World Workshop on Oral Medicine VIII: Barriers to research in oral medicine: results from a global survey.

OBJECTIVES: To explore factors influencing research interest and productivity and perceived barriers to conducting research in Oral Medicine (OM). METHODS: Invitations to participate in an online survey were e-mailed to a network of international OM practitioners and related professional organizations. Questions captured respondents' demographic/professional variables and gauged research interest, productivity, and perceived barriers to conducting research specifically in OM. Statistical analysis was conducted via descriptive, logistic regression, and multivariate modeling. RESULTS: Five hundred and ninety-three OM practitioners from 55 countries completed the survey, with 54%, 25%, and 21% practicing in high, upper-middle, and lower-middle-income countries, respectively. Eighty-six percent of respondents were interested in conducting research. Age (less interest with an increase in age), working in academia, and practicing in a lower-middle vs high-income country were significant predictors of research interest. Self-reported research productivity was significantly greater among males, those working in academia, and those who graduated from programs that mandated research presentation/publication. Obtaining research funding was a significant barrier among respondents from lower and upper-middle-income countries, whereas finding time for research was a reported barrier by respondents from high-income countries. CONCLUSION: The results of this survey identified perceived barriers to conducting research in OM and highlighted solutions to address such barriers.

Neural network and spline-based regression for the prediction of salivary hypofunction in patients undergoing radiation therapy.

BACKGROUND: This study leverages a large retrospective cohort of head and neck cancer patients in order to develop machine learning models to predict radiation induced hyposalivation from dose-volume histograms of the parotid glands. METHODS: The pre and post-radiotherapy salivary flow rates of 510 head and neck cancer patients were used to fit three predictive models of salivary hypofunction, (1) the Lyman-Kutcher-Burman (LKB) model, (2) a spline-based model, (3) a neural network. A fourth LKB-type model using literature reported parameter values was included for reference. Predictive performance was evaluated using a cut-off dependent AUC analysis. RESULTS: The neural network model dominated the LKB models demonstrating better predictive performance at every cutoff with AUCs ranging from 0.75 to 0.83 depending on the cutoff selected. The spline-based model nearly dominated the LKB models with the fitted LKB model only performing better at the 0.55 cutoff. The AUCs for the spline model ranged from 0.75 to 0.84 depending on the cutoff chosen. The LKB models had the lowest predictive ability with AUCs ranging from 0.70 to 0.80 (fitted) and 0.67 to 0.77 (literature reported). CONCLUSION: Our neural network model showed improved performance over the LKB and alternative machine learning approaches and provided clinically useful predictions of salivary hypofunction without relying on summary measures.

NAD+ Biosynthesis Impairment and Acute Kidney Injury after Major Vascular Surgery.

Acute kidney injury (AKI) is a serious complication after vascular surgery. Reduced synthesis of nicotinamide adenine dinucleotide (NAD+) from tryptophan is associated with an increased risk of AKI in critically ill patients, patients hospitalized with COVID-19, and cardiac surgery patients, and is marked by elevated urinary quinolinate and quinolinate to tryptophan ratios. We measured quinolinate concentrations in vascular surgery patients to determine if impaired NAD+ synthesis was associated with AKI in this patient population. Eight preoperative and eight postoperative vascular surgery patients who developed AKI were selected from a parent study to participate in this single-center case-control study. They were matched with controls who did not develop AKI based on age, sex, BMI, eGFR, hypertension, and diabetes. Urinary quinolinate and tryptophan concentrations were measured at anesthetic induction and on postoperative day one. Two-sided Mann-Whitney U tests were used to compare quinolinate and quinolinate to tryptophan ratios. Multivariate linear regression modeling was used to estimate the relationship between quinolinate and serum creatinine. There was no difference in preoperative or postoperative urine quinolinate concentrations or the preoperative quinolinate to tryptophan ratio between patients that did and did not develop AKI (p = 0.07, 0.50, and 0.32, respectively). However, postoperative quinolinate to tryptophan ratios were higher in AKI patients (p = 0.04). Further, after adjustment for AKI risk factors, higher preoperative quinolinate concentrations and higher postoperative quinolinate to tryptophan ratios were associated with greater postoperative creatinine increases (p = 0.04 and 0.04, respectively). These data suggest that impaired NAD+ synthesis may contribute to AKI development in vascular surgery patients.

Conscientious use of patient-reported outcome measures in supportive care.

