Publications by authors named "Nathaniel S Treister"

61 Publications

Oral Appliances in the Management of Neuropathic Orofacial Pain: A Retrospective Case Series.

Oral Dis 2021 Mar 1. Epub 2021 Mar 1.

Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, 75 Francis St, Boston, MA, 02115, USA.

Objective: Neuropathic orofacial pain disorders are frequently managed with topical or systemic medications that carry risk for dangerous side effects such as drowsiness, disorientation, and/or physical addiction. The aim of this paper is to report the use of neurosensory oral appliances as a safe means of providing symptomatic relief for neuropathic orofacial pain.

Study Design: This is a retrospective chart review of patients with diagnoses of persistent idiopathic facial pain (PIFP), painful post-traumatic trigeminal neuropathy (PTTN), or an oral dysesthesia, who utilized neurosensory appliances with or without the use of topical anesthetic gel.

Results: Eleven patients were identified. Eight patients (62.5%) found benefit with the neurosensory appliance alone, and three patients (37.5%) found relief with the addition of lidocaine 2% gel. All patients reported >50% resolution of their symptoms, with three (37.5%) reporting complete resolution. Seven patients maintained follow up ≥ 3 months, with efficacy lasting for a range of at least 3 - 8 months.

Conclusion: Oral neurosensory appliances, whether used alone as a physical barrier or as a vehicle to deliver topical anesthetic, represent a safe and effective modality for the management of neuropathic orofacial pain disorders. Additional studies are needed to assess long-term efficacy.
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http://dx.doi.org/10.1111/odi.13824DOI Listing
March 2021

Pathologies of oral and sinonasal mucosa following facial vascularized composite allotransplantation.

J Plast Reconstr Aesthet Surg 2020 Dec 11. Epub 2020 Dec 11.

Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. Electronic address:

Background: Cutaneous changes of facial vascularized composite allotransplants (fVCAs) are extensively described in the literature. Parts of the nose, nasal, and oral cavities are included in most fVCAs. Distinctively, the nose and mouth are lined by mucosa. Little is known about the histopathology and complications of the mucosa involved in fVCA patients.

Methods: The study constitutes a retrospective cohort study of nine fVCA patients. Medical records were reviewed for information about changes of oral and nasal mucous membranes. Types of mucosal lesions were recorded and analyzed. Uni- and multivariate generalized estimating equation (GEE) models were used to assess the odds of developing mucosal inflammation in the presence of clinico-pathologic variables.

Results: A total of 186 clinical encounters with examination of oral and nasal mucous membranes were included. Membranes were devoid of clinical pathology in 101 instances (53% of all clinical assessments). Ulcerations/erosions (27%), edema (18%), and erythema (14%) were the most common lesions. Oral lesions affected the lips (58%), buccal mucosa (38%), and palate (5%). Sinonasal processes predominantly affected nasal vestibules and septae. In univariate analysis, sirolimus, skin rejection, and skin Banff grade were associated with the presence of an acute inflammatory mucosal lesion (p<0.05). In multivariate analysis, skin Banff grade and sirolimus were independent predictors of mucosal inflammation.

Conclusion: Pathologies of fVCA mucous membranes are more common than previously reported. Mucosal assessment plays an important role in the pleomorphic allograft rejection process evaluation rather than diagnosis and treatment based on cutaneous pathology.  A closer look at the pathophysiology of fVCA mucosal rejection and inflammation is warranted.
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http://dx.doi.org/10.1016/j.bjps.2020.11.028DOI Listing
December 2020

Oral chronic graft-versus-host disease: What the general dental practitioner needs to know.

J Am Dent Assoc 2020 Nov;151(11):846-856

Background: Long-term survivors of allogeneic hematopoietic cell transplantation will increasingly seek care from dental providers.

Methods: The authors highlight the importance of minimizing oral symptoms and complications associated with oral chronic graft-versus-host-disease (cGVHD).

Results: Chronic GVHD is the result of an immune response of donor-derived cells against recipient tissues. Oral cGVHD can affect the mucosa and damage salivary glands and cause sclerotic changes. Symptoms include sensitivity and pain, dry mouth, taste changes, and limited mouth opening. Risk of developing caries and oral cancer is increased. Food intake, oral hygiene, and dental interventions can represent challenges. Oral cGVHD manifestations and dental interventions should be managed in close consultation with the medical team, as systemic treatment for cGVHD can have implications for dental management.

