American Association of Oral and Maxillofacial Surgeon's Position Paper on Oral Mucosal Dysplasia.

Oral potentially malignant disorders (OPMDs) of the oral mucosa include leukoplakia, erythroplakia, erythroleukoplakia, lichen planus, and oral lichenoid lesions, each with varying incidences of dysplastic disease at the time of presentation and each with observed incidences of malignant transformation over time. The primary goal of the management of dysplasia, therefore, includes their early detection and treatment prior to malignant transformation. The recognition and management of these OPMDs and an understanding of their potential progression to oral squamous cell carcinoma will reduce the morbidity and mortality associated with these lesions with expedient and properly executed treatment strategies that will have a positive effect on patient survival. It is the purpose of this position paper to discuss oral mucosal dysplasia in terms of its nomenclature, epidemiology, types, natural history, and treatment to acquaint clinicians regarding the timing of biopsy, type of biopsy, and follow-up of patients with these lesions of the oral mucosa. This position paper represents a synthesis of existing literature on this topic with the intention of closing gaps in our understanding of oral mucosal dysplasia while also stimulating new thinking to guide clinicians in the proper diagnosis and management of OPMDs. The fifth edition of the World Health Organization classification of head and neck tumors published in 2022 represents new information regarding this topic and a construct for this position paper.

Family history of cancer is associated with poorer prognosis in oral squamous cell carcinoma.

OBJECTIVE: The purpose of this study was to investigate the prognostic value of the family history of cancer (FHC) in predicting survival and clinicopathological features in oral squamous cell carcinoma (OSCC) patients. MATERIALS AND METHODS: This single-institution study utilized data from 610 patients undergoing surgery from 2014 to 2020 that was prospectively collected and cataloged for research purposes. All patients underwent standard surgery with/without radiotherapy or chemoradiotherapy. We statistically evaluated whether FHC was associated with changes in disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: Among 610 patients, 141 (23.1%) reported a family history of cancer. The distribution of clinicopathological characteristics was balanced between FHC-positive and FHC-negative OSCC patients. FHC-positive patients had decreased DFS (p = 0.005) and DSS (p = 0.018) compared to FHC-negative patients. CONCLUSIONS: FHC-positive OSCC patients have a poorer prognosis. FHC positivity is an independent predictor of negative outcomes based on DFS and DSS. FHC should be a consideration in screening, evaluating, counseling, and treating OSCC patients.

American Association of Oral and Maxillofacial Surgeons' Position Paper on Medication-Related Osteonecrosis of the Jaws-2022 Update.

Strategies for management of patients with, or at risk for, medication-related osteonecrosis of the jaws (MRONJ) - formerly referred to as bisphosphonate-related osteonecrosis of the jaws (BRONJ)-were set forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) position papers in 2007, 2009 and 2014. The position papers were developed by a committee appointed by the AAOMS Board of Trustees and comprising clinicians with extensive experience in caring for these patients, as well as clinical and basic science researchers. The knowledge base and experience in addressing MRONJ continues to evolve and expand, necessitating modifications and refinements to the previous position papers. Three members of the AAOMS Committee on Oral, Head, and Neck Oncologic and Reconstructive Surgery (COHNORS) and three authors of the 2014 position paper were appointed to serve as a working group to analyze the current literature and revise the guidance as indicated to reflect current knowledge in this field. This update contains revisions to diagnosis and management strategies and highlights the current research status. AAOMS maintains that it is vitally important for this information to be disseminated to other relevant healthcare professionals and organizations.

Anti-tumor Effect of Folate-Binding Protein: In Vitro and In Vivo Studies.