PURPOSE: Patient-reported outcome measures (PRO) are critical tools to developing an understanding of cancer patients' experience. This paper presents some of the lesser-understood implications of using patient-reported outcome measures in clinical research. METHODS: This study uses a combination of literature sources, real-world examples from supportive care studies, and statistical simulations to demonstrate the operating characteristics of patient-reported measures. RESULTS: It is demonstrated that care must be taken in the analysis of PROs as the assumptions of the most common mean-based approaches are often violated including linearity, normally distributed errors, interference with asymptotic convergence via boundary values, and more. Further, the implications of subjective discretization are shown to reduce the apparent statistical power of PRO-based studies. CONCLUSIONS: PRO-based studies must be designed conscientiously as each PRO item will demonstrate a varying degree of subjectivity in a given population. Sample sizes of randomized studies using PROs must be inflated to account for this. Analyses should consider using ordinal statistical models until such time as the assumptions of mean-based models can be verified.

Prophylactic gabapentin during head and neck cancer therapy: a systematic review and meta-analysis.

PURPOSE: This review was designed to compile the currently available evidence on the prophylactic use of gabapentin in the head and neck cancer patient population. METHODS: A systematic search was conducted of PubMed, Web of Science, and Google Scholar to identify articles related to the use of prophylactic gabapentin in patients undergoing head and neck cancer therapy. Candidate studies were screened for inclusion and a subsequent bias assessment was conducted by multiple reviewers. Meta-analysis was conducted in cases in which the studies used compatible outcome measures. RESULTS: Ten studies were identified that met the inclusion criteria and were assessed for bias. Among the four small studies that examined pain prevention, 2 were positive and 2 were inconclusive. Three of the four studies examiniRDng opioid use noted less need for opioids in the treatment arm. Meta-analysis of the pertinent studies showed no difference in feeding tube placement (RD = 0.64%, 95%CI: (- 25.8%, 27.1%), p = 0.962) but substantially less weight loss among those in the treatment arm (p = 0.047). CONCLUSION: Prophylactic gabapentin appears to be a promising treatment option for preventing pain, reducing opioids, and reducing weight loss in patients undergoing head and neck cancer therapy. However, the studies on the treatment to date are small and several have a substantial risk of bias.

Salivary Gland Hypofunction and/or Xerostomia Induced by Nonsurgical Cancer Therapies: ISOO/MASCC/ASCO Guideline.

PURPOSE: To provide evidence-based recommendations for prevention and management of salivary gland hypofunction and xerostomia induced by nonsurgical cancer therapies. METHODS: Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library were searched for randomized controlled trials published between January 2009 and June 2020. The guideline also incorporated two previous systematic reviews conducted by MASCC/ISOO, which included studies published from 1990 through 2008. RESULTS: A total of 58 publications were identified: 46 addressed preventive interventions and 12 addressed therapeutic interventions. A majority of the evidence focused on the setting of radiation therapy for head and neck cancer. For the prevention of salivary gland hypofunction and/or xerostomia in patients with head and neck cancer, there is high-quality evidence for tissue-sparing radiation modalities. Evidence is weaker or insufficient for other interventions. For the management of salivary gland hypofunction and/or xerostomia, intermediate-quality evidence supports the use of topical mucosal lubricants, saliva substitutes, and agents that stimulate the salivary reflex. RECOMMENDATIONS: For patients who receive radiation therapy for head and neck cancer, tissue-sparing radiation modalities should be used when possible to reduce the risk of salivary gland hypofunction and xerostomia. Other risk-reducing interventions that may be offered during radiation therapy for head and neck cancer include bethanechol and acupuncture. For patients who develop salivary gland hypofunction and/or xerostomia, interventions include topical mucosal lubricants, saliva substitutes, and sugar-free lozenges or chewing gum. For patients with head and neck cancer, oral pilocarpine and oral cevimeline, acupuncture, or transcutaneous electrostimulation may be offered after radiation therapy.Additional information can be found at www.asco.org/supportive-care-guidelines.

An improved predictive model for postoperative pulmonary complications after free flap reconstructions in the head and neck.

BACKGROUND: Commonly used predictive models for postoperative pulmonary complications (PPCs) do not perform when applied to head and neck cases. A head and neck-specific risk prediction tool is needed. METHODS: Data on 794 free flap head and neck surgery cases at a single center were abstracted from the electronic medical record. Each case was reviewed for the development of PPCs. A predictive model was developed and was then compared to existing predictive models for PPCs. RESULTS: The least absolute shrinkage and selection operator procedure identified age, alcohol use, history of congestive heart failure, preoperative packed cell volume, preoperative oxygen saturation, and preoperative metabolic equivalents as predictors of PPCs in the head and neck population. The model demonstrated an area under the receiving operating characteristic curve of 0.75 (0.69-0.80) with moderately good calibration. Comparisons to the performance of existing models demonstrate superior performance. CONCLUSIONS: The model for the development of PPCs developed in this article displays superior performance to existing models.