Conclusions: General dental practitioners can contribute substantially to alleviating oral cGVHD involvement and preventing additional oral health deterioration.

Practical Implications: Frequent examinations, patient education, oral hygiene reinforcement, dry mouth management, caries prevention, and management of dental needs are indicated. In addition, oral physical therapy might be needed. Invasive dental interventions should be coordinated with the transplantation team. Screening for oral malignancies is important even years after resolution of GVHD symptoms. Management of the oral manifestations of cGVHD might require referral to an oral medicine professional.
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http://dx.doi.org/10.1016/j.adaj.2020.08.001DOI Listing
November 2020

Rural patients with oral squamous cell carcinoma experience better prognosis and long-term survival.

Oral Oncol 2020 12 20;111:105037. Epub 2020 Oct 20.

Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA, United States.

Objectives: No studies have attempted to examine the role of geographic location on oral squamous cell carcinoma (OSCC) disease progression in the United States (US). The purpose of this study is to analyze rural-urban differences in prognosis and long-term survival in patients with OSCC.

Materials And Methods: This retrospective cohort study utilizes the National Cancer Institute's (NCI) Surveillance, Epidemiology and End Results (SEER) database to examine primary OSCC diagnoses from 1990 to 2015 in the US. The primary predictor variable was patient Rural-Urban Continuum Code (RUCC) (rural vs. urban). The primary outcome variable consisted of overall survival time after initial diagnosis. Additional variables assessed include patient demographics, primary anatomical site of the cancer, histological diagnosis, stage/grade at time of diagnosis, and disease outcome. Descriptive statistics were calculated, and categorical variables were compared. Additional cumulative survival and univariate/multivariate analyses were performed.

Results: 46,678 cases of OSCC between 1990 and 2015 were identified. The rural subgroup was more likely to present at the time of diagnosis with a lower grade (p < 0.001) and an earlier stage (p < 0.001). Rural populations demonstrated superior overall survival (p < 0.001), whereas urban populations were more likely to die as a result of their OSCC (p < 0.001). After adjusting for all patient-specific factors, urban status still yielded a poorer disease prognosis.

Conclusion: Living in rural areas is associated with better prognosis and long-term survival in patients with OSCC. Further studies are needed to better elucidate the mechanisms underlying these findings.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105037DOI Listing
December 2020

Epidemiologic factors in patients with advanced head and neck cancer treated with radiation therapy.

Head Neck 2021 Jan 29;43(1):164-172. Epub 2020 Sep 29.

Section of Oral Medicine, University of Connecticut Health, Farmington, Connecticut, USA.

Background: Approximately 50% of patients with head and neck cancer (HNC) initially were seen with advanced disease. We aimed to evaluate the association of epidemiologic factors with advanced HNC at diagnosis.

Methods: The OraRad multicenter prospective cohort study enrolled HNC patients receiving curative-intent radiation therapy. Factors assessed for association with advanced HNC presentation at diagnosis included demographics, social and medical history, cancer characteristics, human papilloma virus (HPV) status, and dental disease measures.

Results: We enrolled 572 participants; 77% male and mean (SD) age of 61.7 (11.2) years. Oropharyngeal squamous cell carcinomas (88% HPV-related) were seen with smaller tumors, but more frequent nodal involvement. Private medical insurance and no Medicaid were associated with smaller tumors. A higher dental disease burden was associated with larger tumors.

Conclusions: Insurance status, cancer type/location, and dental disease are associated with advanced HNC and may represent potentially modifiable factors or factors to be considered in the screening process of new lesions.
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http://dx.doi.org/10.1002/hed.26468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756563PMC
January 2021

Chronic Oral Lesions.

Dermatol Clin 2020 Oct 11;38(4):451-466. Epub 2020 Aug 11.

Division of Oral and Maxillofacial Surgery, Oral Medicine and Dentistry, Brigham and Women's Hospital, 1620 Tremont Street, Boston, MA 02115, USA.

Chronic oral mucosal lesions can be associated with several mucocutaneous diseases. This article reviews the autoimmune and immune-mediated, reactive, genetic, and infectious diseases that may present with chronic oral and/or cutaneous manifestations and provides a rational approach to diagnosis and management.
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http://dx.doi.org/10.1016/j.det.2020.05.006DOI Listing
October 2020

Implication of COVID-19 in oral oncology practices in Brazil, Canada, and the United States.