Folate receptor (FR) overexpression in a wide range of solid tumors provides an opportunity to develop novel, targeted cancer therapeutics. In this study, we investigated whether prebinding the chemotherapeutic methotrexate (MTX) to folate-binding protein (FBP), the soluble form of FR, would enable the protein to serve as a targeted therapeutic vector, enhancing uptake into tumor cells and improving therapeutic efficacy. In an in vivo study, using an FR-overexpressing KB xenograft model in SCID mice, modest improvement in inhibiting tumor growth was observed for the MTX/FBP mixtures as compared to saline control and free MTX. Surprisingly, FBP alone inhibited tumor growth compared to saline control, free MTX, and FBP/MTX. In order to better understand this effect, we investigated the cytotoxicity of micromolar concentrations of FBP in vitro using the KB, HeLa, and A549 cancer cell lines. Our results revealed concentration-dependent apoptosis (24 h; 10-50 µM) in all three cell lines accompanied by a time- and concentration-dependent reduction (6, 12, and 24 h; 10-50 µM) in metabolic activity and compromised cell plasma membrane integrity. This study demonstrates an apoptosis pathway for cytotoxicity of FBP, an endogenous serum protein, in cancer cell lines with widely varying levels of FR expression. Furthermore, in vivo tumor growth suppression for xenograft KB tumors in SCID mice was observed. These studies suggest novel strategies for the elimination of cancer cells employing endogenous, serum transport proteins.

The Opioid Analgesic Reduction Study (OARS)-a comparison of opioid vs. non-opioid combination analgesics for management of post-surgical pain: a double-blind randomized clinical trial.

BACKGROUND: Everyday people die unnecessarily from opioid overdose-related addiction. Dentists are among the leading prescribers of opioid analgesics. Opioid-seeking behaviors have been linked to receipt of initial opioid prescriptions following the common dental procedure of third molar extraction. With each opioid prescription, a patient's risk for opioid misuse or abuse increases. With an estimated 56 million tablets of 5 mg hydrocodone annually prescribed after third molar extractions in the USA, 3.5 million young adults may be unnecessarily exposed to opioids by dentists who are inadvertently increasing their patient's risk for addiction. METHODS: A double-blind, stratified randomized, multi-center clinical trial has been designed to evaluate whether a combination of over-the-counter non-opioid-containing analgesics is not inferior to the most prescribed opioid analgesic. The impacted 3rd molar extraction model is being used due to the predictable severity of the post-operative pain and generalizability of results. Within each site/clinic and gender type (male/female), patients are randomized to receive either OPIOID (hydrocodone/acetaminophen 5/300 mg) or NON-OPIOID (ibuprofen/acetaminophen 400/500 mg). Outcome data include pain levels, adverse events, overall patient satisfaction, ability to sleep, and ability to perform daily functions. To develop clinical guidelines and a clinical decision-making tool, pain management, extraction difficulty, and the number of tablets taken are being collected, enabling an experimental decision-making tool to be developed. DISCUSSION: The proposed methods address the shortcomings of other analgesic studies. Although prior studies have tested short-term effects of single doses of pain medications, patients and their dentists are interested in managing pain for the entire post-operative period, not just the first 12 h. After surgery, patients expect to be able to perform normal daily functions without feeling nauseous or dizzy and they desire a restful sleep at night. Parents of young people are concerned with the risks of opioid use and misuse, related either to treatments received or to subsequent use of leftover pills. Upon successful completion of this clinical trial, dentists, patients, and their families will be better able to make informed decisions regarding post-operative pain management. TRIAL REGISTRATION: ClinicalTrials.gov NCT04452344 . Registered on June 20, 2020.

Phosphorylation of TRIP13 at Y56 induces radiation resistance but sensitizes head and neck cancer to cetuximab.

Radiation therapy, a mainstay of treatment for head and neck cancer, is not always curative due to the development of treatment resistance; additionally, multi-institutional trials have questioned the efficacy of concurrent radiation with cetuximab, the epidermal growth factor receptor (EGFR) inhibitor. We unraveled a mechanism for radiation resistance; that is, radiation induces EGFR, which phosphorylates TRIP13 (thyroid hormone receptor interactor 13) on tyrosine 56. Phosphorylated (phospho-)TRIP13 promotes non-homologous end joining (NHEJ) repair to induce radiation resistance. NHEJ is the main repair pathway for radiation-induced DNA damage. Tumors expressing high TRIP13 do not respond to radiation but are sensitive to cetuximab or cetuximab combined with radiation. Suppression of phosphorylation of TRIP13 at Y56 abrogates these effects. These findings show that EGFR-mediated phosphorylation of TRIP13 at Y56 is a vital mechanism of radiation resistance. Notably, TRIP13-pY56 could be used to predict the response to radiation or cetuximab and could be explored as an actionable target.

