Faculty Bibliography

Purpose/Objective(s): Human-papilloma virus-positive (HPV+) OPSCC is known to have an excellent prognosis with a favorable response to CRT. Several studies have shown that de-intensified treatment in select patients (pts) can achieve similar survival outcomes to standard treatment while reducing acute and long-term toxicity. Additionally, rapid clearance of circulating tumor HPV DNA may be useful in predicting the likelihood of disease control. Materials/Methods: We evaluated pts enrolled on a phase II institutional clinical trial. Pts with HPV+ OPSCC were included and were treated with definitive CRT with cisplatin. All pts were initially planned to receive standard radiation dose (S-RT) to 70 Gy; those who achieved a favorable mid-treatment response (FMTR) of >40% lymph node shrinkage at week 4 of radiation (RT) received a de-escalated dose (D-RT) to 60 Gy. Blood samples were taken at screening, week 4 of RT, and at follow-up visit after RT and circulating tumor tissue modified viral HPV NDA (TTMV) was qualtified. We define a "substantial TTMV clearance" as either >95% reduction in TTMV from screening to week 4 (screening level >200 copies/ml) or undetectable ctHPVDNA at week 4 (any detectable screening level). Fisher tests were used to evaluate the association of TTMV and treatment group.
Result(s): At the time of this analysis, 35 pts were enrolled in the clinical trial with a median age of 60 years at diagnosis (range 38 to 76). 25 pts achieved a FMTR and received D-RT while 10 pts received S-RT. 29 pts (7 S-RT, 18 D-RT) had detectable screening TTMV and week 4 TTMV samples available for analysis. D-RT pts had a significantly higher rate of substantial TTMV clearance at week 4 compared to S-RT: 14.3% (1/7) pts in the S-RT vs. 61.1% (11/18) pts in the D-RT (OR 0.090 [0.002 - 0.105], p=0.036). 6 of 25 pts (24%) had a flare in their TTMV from screening to week 4 including 57.1% (4/7) of the S-RT and 11.1% (2/18) of the D-RT; there was a significantly higher likelihood of TTMV flare in the S-RT group (OR 9.34 [0.898 - 150.960], p=0.032). 24 pts (6 S-RT, 18 D-RT) with initial detectable screening TTMV also had a follow-up TTMV sample available. The median time from screening to follow-up was 81.0 days for all pts (76.5 days for D-RT, 84.0 days for S-RT). 95.7% of pts (83.3% of S-RT, 100%% of D-RT) had complete TTMV clearance at follow-up.
Conclusion(s): We report a statistically significant correlation between substantial TTMV clearance and a FMTR of >40% nodal shrinkage. 61.1% of D-RT pts achieved a substantial TTMV clearance compared to 14.3% in the S-RT group. Additionally, we observed that pts who did not achieve a FMTR had a higher likelihood of TTMV flare at week 4. Nearly all pts achieved a complete TTMV clearance by follow-up. Mid-treatment TTMV clearance may help identify pts who may benefit from further de-escalation as well as those who should continue with standard therapy. This study has the ClinicalTrials.gov identifier NCT03215719.
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The effect of electronic cigarette (e-cigarette) smoking, especially its long-term impact on oral health, is poorly understood. Here, we conducted a longitudinal clinical study with two study visits, 6 months apart, to investigate the effect of e-cigarette use on the bacterial community structure in the saliva of 101 periodontitis patients. Our data demonstrated that e-cigarette use altered the oral microbiome in periodontitis patients, enriching members of the Filifactor, Treponema, and Fusobacterium taxa. For patients at the same periodontal disease stage, cigarette smokers and e-cigarette smokers shared more similarities in their oral bacterial composition. E-cigarette smoking may have a similar potential as cigarette smoking at altering the bacterial composition of saliva over time, leading to an increase in the relative abundance of periodontal disease-associated pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum. The correlation analysis showed that certain genera, such as Dialister, Selenomonas, and Leptotrichia in the e-cigarette smoking group, were positively correlated with the levels of proinflammatory cytokines, including IFN-γ, IL-1β, and TNF-α. E-cigarette use was also associated with elevated levels of proinflammatory cytokines such as IFN-γ and TNF-α, which contribute to oral microbiome dysbiosis and advanced disease state. This article is protected by copyright. All rights reserved.