Oral Dis 2020 Jun 17. Epub 2020 Jun 17.

Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1111/odi.13493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323326PMC
June 2020

Oral health in allogeneic hematopoietic stem cells transplantation survivors.

Bone Marrow Transplant 2020 11 7;55(11):2211-2214. Epub 2020 May 7.

Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA, USA.

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http://dx.doi.org/10.1038/s41409-020-0927-0DOI Listing
November 2020

Burning mouth syndrome: a diagnostic challenge.

Oral Surg Oral Med Oral Pathol Oral Radiol 2020 Feb 12;129(2):120-124. Epub 2019 Oct 12.

Harvard School of Dental Medicine, Boston, MA, USA; Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA, USA.

Objectives: The aim of this study was to characterize the diagnostic process that patients with burning mouth syndrome (BMS) undergo and to identify the potential pitfalls encountered in the workup and management of BMS.

Study Design: A retrospective chart review of patients with BMS seen at the Oral Medicine clinic at Brigham and Women's Hospital (Boston, MA) was conducted from January 2014 to April 2017. Abstracted data focused on the period from onset of symptoms to referral to the Oral Medicine clinic for definitive diagnosis and included providers consulted, symptom characteristics, diagnostic tests performed, and provisional diagnoses and treatments offered.

Results: One hundred and two patients (86.3% females) were included (median age 60 years). Median time from onset of symptoms to referral to the Oral Medicine clinic was 12 months (range 4-370 months). Patients saw a median of 3 providers (range 1-7); 30.4% had undergone a diagnostic test; 63.7% had been given a provisional diagnosis; and 78.4% had received treatment. Candidiasis was the most common misdiagnosis (25.5%), and antifungal medication was the most frequently prescribed therapy (27.5%).

Conclusions: Patients with BMS experience delay in diagnosis and management despite seeking and receiving professional care. Many undergo unnecessary tests and tend to be misdiagnosed or receive no diagnosis at all. Even those correctly diagnosed with BMS often receive inappropriate or ineffective treatment.
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http://dx.doi.org/10.1016/j.oooo.2019.09.015DOI Listing
February 2020

A mobile molar with furcation involvement.

J Am Dent Assoc 2019 11 18;150(11):972-978. Epub 2019 Mar 18.

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http://dx.doi.org/10.1016/j.adaj.2018.12.003DOI Listing
November 2019

Integrated genomic characterization of oral carcinomas in post-hematopoietic stem cell transplantation survivors.

Oral Oncol 2018 06 10;81:1-9. Epub 2018 Apr 10.

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, USA.

Objectives: Secondary oral squamous cell carcinoma (OSCC) is a late complication in allogeneic hematopoietic stem cell transplantation (HSCT) patients, but little is known about long-term outcomes and prognostication. Additionally, molecular alterations and immunologic insights unique to this disease remain largely unexplored.

Methods: We present a cohort of 31 patients with post-HSCT OSCC and reported on clinicopathologic predictors of survival. Whole-exome sequencing was performed on 6 (19%) matched pairs of peripheral blood (post-conditioning, pre-HSCT) and tumor samples. The entire cohort had archival tumor available for immunoprofiling with PD-1/L1 immunohistochemistry.

Results: Five-year overall survival (OS) was 57% (95% CI: 46.1-69.8) with a median disease-free survival (DFS) of 13.3 months. Advanced initial staging, a buccal or oral tongue subsite, chronic oral graft-versus-host disease (GVHD) and smoking all negatively impacted survival. High tumor mutational burden (TMB) (median 11.3 vs. 5.0) and unique mutational signatures were noted between unrelated and related donor groups - with a strong correlation between infiltrating PD-1+ lymphocytes and TMB (R = 0.98, p < 0.01). Some differences were observed when comparing commonly mutated genes among our cohort and TCGA, with a predominance of TP53 events.

Conclusion: Survival outcomes appear similar in HSCT survivors with OSCC compared with non-HSCT OSCC populations. We identified somatic alterations in genes with therapeutic potential unique to this subpopulation of oral cancers.
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http://dx.doi.org/10.1016/j.oraloncology.2018.04.007DOI Listing
June 2018

Economic and Practical Considerations in the Treatment of Oral Mucosal Chronic Graft-Versus-Host Disease.

Biol Blood Marrow Transplant 2018 08 2;24(8):1748-1753. Epub 2018 Mar 2.