Current Practices in Microvascular Reconstruction by Oral and Maxillofacial Surgeons.

PURPOSE: Microvascular free tissue transfer (MFTT) is a reliable reconstructive option with variation in perioperative care and a general lack of clinical practice guidelines. Oral and maxillofacial surgeons' (OMSs) current MFTT perioperative practices in the United States have not been described. This study describes these practices including surgeon practice environment, operative practices, perioperative management, and success. METHODS: The study design is cross sectional. The sample is composed of OMSs who completed an Oral/Head and Neck Oncologic and Microvascular Surgery Fellowship prior to 2018 in the United States. Data were collected by means of a survey of the study sample. Descriptive statistics were reported. RESULTS: Forty surgeons responded to the survey for a response rate of 33.9%. Respondents were 97.5% (n = 39) male and worked in private (n = 8), combination (n = 10), and academic practices (n = 23). Surgeons in private and academic practice performed an average of 23.3 (SD 13.9) and 48.6 (SD 28.6) flaps per year, respectively. The 2-team approach was used by 88.2% of surgeons. Immediate dental implants were placed in osteocutaneous free flaps by 28.6% (n = 2) of private practice surgeons and 70% (n = 14) of academic surgeons. Postoperatively, most patients went to an intensive care unit (ICU) (82.7%, average duration 2.6 days). Anticoagulation or antiplatelet medications were routinely used with the most common choice being aspirin (77.4%, n = 24). Antibiotics were universally administered, often for 3 days or longer (74.2%, n = 23). Self-reported success rates were 95.3% (SD 4.1) and 96.0% (SD 1.7) in private and academic settings, respectively. CONCLUSION: This is the first report of practice trends by microvascular OMSs in the United States. The results of this study suggest that there is variation in MFTT operative and perioperative practices by individual surgeons and practice environment with minimal variation in self-reported success rates.

Using business intelligence and data visualization to understand the characteristics of failed appointments in dental school clinics.

PURPOSE/OBJECTIVES: Broken appointments are an important cause of waste in health care. Patients who fail to attend incur costs to providers, deny trainees learning opportunities, and impact their own health as well as that of other patients who are waiting for care. METHODS: A total of 410,000 appointment records over 3 years were extracted from our electronic health record. We conducted exploratory data analysis and assessed correlations between appointment no-shows and other attributes of the appointment and the patient. The University of Michigan Medical School's Committee on Human Research reviewed the study and deemed that no Institutional Review Board oversight was necessary for this quality improvement project that was, retrospectively, turned into a study with previously de-identified data. RESULTS: The patient's previous attendance record is the single most significant correlation with attendance. We found that patients who said they are "scared" of dental visits were 62% as likely to attend as someone reporting "no problem." Patients over 65 years of age have better attendance rates. There was a positive association between receiving email/text confirmation and attendance. A total of 94.9% of those emailed a reminder and 92.2% of those who were texted attended their appointment. CONCLUSION(S): We were able to identify relationships of several variables to failed and attended appointments that we were previously unknown to us. This knowledge enabled us to implement interventions to support better attendance at Dental Clinics at the University of Michigan, improving patient health, student training, and efficient use of resources.

Squamous Cell Carcinoma of the Tongue in Young Patients: A Case Series and Literature Review.

PURPOSE: The purpose of this study was to describe 3 cases of tongue cancer in patients less than 21 years of age. Secondarily, a literature review was performed to examine disease presentation, risk factors, prognosis, and treatment strategies for young persons with tongue cancer. METHODS: The authors presented 3 cases of childhood tongue cancer between 2009 and 2020 at the University of Michigan Department of Oral and Maxillofacial Surgery (Ann Arbor, MI). An electronic literature review was conducted via PubMed, Embase, Web of Science, and MLibrary. RESULTS: Including the present case series, 64 studies reporting 108 cases were identified. Age at presentation ranged from newborn to 20 years, with a mean age of 14.5 years. The majority of patients were female (52.2%); 68.1% of patients presented with T1 or T2 disease. Nodal metastases were seen in 56.1% of patients. The most commonly identified predisposing factors included Fanconi anemia (13.9%), bone marrow transplant (9.3%), tobacco use (6.5%), and xeroderma pigmentosum (4.6%). Most patients received surgery alone (37.5%), followed by surgery with adjuvant radiation (33.8%); 60.6% underwent neck dissection. Overall survival was 60.3% at 1 year and 43.6% at 5 years. CONCLUSIONS: Oral tongue cancer in the young is a rare disease with poorly understood etiology. There is a need for oncologists and maxillofacial surgeons to collaborate in the study of genetic, social, environmental, and medical risk factors contributing to the disease. All patients should undergo high-throughput genetic sequencing to expand our understanding of the disease process and allow for targeted treatment strategies.