Electronic cigarettes (e-cigs) have become prevalent as an alternative to conventional cigarette smoking, particularly in youth. E-cig aerosols contain unique chemicals which alter the oral microbiome and promote dysbiosis in ways we are just beginning to investigate. We conducted a 6-month longitudinal study involving 84 subjects who were either e-cig users, conventional smokers, or nonsmokers. Periodontal condition, cytokine levels, and subgingival microbial community composition were assessed, with periodontal, clinical, and cytokine measures reflecting cohort habit and positively correlating with pathogenic taxa (e.g., Treponema, Saccharibacteria, and Porphyromonas). α-Diversity increased similarly across cohorts longitudinally, yet each cohort maintained a unique microbiome. The e-cig microbiome shared many characteristics with the microbiome of conventional smokers and some with nonsmokers, yet it maintained a unique subgingival microbial community enriched in Fusobacterium and Bacteroidales (G-2). Our data suggest that e-cig use promotes a unique periodontal microbiome, existing as a stable heterogeneous state between those of conventional smokers and nonsmokers and presenting unique oral health challenges. IMPORTANCE Electronic cigarette (e-cig) use is gaining in popularity and is often perceived as a healthier alternative to conventional smoking. Yet there is little evidence of the effects of long-term use of e-cigs on oral health. Conventional cigarette smoking is a prominent risk factor for the development of periodontitis, an oral disease affecting nearly half of adults over 30 years of age in the United States. Periodontitis is initiated through a disturbance in the microbial biofilm communities inhabiting the unique space between teeth and gingival tissues. This disturbance instigates host inflammatory and immune responses and, if left untreated, leads to tooth and bone loss and systemic diseases. We found that the e-cig user's periodontal microbiome is unique, eliciting unique host responses. Yet some similarities to the microbiomes of both conventional smokers and nonsmokers exist, with strikingly more in common with that of cigarette smokers, suggesting that there is a unique periodontal risk associated with e-cig use.

Disclaimer/UNASSIGNED:WALT Congress, Nice, October 3-6, 2018, and a follow-up review of the existing data and the clinical observations of an international multidisciplinary panel of clinicians and researchers with expertise in the area of supportive care in cancer and/or PBM clinical application and dosimetry. This article is informational in nature. As with all clinical materials, this paper should be used with a clear understanding that continued research and practice could result in new insights and recommendations. The review reflects the collective opinion and, as such, does not necessarily represent the opinion of any individual author. In no event shall the authors be liable for any decision made or action taken in reliance on the proposed protocols. Objective/UNASSIGNED:This position paper reviews the potential prophylactic and therapeutic effects of photobiomodulation (PBM) on side effects of cancer therapy, including chemotherapy (CT), radiation therapy (RT), and hematopoietic stem cell transplantation (HSCT). Background/UNASSIGNED:There is a considerable body of evidence supporting the efficacy of PBM for preventing oral mucositis (OM) in patients undergoing RT for head and neck cancer (HNC), CT, or HSCT. This could enhance patients' quality of life, adherence to the prescribed cancer therapy, and treatment outcomes while reducing the cost of cancer care. Methods/UNASSIGNED:A literature review on PBM effectiveness and dosimetry considerations for managing certain complications of cancer therapy were conducted. A systematic review was conducted when numerous randomized controlled trials were available. Results were presented and discussed at an international consensus meeting at the World Association of photobiomoduLation Therapy (WALT) meeting in 2018 that included world expert oncologists, radiation oncologists, oral oncologists, and oral medicine professionals, physicists, engineers, and oncology researchers. The potential mechanism of action of PBM and evidence of PBM efficacy through reported outcomes for individual indications were assessed. Results/UNASSIGNED:There is a large body of evidence demonstrating the efficacy of PBM for preventing OM in certain cancer patient populations, as recently outlined by the Multinational Association for Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Building on these, the WALT group outlines evidence and prescribed PBM treatment parameters for prophylactic and therapeutic use in supportive care for radiodermatitis, dysphagia, xerostomia, dysgeusia, trismus, mucosal and bone necrosis, lymphedema, hand-foot syndrome, alopecia, oral and dermatologic chronic graft-versus-host disease, voice/speech alterations, peripheral neuropathy, and late fibrosis amongst cancer survivors. Conclusions/UNASSIGNED:There is robust evidence for using PBM to prevent and treat a broad range of complications in cancer care. Specific clinical practice guidelines or evidence-based expert consensus recommendations are provided. These recommendations are aimed at improving the clinical utilization of PBM therapy in supportive cancer care and promoting research in this field. It is anticipated these guidelines will be revised periodically.

Introduction Photobiomodulation therapy has been shown to be an effective treatment for reducing the incidence and severity of oral mucositis (OM). The objective of this study is to determine the range of effective PBM dose, and review the adequacy of reporting irradiation parameters. Methods Online databases were searched to compare efficacy of PBM versus controls for preventing or treating cancer therapy-induced OM. Irradiation parameters were reviewed for accuracy. Results A total of 53 clinical trials were identified and 29 papers were excluded, leaving 24 papers for review. Only 1 study reported all parameters accurately. Seven studies reported a difference in OMgrade >= 3 (WHO) between the placebo and PBM groups greater than 40% when PBM was used prophylactically with greater irradiation parameters (mean energy dose 50%, beam area 58%, irradiance 246%, and treatment time per point 290% greater than the overall mean values).Aplot of effect size (%) vs. total energy per session was created using studies that reported adequate information to determine both total energy per session and the difference in the percent of patients with OMgrade >= 3 between the study group and placebo group. These data points were fit with a quadratic curve to evaluate if the data may resemble the parabolic relationship observed in previous studies. Conclusions This review has reconfirmed the lack of accurate reporting of PBM parameters. Total energy per session may be used to guide PBM dose parameters