Division of Oral Medicine and Dentistry, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts.

Chronic graft-versus-host disease (cGVHD) frequently affects the oral mucosa and is generally responsive to topical immunomodulatory therapies. Clinicians may benefit from guidance in choosing the most appropriate therapy with respect to practicality and cost. To assess the economic considerations related to topical immunomodulatory treatments for management of oral mucosal cGVHD and their practical implications. Topical treatments used for management of oral cGVHD were obtained from the National Institutes of Health Consensus document for ancillary and supportive care. Cost data for a standard 1-month prescription was obtained from national databases for commercially available formulations and from compounding pharmacies for formulations requiring compounding. There are numerous topical preparations used for the management of oral cGVHD, many of which require compounding. The average wholesale price of the commercially available agents ranges from $5 to $277/month, and the cost of the compounded preparations ranges from $43 to $499/month. Costs can be influenced by drug-, patient-, and pharmacy-related factors. The costs associated with topical treatment of oral cGVHD are substantial, particularly because the disease is chronic and expenses accumulate over time. Rational prescribing according to a proposed algorithm, including de-escalation of therapy when indicated, can help to minimize associated costs. This has practical implications for patients, physicians, pharmacies, and insurance providers.
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http://dx.doi.org/10.1016/j.bbmt.2018.02.022DOI Listing
August 2018

Dental disease before radiotherapy in patients with head and neck cancer: Clinical Registry of Dental Outcomes in Head and Neck Cancer Patients.

J Am Dent Assoc 2017 12;148(12):868-877

Background: No evidence-based guidelines exist for preventive dental care before radiation therapy (RT) in patients with head and neck cancer (HNC). An ongoing multicenter, prospective cohort study, Clinical Registry of Dental Outcomes in Head and Neck Cancer Patients (OraRad), is addressing this knowledge gap. The authors evaluated the level of dental disease before RT in the OraRad cohort, factors associated with dental disease, and dental treatment recommendations made before RT.

Methods: As part of OraRad, the authors assessed caries, periodontal disease, dental recommendations, and dental interventions performed before RT.

Results: Baseline measures were reported for 356 participants (77% men) with mean (standard deviation) age of 59.9 (11.0) years. Measures included mean number of teeth (22.9), participants with at least 1 tooth with caries (37.2%), and participants with at least 1 tooth with probing depth 5 millimeters or greater (47.4%). Factors associated with less extensive dental disease before RT included having at least a high school diploma, having dental insurance, history of routine dental care, and a smaller tumor size (T1 or T2). Based on the dental examination before RT, 163 (49.5%) participants had dental treatment recommended before RT, with extractions recommended most frequently.

Conclusion: Many patients with HCN require dental treatment before RT; more than one-third require extractions.

Practical Implications: Most patients have some level of dental disease at the start of RT, indicating the importance of dental evaluation before RT. By observing dental outcomes after RT, OraRad has the potential to determine the best dental treatment recommendations for patients with HCN.
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http://dx.doi.org/10.1016/j.adaj.2017.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777182PMC
December 2017

Oral health status and risk of bacteremia following allogeneic hematopoietic cell transplantation.

Oral Surg Oral Med Oral Pathol Oral Radiol 2017 Sep 16;124(3):253-260. Epub 2017 Jun 16.

Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, MA, USA; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA.

Objectives: The aim of this study was to evaluate the impact of oral health status on bacteremia risk in a cohort of patients with acute myeloid leukemia (AML) who underwent chemotherapy followed by myeloablative allogeneic hematopoietic cell transplantation (allo-HCT).

Study Design: A retrospective study was conducted in patients with AML from 2007 to 2011. Oral health status was determined from a pre-allo-HCT dental evaluation. Positive blood cultures were recorded from AML induction to post-allo-HCT day +60. Organisms that caused bacteremia were classified as "of possible oral source" by a blinded microbiologist. Two-sided Fisher's exact test was used to compare the oral health status of the entire cohort with that of patients with blood cultures of potential oral source.

Results: Pre-allo-HCT dental evaluations were completed in 91 (99%) of 92 patients. Of these 91 patients, 13 (14%) with dental pathology (13 of 13 [100%]) completed all required dental treatment before allo-HCT. Bacteremias occurred in 63 of 92 patients (68%), and 12 (19%) of 63 patients had positive blood cultures of potential oral source. Of these, 1 of 12 patients developed bacteremia during AML induction, and 11 of 12 developed bacteremia during allo-HCT.