An In-House Computer-Aided Design and Computer-Aided Manufacturing Workflow for Maxillofacial Free Flap Reconstruction is Associated With a Low Cost and High Accuracy.

PURPOSE: In-house computer-aided surgical design and computer-aided manufacturing (CAD/CAM) can be used in oral and maxillofacial surgery for virtual surgical planning and 3-dimensional printing of patient-specific models. The purpose of this study was to measure the cost and accuracy of an in-house CAD/CAM workflow for maxillofacial free flap reconstruction. MATERIALS AND METHODS: A retrospective cohort study of patients undergoing mandibular resection and free flap reconstruction was performed between July 2017 and March 2018 in which in-house CAD/CAM was used. The predictor variable was the in-house CAD/CAM workflow. The outcome variables were in-house workflow cost, as measured by the material expenses, and accuracy, as measured by comparative distance, osteotomy angle, and surfaced overlay measurements and the root mean square (RMS) between the preoperative virtual reconstructive plan and the postoperative computed tomography scan. Additional variables evaluated were time required for in-house CAD/CAM workflow, and clinical and radiographic outcomes. RESULTS: In-house CAD/CAM was used for 26 patients undergoing mandibular resection for benign or malignant disease and free flap reconstruction with fibula (n = 24) or scapula free flap (n = 2). Overall flap success rate was 95%. The mean in-house workflow cost per case was $3.87 USD. There were no significant differences between the mean comparative distance and osteotomy angle measurements between the planned and actual mandibular reconstructions with an RMS ranging from 5.11 to 9.00 mm for distance measurements and 17.41° for the osteotomy angle measurements. The mean surface overlay difference was 1.90 mm with an RMS of 3.72 mm. CONCLUSIONS: The in-house CAD/CAM workflow is a low cost and accurate option for maxillofacial free flap reconstruction. The in-house workflow should be considered as an alternative to current practices using proprietary systems in select cases.

Is Perineural Invasion a Reasonable Indicator for Neck Dissection in cT1N0M0 Squamous Cell Carcinoma of the Oral Cavity?

PURPOSE: Perineural invasion (PNI) is considered an adverse histological feature in oral squamous cell carcinoma (OSCC). Controversy exists regarding elective neck dissection (END) in cT1N0M0 OSCC with PNI as the only risk factor. The purpose of this study was to evaluate PNI as an indicator for END, as well as its utility when combined with the depth of invasion (DOI) as a second indicator. PATIENTS AND METHODS: cT1N0M0 (AJCC8) OSCC patients treated from August 1998 to July 2017 in the Department of Oral and Maxillofacial Surgery, University of Michigan (MI), and Beijing Stomatological Hospital, Capital Medical University (BSH) were reviewed. Data from these sites included both prospectively captured data housed in a database and retrospective data. RESULTS: 283 cT1N0M0 OSCC patients were analyzed. The tongue was the most common subsite (56.2%). Ninety-nine (99) patients received END and 184 neck observation. PNI was found in only 8 patients (2.83%) all in the tongue or inferior gingiva. END was performed in 7 of the PNI patients. The mean depth of invasion for tumors with PNI was 3.97 mm, compared to 2.54 mm in tumors without PNI. PNI was statistically correlated with nodal disease (pN+) and extranodal extension (ENE+). After using DOI as a primary indicator for END, no additional PNI patients benefited from END. In addition, only 2 patients had PNI identified preoperatively both with 5 mm DOI, and therefore, already indicated for END on the basis of DOI status. CONCLUSIONS: PNI status is statistically correlated with pN+ and ENE + pathology in cT1N0M0 OSCC. After using DOI as a primary indicator for END, PNI status had no added value in decision making. Even surgeons who do not use DOI will find very limited value in PNI status with less than 1% preoperative prevalence (0.71%) in this patient population.