Perioperative high density lipoproteins, oxidative stress, and kidney injury after cardiac surgery.

Oxidative stress promotes acute kidney injury (AKI). Higher HDL cholesterol concentrations are associated with less AKI. To test the hypothesis that HDL antioxidant activity is associated with AKI after cardiac surgery, we quantified HDL particle (HDL-P) size and number, paraoxonase-1 (PON-1) activity, and isofuran concentrations in 75 patients who developed AKI and 75 matched control patients. Higher preoperative HDL-P was associated with less AKI (OR: 0.80; 95% CI, 0.71-0.91; P = 0.001), higher PON-1 activity ( P < 0.001), and lower plasma concentrations of isofurans immediately after surgery (P = 0.02). Similarly, higher preoperative small HDL-P was associated with less AKI, higher PON-1 activity, and lower isofuran concentrations. Higher intraoperative particle losses were associated with less AKI (OR: 0.79; 95% CI 0.67-0.93; P = 0.005), and with decreased postoperative isofuran concentrations (P = 0.04) . Additionally, higher preoperative small HDL-P and increased intraoperative small particle loss were associated with improved long-term renal function (P = 0.003, 0.01, respectively). In conclusion, a higher preoperative concentration of HDL-P, particularly small particles, is associated with lower oxidative damage and less AKI. Perioperative changes in HDL-P concentrations are also associated with AKI. Small HDL-P may represent a novel modifiable risk factor for AKI.

Elevated Serum Amino Acids Induce a Subpopulation of Alpha Cells to Initiate Pancreatic Neuroendocrine Tumor Formation.

The cellular origin of sporadic pancreatic neuroendocrine tumors (PNETs) is obscure. Hormone expression suggests that these tumors arise from glucagon-producing alpha cells or insulin-producing ß cells, but instability in hormone expression prevents linage determination. We utilize loss of hepatic glucagon receptor (GCGR) signaling to drive alpha cell hyperproliferation and tumor formation to identify a cell of origin and dissect mechanisms that drive progression. Using a combination of genetically engineered Gcgr knockout mice and GCGR-inhibiting antibodies, we show that elevated plasma amino acids drive the appearance of a proliferative population of SLC38A5+ embryonic progenitor-like alpha cells in mice. Further, we characterize tumors from patients with rare bi-allelic germline GCGR loss-of-function variants and find prominent tumor-cell-associated expression of the SLC38A5 paralog SLC7A8 as well as markers of active mTOR signaling. Thus, progenitor cells arise from adult alpha cells in response to metabolic signals and, when inductive signals are chronically present, drive tumor initiation.

Preventive use of gabapentin to decrease pain and systemic symptoms in patients with head and neck cancer undergoing chemoradiation.

BACKGROUND: Radiation for patients with head and neck cancer (HNC) is associated with painful mucositis that impacts the delivery of treatment and contributes to high symptom burden. METHODS: This was a prospective, randomized pilot trial. Eligible patients received primary or adjuvant chemoradiation. Patients were randomized to usual care vs usual care plus gabapentin titrated to drug tolerance during radiation. Patients completed a symptom survey at baseline and weekly during therapy. RESULTS: Seventy-nine patients were enrolled in the study (38 control, 41 treatment). At interim analysis, gabapentin use resulted in a decrease in pain (P = .004), with the biggest decreases being in the latter weeks of therapy. By week 7, the median pain score in the treatment group was below the 0.25 quantile of the control group. CONCLUSION: Prophylactic use of gabapentin during chemoradiation for HNC patients resulted in a decrease in pain, neurosensory symptoms, and general systemic symptoms.

A Bayesian method to estimate variant-induced disease penetrance.

A major challenge emerging in genomic medicine is how to assess best disease risk from rare or novel variants found in disease-related genes. The expanding volume of data generated by very large phenotyping efforts coupled to DNA sequence data presents an opportunity to reinterpret genetic liability of disease risk. Here we propose a framework to estimate the probability of disease given the presence of a genetic variant conditioned on features of that variant. We refer to this as the penetrance, the fraction of all variant heterozygotes that will present with disease. We demonstrate this methodology using a well-established disease-gene pair, the cardiac sodium channel gene SCN5A and the heart arrhythmia Brugada syndrome. From a review of 756 publications, we developed a pattern mixture algorithm, based on a Bayesian Beta-Binomial model, to generate SCN5A penetrance probabilities for the Brugada syndrome conditioned on variant-specific attributes. These probabilities are determined from variant-specific features (e.g. function, structural context, and sequence conservation) and from observations of affected and unaffected heterozygotes. Variant functional perturbation and structural context prove most predictive of Brugada syndrome penetrance.