Conclusions: Oral health status was not associated with risk of bacteremia of potential oral source either at AML induction or consolidation or at allo-HCT.
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http://dx.doi.org/10.1016/j.oooo.2017.06.003DOI Listing
September 2017

Topical Clonazepam Solution for the Management of Burning Mouth Syndrome: A Retrospective Study.

J Oral Facial Pain Headache 2017 Summer;31(3):257-263

Aims: To evaluate and compare the effectiveness of two concentrations of topical clonazepam solution in improving symptoms of burning mouth syndrome (BMS).

Methods: A retrospective chart review was conducted of patients diagnosed with BMS and managed with topical clonazepam solution between 2008 and 2015. A 0.5-mg/mL solution was prescribed until 2012, when this was changed to a 0.1 mg/mL solution. Patients were instructed to swish with 5 mL for 5 minutes and spit two to four times daily. The efficacies of the two concentrations were compared using patient-reported outcome measures at the first follow-up, including the reported percentage of improvement in burning symptoms and the change in burning severity from baseline ranked on an 11-point numeric rating scale (NRS). Response to treatment was compared between the two concentrations using Wilcoxon rank sum test.

Results: A total of 57 subjects were included, 32 in the 0.1-mg/mL cohort and 25 in the 0.5-mg/mL cohort, and evaluated at a median follow-up of 7 weeks. The median overall percentage improvement was 32.5% in the 0.1-mg/mL cohort and 75% in the 0.5-mg/mL cohort. The median reduction in NRS score was 0.5 points in the 0.1-mg/mL cohort and 6 points in the 0.5-mg/mL cohort. The use of either outcome measure revealed that the response to treatment with the 0.5-mg/mL solution was superior to that of the 0.1 mg/mL solution (P < .01).

Conclusion: These findings suggest that a 0.5-mg/mL topical clonazepam solution is effective in the management of BMS. Future randomized clinical trials are warranted.
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http://dx.doi.org/10.11607/ofph.1754DOI Listing
November 2017

Safety and tolerability of topical clonazepam solution for management of oral dysesthesia.

Oral Surg Oral Med Oral Pathol Oral Radiol 2017 Aug 11;124(2):146-151. Epub 2017 May 11.

Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA, USA; Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, MA, USA.

Objectives: The aim of the study was to determine the absolute and relative safety of treatment with 2 concentrations of topical clonazepam solution (0.1 mg/mL, 0.5 mg/mL) for management of oral dysesthesia.

Study Design: The study was a retrospective chart review of patients diagnosed with oral dysesthesia and managed with topical clonazepam solution (swish and spit) between 2008 and 2015. The relative safety of the 2 concentrations was evaluated in terms of occurrence of adverse drug reactions (ADRs) and occurrence of change to treatment plan secondary to ADRs.

Results: For the study, 162 patients were included-84 patients in the 0.1 mg/mL cohort and 78 in the 0.5 mg/mL cohort, who were evaluated for a median follow-up period of 6 weeks. Thirty-eight (23%) patients developed ADRs. The most frequently reported ADR was sedation (62% of ADRs), followed by altered mental status and dizziness (7% each). Dose adjustments were required in 9 patients (6%) and treatment discontinuation in 13 (8%). ADRs were more frequently reported in the 0.5 mg/mL cohort, but no significant difference was found in terms of occurrence of ADRs, change to treatment plan secondary to ADRs, or types of ADRs (P > .05).

Conclusions: Treatment with topical clonazepam solution in either 0.5 mg/mL or 0.1 mg/mL concentration appears to be safe and well-tolerated. Future prospective studies are needed to confirm this finding.
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http://dx.doi.org/10.1016/j.oooo.2017.05.470DOI Listing
August 2017

The Use of Hyperbaric Oxygen for the Prevention and Management of Osteoradionecrosis of the Jaw: A Dana-Farber/Brigham and Women's Cancer Center Multidisciplinary Guideline.

Oncologist 2017 03 16;22(3):343-350. Epub 2017 Feb 16.