Comparison of Early Oral Cancer Depth of Invasion From the American Joint Committe on Cancer 7th to 8th Edition Criteria. Does the Difference Impact the Accuracy of Clinical Decision Making?

PURPOSE: Depth of invasion (DOI) is an independent predictor of regional metastasis in oral squamous cell carcinoma. Measurement criteria for DOI were modified in the American Joint Committee on Cancer (AJCC) eighth edition. The purpose of this study was to compare DOI AJCC seventh (DOI7) and eighth (DOI8) edition criteria on frozen section accuracy for decisions regarding elective neck dissection (END) in cT1N0 oral squamous cell carcinoma. PATIENTS AND METHODS: A blinded, retrospective, comparative study of patients who underwent ablative surgery at the University of Michigan was completed. The predictor variable was criteria for DOI measurement. The outcome variables were concordance between DOI7 and DOI8 measurements and accuracy using thresholds for END. Effect of tumor growth pattern and worst pattern of invasion, and the difference between DOI8 on frozen and permanent specimen were assessed. RESULTS: A total of 30 specimens of T1N0 oral squamous cell carcinoma (16 tongue, 5 alveolus, 5 floor of mouth, 4 buccal mucosa) were included. DOI7 versus DOI8 on frozen and permanent specimen were significantly different (P < .05) but clinically insignificant and highly correlated (r > 0.99, P < .001). One hundred percent concordance between DOI7 and DOI8 was noted on frozen specimen in predicting the need for END when compared with permanent pathology DOI. There was no significant impact of tumor growth pattern or worst pattern of invasion on measurements and no significant difference in DOI on frozen and permanent specimen for DOI8 (P = .68). Excellent agreement between pathologists for all measurements was observed (ICC>0.99, P < 0001). CONCLUSIONS: High concordance between DOI measurements by AJCC seventh and eighth edition criteria suggests that guidelines for DOI thresholds for END in patients with T1N0 tumors developed using the AJCC seventh edition can be safely applied using AJCC eighth edition criteria. DOI measurement by AJCC 8 criteria on frozen specimen can be used to guide decision-making regarding END, given the high correlation to AJCC 8 permanent DOI measurement.

Elective Neck Dissection in T1N0M0 Oral Squamous Cell Carcinoma: When Is It Necessary?

PURPOSE: Elective neck dissection (END) versus observation remains controversial for cT1N0M0 oral cavity squamous cell carcinoma (OSCC). The aim of this study was to determine whether neck dissection is indicated for cT1N0M0 OSCC versus observation when considering oral cavity subsites and depth of invasion (DOI) as predictors. PATIENTS AND METHODS: A multicenter, ambispective cohort study of patients with cT1N0M0 OSCC treated at the University of Michigan and Beijing Stomatological Hospital from August 1998 to July 2017 with a follow-up end date of July 2019 was performed. Patients were excluded if follow-up was less than 2 years and no neck disease had occurred or if the final pathologic analysis resulted in upstaging to T2 using American Joint Committee on Cancer criteria, eighth edition. A total of 283 patients met the criteria. The main outcome parameter was the 2-year neck metastatic rate. RESULTS: The total 2-year lymph node metastatic rate was 11.3%. Overall neck metastatic rates escalated consistently according to DOI: less than 2 mm, 2.1%; 2 to 3 mm, 9.4%; 3 to 4 mm, 15.2%; and 4 to 5 mm, 24.6%. On univariate Cox regression analysis, DOI greater than 3 mm, tumor grade, and perineural invasion were statistically significant indicators of 2-year neck metastasis. On multivariate analysis, only DOI and tumor grade remained. On multivariate analysis of 2-year survival, no factors were independent predictors. Our proposed treatment strategy for END based both on statistically significant results for DOI and on review of the raw data using a 20% cutoff analysis showed cutoffs of 2 mm for the tongue (18.2%), 3 mm for the floor of the mouth (40.0%) and upper gingiva (20%), and 4 mm for the lower gingiva (33.3%) and no cutoff for the hard palate (0.0%). CONCLUSIONS: The watch-and-wait approach remains a reasonable approach in selected patients with cT1N0M0 OSCC. Decision making for END in T1N0M0 patients should minimally consider tumor grade, DOI, and oral cavity subsite.