Transcervical sonography and human papillomavirus 16 E6 antibodies are sensitive for the detection of oropharyngeal cancer.

BACKGROUND: Human papillomavirus 16 (HPV-16) E6 seropositivity is a promising early marker of human papillomavirus-driven oropharyngeal cancer (HPV-OPC), yet more sensitive imaging modalities are needed before screening is considered. The objective of this study was to determine the sensitivity of transcervical sonography (TCS) for detecting clinically apparent HPV-OPC in comparison with computed tomography (CT) and positron emission tomography (PET)/CT. METHODS: Fifty-one patients with known or suspected HPV-OPC without prior treatment underwent oropharyngeal TCS and blood collection (for HPV multiplex serology testing). Eight standard sonographic images were collected; primary-site tumors were measured in 3 dimensions if identified. Each patient underwent a full diagnostic workup as part of standard clinical care. The pathologic details, HPV status, final staging, and imaging findings were abstracted from the medical record. The sensitivity of each imaging modality was compared with the final clinical diagnosis (the gold standard). RESULTS: Twenty-four base of tongue cancers (47%), 22 tonsillar cancers (43%), and 2 unknown primary cancers (4%) were diagnosed; 3 patients (6%) had no tumors. All p16-tested patients were positive (n = 47). Primary-site tumors were correctly identified in 90.2% (95% confidence interval [CI], 78.6%-96.7%) with TCS, in 69.4% (95% CI, 54.6%-81.7%) with CT, and in 83.3% (95% CI, 68.6%-93.0%) with PET/CT. TCS identified tumors in 10 of 14 cases missed by CT and recognized the absence of tumors in 3 cases for which CT or PET/CT was falsely positive. The smallest sonographically identified primary-site tumor was 0.5 cm in its greatest dimension; the average size was 2.3 cm. Among p16-positive patients, 76.1% (95% CI, 61.2%-87.4%) were seropositive for HPV-16 E6. CONCLUSIONS: TCS and HPV-16 E6 antibodies are sensitive for the diagnosis of HPV-OPC.

SOX4-mediated repression of specific tRNAs inhibits proliferation of human glioblastoma cells.

Transfer RNAs (tRNAs) are products of RNA polymerase III (Pol III) and essential for mRNA translation and ultimately cell growth and proliferation. Whether and how individual tRNA genes are specifically regulated is not clear. Here, we report that SOX4, a well-known Pol II-dependent transcription factor that is critical for neurogenesis and reprogramming of somatic cells, also directly controls, unexpectedly, the expression of a subset of tRNA genes and therefore protein synthesis and proliferation of human glioblastoma cells. Genome-wide location analysis through chromatin immunoprecipitation-sequencing uncovers specific targeting of SOX4 to a subset of tRNA genes, including those for tRNAiMet Mechanistically, sequence-specific SOX4-binding impedes the recruitment of TATA box binding protein and Pol III to tRNA genes and thereby represses their expression. CRISPR/Cas9-mediated down-regulation of tRNAiMet greatly inhibits growth and proliferation of human glioblastoma cells. Conversely, ectopic tRNAiMet partially rescues SOX4-mediated repression of cell proliferation. Together, these results uncover a regulatory mode of individual tRNA genes to control cell behavior. Such regulation may coordinate codon usage and translation efficiency to meet the demands of diverse tissues and cell types, including cancer cells.

Existing Predictive Models for Postoperative Pulmonary Complications Perform Poorly in a Head and Neck Surgery Population.

Postoperative pulmonary complications (PPCs) are common following major surgical procedures. Risk stratification tools have been developed to identify patients at risk for PPCs. While otolaryngology cases were included in the development of common predictive tools, they comprised small percentages in each tool. It is unclear how these tools perform in patients undergoing major head and neck surgery with free flap reconstruction. This retrospective review studied all free flap reconstructions in head and neck surgery over a 12-year period at a single institution in the southeastern US. Baseline demographic and medical information were included for each case. All cases were reviewed for development of major PPCs, including pneumonia and respiratory failure. The cohort underwent risk stratification using the ARISCAT and Gupta pulmonary risk indices. Performance of these predictive models for head and neck surgery was determined through receiver-operator curve comparison. 794 patients were identified with a median age of 62 years (IQR 41-83). Sixty-five percent were male. Forty-three (5.4%) developed pneumonia, 23 patients developed respiratory failure (2.9%), and 38 patients developed both (4.8%), resulting in a total PPC proportion of 13.1% (n = 104). Both ARISCAT and Gupta pulmonary risk indices demonstrated low discrimination to predict PPCs in head and neck free flap reconstruction, with areas under the curve of 0.60 and 0.65, respectively. Two major indices for prediction of postoperative pulmonary complications do not accurately identify risk in patients undergoing major head and neck surgery. Further studies are needed to develop predictive tools for PPCs in this high-risk population.