Department of Diagnostic Sciences, King Abdulaziz University, Faculty of Dentistry, Jeddah, Saudi Arabia

Background: Osteoradionecrosis of the jaw (ORN) is an infrequent yet potentially devastating complication of radiation therapy to the head and neck region. Treatment options include antimicrobial therapy, local sequestrectomy, resection, and the use of hyperbaric oxygen (HBO). Published data on ORN are difficult to compare because of the lack of a universally accepted classification and staging system, and the literature on the use of HBO to either prevent or successfully manage ORN is controversial and inconclusive. Therefore, we aimed to establish a standard approach for using HBO at our institution.

Materials And Methods: A literature search was conducted of articles published in the English language between January 1980 and January 2016. Retrieved articles were evaluated by two independent reviewers. Isolated case reports, abstracts, case series, review articles, and cohort studies without a control group were excluded; summary data were extracted from the remaining studies. A panel of experts from Head and Neck Oncology and Oral Medicine from the Dana-Farber Cancer Institute and Brigham and Women's Hospital reviewed the summary data and established multidisciplinary guidelines on the use of HBO for the prevention and management of ORN.

Results: Seven studies were evaluated and reviewed by the multidisciplinary panel. There was no consistent evidence in support of HBO for either the prevention or management of ORN.

Conclusion: Based on the available evidence and expert opinion, routine use of HBO for the prevention or management of ORN is not recommended and is rarely used at our institution. 2017;22:343-350 IMPLICATIONS FOR PRACTICE: The Division of Head and Neck Oncology of Dana-Farber/Brigham and Women's Cancer Center does not recommend the routine use of HBO for the prevention or management of ORN. Adjunctive HBO may be considered for use on a case-by-case basis in patients considered to be at exceptionally high risk who have failed conservative therapy and subsequent surgical resection.
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http://dx.doi.org/10.1634/theoncologist.2016-0298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344641PMC
March 2017

TET2 Negatively Regulates Nestin Expression in Human Melanoma.

Am J Pathol 2016 06 18;186(6):1427-34. Epub 2016 Apr 18.

Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Although melanoma is an aggressive cancer, the understanding of the virulence-conferring pathways involved remains incomplete. We have demonstrated that loss of ten-eleven translocation methylcytosine dioxygenase (TET2)-mediated 5-hydroxymethylcytosine (5-hmC) is an epigenetic driver of melanoma growth and a biomarker of clinical virulence. We also have determined that the intermediate filament protein nestin correlates with tumorigenic and invasive melanoma growth. Here we examine the relationships between these two biomarkers. Immunohistochemistry staining of nestin and 5-hmC in 53 clinically annotated primary and metastatic patient melanomas revealed a significant negative correlation. Restoration of 5-hmC, as assessed in a human melanoma cell line by introducing full-length TET2 and TET2-mutated constructs, decreased nestin gene and protein expression in vitro. Genome-wide mapping using hydroxymethylated DNA immunoprecipitation sequencing disclosed significantly less 5-hmC binding in the 3' untranslated region of the nestin gene in melanoma compared to nevi, and 5-hmC binding in this region was significantly increased after TET2 overexpression in human melanoma cells in vitro. Our findings provide evidence suggesting that nestin regulation is negatively controlled epigenetically by TET2 via 5-hmC binding at the 3' untranslated region of the nestin gene, providing one potential pathway for understanding melanoma growth characteristics. Studies are now indicated to further define the interplay between 5-hmC, nestin expression, and melanoma virulence.
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http://dx.doi.org/10.1016/j.ajpath.2016.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4901139PMC
June 2016

A Feasibility Study Evaluating Extraoral Photobiomodulation Therapy for Prevention of Mucositis in Pediatric Hematopoietic Cell Transplantation.

Photomed Laser Surg 2016 Apr 16;34(4):178-84. Epub 2016 Mar 16.

3 Division of Pediatric Hematology-Oncology, Dana-Farber Cancer Institute/Boston Children's Hospital , Boston, Massachusetts.

Objective: The objective of this study was to determine the feasibility, safety, and tolerability of providing extraoral photobiomodulation therapy (PBT) for prevention of oral mucositis (OM) in pediatric hematopoietic cell transplantation (HCT).

Background Data: OM is a frequent complication in pediatric HCT.

Methods: Patients 4-21 years of age scheduled for myeloablative HCT were eligible to participate. PBT was delivered using a THOR Model LX2M with a 69 Diode LED Cluster Probe (34 × 660 nm 10 mW, 35 × 850 nm 30 mW; 1390 mW total power output) at an irradiance of 50 mW/cm(2). Daily treatment exposed six sites (right, left, and midline face and neck) for 60 sec each, for a total dose of 3.0 J/cm(2). Treatment was initiated on the 1st day of conditioning, through day +20. OM assessments were completed at baseline then daily, from day -1 through day +20. Feasibility assessment included both qualitative and quantitative measures and outcomes from patients and providers.