Oral Lichen Planus-Associated Oral Cavity Squamous Cell Carcinoma Is Associated With Improved Survival and Increased Risk of Recurrence.

PURPOSE: We investigated the overall survival (OS), disease-specific survival (DSS), and disease-free survival among patients with oral lichen planus-associated oral cavity squamous cell carcinoma (OLP-OCSCC). The secondary objective was to assess the annual risk of tumor recurrence or second primary tumor (SPT). MATERIALS AND METHODS: A comparative retrospective study was performed of patients with OLP-OCSCC presenting between June 2007 and December 2018 to the Department of Oral and Maxillofacial Surgery, Michigan Medicine (Ann Arbor, MI) and patients with OCSCC in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database (1973 to 2015). RESULTS: A total of 87 patients with OLP-OCSCC met the inclusion criteria, and 55,165 patients with OCSCC from the SEER database were included. The proportion of women was greater in the OLP group than in the SEER group (56.3 vs 38.0%; P < .001). In the OLP group, 47.1% had no smoking history and 43.7% had no alcohol history. Most patients in the OLP group had presented with stage I disease (46.0%) compared with 31.7% in the SEER group (P = .004). Overall, the OS and DSS were significantly greater in the OLP group than in the SEER group at all points from 1 to 5 years (P ≤ .01). In the OLP group, 46 patients (52.9%) had at least 1 recurrence or SPT. At 10 years, the predicted mean number of recurrences was 1.93 per patient (95% confidence interval, 1.56 to 2.39). CONCLUSIONS: OLP-OCSCC frequently affects women, nonsmokers, and nondrinkers and presents with localized disease at a high frequency. Patients with OLP-OCSCC have increased OS and DSS and a greater risk of tumor recurrence or SPT compared with OCSCC in the general population. Lifelong, frequent surveillance is recommended for patients with OLP-OCSCC owing to the risk of late recurrence. Future studies are needed to understand the pathophysiology of OLP-OCSCC.

Clinical Manifestations, Diagnosis, and Management of First Branchial Cleft Fistula/Sinus: A Case Series and Literature Review.

PURPOSE: First branchial cleft fistula/sinus is a rare congenital developmental deformity that can sometimes be acquired from incision and drainage of a branchial cleft cyst. The aim of the present study was to explore the clinical manifestations, diagnosis, and surgical management of first branchial cleft fistula/sinus in both a large patient series and a review of the pertinent literature. MATERIALS AND METHODS: The data from 31 cases diagnosed from February 2004 to April 2019 as first branchial cleft fistula/sinus were retrospectively reviewed. The patient demographic data and outcomes were explored. In addition, we performed a literature review of studies reported from 1923 to 2018 for first branchial cleft fistula/sinus and summarized those results. RESULTS: The present study included 31 patients (15 males, 16 females) with a median age of 4 years. All the patients reviewed had presented with a unilateral first branchial cleft fistula/sinus. The parotid region was the most frequent site of presentation (41.9%) in these cases. The fistula/sinus had occurred on the left side in 13 patients (41.9%) and on the right side in 18 patients (58.1%). Of the 31 patients, 24 (77.4%) had acquired the disease from infection of an existing brachial cleft cyst or incomplete previous excision. Of the 31 cases, 28 (90%) had an intimate relationship between the tract and the facial nerve. Despite this close association, no patient developed postoperative facial nerve palsy. Of the 31 operations, 30 (97%) successfully accomplished complete resection with no recurrence postoperatively. Only 1 patient with a history of multiple recurrences experienced a subsequent recurrence, which was successfully treated with a second surgery. CONCLUSIONS: First branchial cleft fistula/sinus is a frequently misdiagnosed and, therefore, undertreated entity, which leads to recurrence. It is closely associated with the facial nerve and extra auditory canal. The correct diagnosis and meticulous removal can be effectively achieved with minimal risk to the facial nerve.