Lower levels of education and household income mediate lower dental care utilization among survivors of early life cancers.

This study was an examination of dental care utilization among survivors of early life cancers (cancer diagnosis at 20 years of age or younger) and the extent to which socio-economic factors may present a barrier to care. Data were obtained from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016 (n = 28,640). Survey-weighted regression models were used to evaluate associations between early life cancers and subsequent frequency of dental care as adults. A mediation analysis was conducted to test education and household income as potential mediators of this association using a non-parametric bootstrap approach. Early life cancers were associated with a significant decrease in dental care utilization as adults (OR:0.459, 95%CI:(0.226, 0.935)). This diminished utilization was particularly pronounced with survivors in their 20s and 30s. Over time dental care utilization began a slow recovery. The association between early cancer and level of education was estimated to be negative but did not reach statistical significance (OR:0.739, 95%CI:(0.503, 1.086), p = 0.123). Survivors of early life cancers were less likely to be in a higher income bracket (OR:0.663, 95%CI:(0.452, 0.973), p = 0.036)). Decreases in education and household income (p < 0.001) mediated the association between early cancers and lower dental utilization. This pathway accounted for 41.7% (95%CI:(14.1%, 50.6%)) of the association. Survivors of early life cancers did not utilize professional oral health care at a rate commensurate with their risk of dental disease. Providers involved in the long-term care should promote routine dental maintenance. Further study into non-economic barriers in this population is warranted.

Protein structure aids predicting functional perturbation of missense variants in SCN5A and KCNQ1.

Rare variants in the cardiac potassium channel KV7.1 (KCNQ1) and sodium channel NaV1.5 (SCN5A) are implicated in genetic disorders of heart rhythm, including congenital long QT and Brugada syndromes (LQTS, BrS), but also occur in reference populations. We previously reported two sets of NaV1.5 (n = 356) and KV7.1 (n = 144) variants with in vitro characterized channel currents gathered from the literature. Here we investigated the ability to predict commonly reported NaV1.5 and KV7.1 variant functional perturbations by leveraging diverse features including variant classifiers PROVEAN, PolyPhen-2, and SIFT; evolutionary rate and BLAST position specific scoring matrices (PSSM); and structure-based features including "functional densities" which is a measure of the density of pathogenic variants near the residue of interest. Structure-based functional densities were the most significant features for predicting NaV1.5 peak current (adj. R2 = 0.27) and KV7.1 + KCNE1 half-maximal voltage of activation (adj. R2 = 0.29). Additionally, use of structure-based functional density values improves loss-of-function classification of SCN5A variants with an ROC-AUC of 0.78 compared with other predictive classifiers (AUC = 0.69; two-sided DeLong test p = .01). These results suggest structural data can inform predictions of the effect of uncharacterized SCN5A and KCNQ1 variants to provide a deeper understanding of their burden on carriers.

Early onset oral tongue squamous cell carcinoma: Associated factors and patient outcomes.

BACKGROUND: Incidence of oral tongue squamous cell carcinoma (OTC) is rising among those under age 50 years. The etiology is unknown. METHODS: A total of 395 cases of OTC diagnosed and/or treated at Vanderbilt University Medical Center between 2000 and 2017 were identified. Of those, 113 (28.6%) were early onset (age < 50 years). Logistic regression was used to identify factors associated with early onset OTC. Cox proportional hazards models evaluated survival and recurrence. RESULTS: Compared to typical onset patients, patients with early onset OTC were more likely to receive multimodality treatment (surgery and radiation; adjusted odds ratio [aOR], 2.7; 95% confidence interval [CI], 1.2-6.3) and report a history of snuff use (aOR, 5.4; 95% CI, 1.8-15.8) and were less likely to report a history of cigarette use (aOR, 0.5; 95% CI, 0.2-0.9). Early onset patients had better overall survival (adjusted hazard ratio, 0.6). CONCLUSIONS: This is the largest study to evaluate factors associated with early onset OTC and the first to report an association with snuff.