Background/UNASSIGNED:Patients with head and neck cancer (HNC) experience painful, debilitating symptoms and functional limitations that can interrupt cancer treatment, and decrease their health-related quality of life (HRQoL). The Electronic Patient Visit Assessment (ePVA) for head and neck is a web-based mHealth patient-reported measure that asks questions about 21 categories of symptoms and functional limitations common to HNC. This article presents the development and usefulness of the ePVA as a clinical support tool for real-time interventions for patient-reported symptoms and functional limitations in HNC. Methods/UNASSIGNED:Between January 2018 and August 2019, 75 participants were enrolled in a clinical usefulness study of the ePVA. Upon signing informed consent, participants completed the ePVA and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) general (C30) questionnaire v3.0 (scores range from 0 to 100 with 100 representing best HRQoL). Clinical usefulness of the ePVA was defined as demonstration of reliability, convergent validity with HRQoL, and acceptability of the ePVA (i.e., >70% of eligible participants complete the ePVA at two or more visits and >70% of ePVA reports are read by providers). Formal focus group discussions with the interdisciplinary team that cared for patients with HNC guided the development of the ePVA as a clinical support tool. Qualitative and quantitative methods were used throughout the study. Descriptive statistics consisting of means and frequencies, Pearson correlation coefficient, and Student's t-tests were calculated using SAS 9.4 and STATA. Results/UNASSIGNED:The participants were primarily male (71%), White (76%), diagnosed with oropharyngeal or oral cavity cancers (53%), and undergoing treatment for HNC (69%). Data analyses supported the reliability (alpha =0.85), convergent validity with HRQoL scores, and acceptability of the ePVA. Participants with the highest number of symptoms and functional limitations reported significantly worse HRQoL (sum of symptoms: r=-0.50, P<0.0001; sum of function limitations: r=-0.56, P<0.0001). Ninety-two percent of participants (59 of 64) who had follow-up visits within the 6-month study period completed the ePVA at two or more visits and providers read 89% (169 of 189) of automated ePVA reports. The use of the ePVA as a clinical support tool for real-time interventions for symptoms and functional limitations reported by patients is described in a clinical exemplar. Conclusions/UNASSIGNED:This research indicates that the ePVA may be a useful mHealth tool as a clinical support tool for real-time interventions for patient-reported symptoms and functional limitations in HNC. The study findings support future translational research to enhance the usefulness of the ePVA in real world settings for early interventions that decrease symptom burden and improve the QoL of patients with HNC.

Introduction/UNASSIGNED:Periodontal disease is a chronic, inflammatory bacterial dysbiosis that is associated with both Alzheimer's disease (AD) and Down syndrome. Methods/UNASSIGNED:A total of 48 elderly cognitively normal subjects were evaluated for differences in subgingival periodontal bacteria (assayed by 16S rRNA sequencing) between cerebrospinal fluid (CSF) biomarker groups of amyloid and neurofibrillary pathology. A dysbiotic index (DI) was defined at the genus level as the abundance ratio of known periodontal bacteria to healthy bacteria. Analysis of variance/analysis of covariance (ANOVA/ANCOVA), linear discriminant effect-size analyses (LEfSe) were used to determine the bacterial genera and species differences between the CSF biomarker groups. Results/UNASSIGNED: = 0.02 and 0.01) but not with P-tau. Discussion/UNASSIGNED:We show a selective relationship between periodontal disease bacterial dysbiosis and CSF biomarkers of amyloidosis, but not for tau. Further modeling is needed to establish the direct link between oral bacteria and Aβ.

There is currently no criterion to select appropriate bioinformatics tools and reference databases for analysis of 16S rRNA amplicon data in the human oral microbiome. Our study aims to determine the influence of multiple tools and reference databases on α-diversity measurements and β-diversity comparisons analyzing the human oral microbiome. We compared the results of taxonomical classification by Greengenes, the Human Oral Microbiome Database (HOMD), National Center for Biotechnology Information (NCBI) 16S, SILVA, and the Ribosomal Database Project (RDP) using Quantitative Insights Into Microbial Ecology (QIIME) and the Divisive Amplicon Denoising Algorithm (DADA2). There were 15 phyla present in all of the analyses, four phyla exclusive to certain databases, and different numbers of genera were identified in each database. Common genera found in the oral microbiome, such as Veillonella, Rothia, and Prevotella, are annotated by all databases; however, less common genera, such as Bulleidia and Paludibacter, are only annotated by large databases, such as Greengenes. Our results indicate that using different reference databases in 16S rRNA amplicon data analysis could lead to different taxonomic compositions, especially at genus level. There are a variety of databases available, but there are no defined criteria for data curation and validation of annotations, which can affect the accuracy and reproducibility of results, making it difficult to compare data across studies.