using FDG PET-CT was conducted. Data were collected on FDG uptake patterns, healing, follow-up, demographics, lesion characteristics, antiresorptive therapy, and adjunctive therapy. Panoramic and periapical radiographs were used to identify non-restorable teeth and PET-CT images were used to identify sequestra and FDG uptake. Above the mandibular canal, surgery consisted of marginal resection or debridement of clinically involved bone and exposure of clinically uninvolved bone identified by FDG uptake. Below the mandibular canal, mobile segments of bony sequestra were removed, but areas of clinically uninvolved bone with FDG uptake were not. Patients who did not heal underwent segmental resection and reconstruction with rigid fixation and a local or regional soft tissue flap or free fibular flap. The primary predictor variable was the FDG uptake pattern for each patient. The outcome variable was postoperative healing defined by mucosal closure without signs of infection or exposed bone at the time of evaluation. RESULTS: Two risk groups were identified based on FDG uptake pattern. The low-risk group, type A, included 22 patients with activity limited to the alveolus, torus, and basal bone superior to the mandibular canal. The high-risk group, type B, included 11 patients with type A FDG activity with extension inferior to the mandibular canal. Treatment of type A MRONJ lesions was more successful than treatment of type B MRONJ lesions (100 vs 27%; P < .001). Seven of the type B failures were successfully retreated by segmental resection and reconstruction (1 patient refused further treatment). CONCLUSION: These results showed that low-risk FDG PET-CT findings predicted successful healing with surgery above the mandibular canal. In contrast, high-risk FDG findings were associated with a greater than 50% risk of failure for treatment that extended below the mandibular canal. Although these failures suggest that FDG uptake indicates infected tissue, further research is needed to identify which high-risk patients are most likely to benefit from a conservative treatment protocol.