Results: Thirteen patients with a median age of 15 years (range, 4.8-21.6) were consented and enrolled, and completed the protocol. The incidence of severe OM [World Health Organization (WHO) Grade ≥3] was 77%, with a median duration of 4 days (range, 1-14). Of 355 attempted PBT administrations, there were six refusals, and the mean proportion of days with data submitted was 96.2% [95% confidence interval (CI): 78.5-97.2%]. The 10 trained nurses all reported that the device was accessible, maneuverable, and lightweight, and that training was effective. There was no reported toxicity attributed to the PBT.

Conclusions: Daily delivery of external PBT and completion of OM evaluations is feasible in children undergoing HCT.
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http://dx.doi.org/10.1089/pho.2015.4021DOI Listing
April 2016

Oral adverse events in cancer patients treated with VEGFR-directed multitargeted tyrosine kinase inhibitors.

Oral Oncol 2015 Nov 5;51(11):1026-1033. Epub 2015 Oct 5.

Division of Oral Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA.

Objectives: This study characterized the incidence and clinical features of oral adverse events among cancer patients who received VEGFR-directed multitargeted tyrosine kinase inhibitor (VR-TKI) therapies.

Methods: Electronic medical records of adult cancer patients treated with sunitinib, sorafenib, regorafenib, pazopanib, cabozantinib, imatinib, and bevacizumab therapy at Dana-Farber Cancer Institute from 2009 to 2012 were reviewed. Data collected included patient characteristics, oral and non-oral adverse events, and time to onset. Time oral adverse event-free was the primary outcome.

Results: A total of 747 patients with 806 individual courses of therapy were treated for a median of 3.9months with sunitinib (n=161), sorafenib (n=172), regorafenib (n=15), pazopanib (n=132), cabozantinib (n=23), imatinib (n=144), or bevacizumab (n=159) for lung cancer (21%), gastrointestinal stromal tumor (15%), and metastatic renal cell carcinoma (13%). An oral adverse event was reported in 23.7% of patients at a median of 1.9months after starting therapy. The most commonly reported oral adverse event was oral mucosal sensitivity (dysesthesia), occurring in 12% of patients, typically without clinical findings. Multivariate models showed patients who received VR-TKI therapy were at greater risk of any oral adverse event compared with patients treated with imatinib or bevacizumab. Patients receiving VR-TKI therapy who developed an oral adverse event were also at increased risk for hand-foot skin reaction (15.9%).

Conclusions: VR-TKI associated oral adverse events are characterized primarily by dysesthesia with lack of clinical signs. Oral dysesthesia is more commonly associated with VR-TKIs than with bevacizumab or imatinib. Management is largely empirical and requires further investigation.
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http://dx.doi.org/10.1016/j.oraloncology.2015.09.003DOI Listing
November 2015

Oral lesions you can't afford to miss.

J Fam Pract 2015 Jul;64(7):392-9

Harvard Medical School, Boston, MA, USA.

Being able to promptly recognize and diagnose oral lesions is critical to heading off several potentially serious conditions. This article and photo guide can help.
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July 2015

Competencies for the new postdoctoral Oral Medicine graduate in the United States.

Oral Surg Oral Med Oral Pathol Oral Radiol 2015 Sep 25;120(3):324-8. Epub 2015 Apr 25.

Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA.

Oral Medicine is primarily a nonsurgical dental discipline that includes management of (1) oral mucosal and salivary gland diseases; (2) temporomandibular disorders and orofacial pain; (3) oral complications of systemic disease; and (4) dental management of medically complex patients within its scope of practice. In the United States, the American Academy of Oral Medicine (AAOM) is the professional organization that primarily supports Oral Medicine education, research, and patient care. This document informs the knowledge, skills, and behaviors of beginning Oral Medicine graduates in the United States in three domains: Diagnosis and primarily nonsurgical management of oral mucosal and salivary gland disorders. Diagnosis and primarily nonsurgical management of temporomandibular, orofacial pain, and neurosensory disorders. Management of the medically complex patient. Each domain is subsequently expanded with major competencies and supporting competencies.
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http://dx.doi.org/10.1016/j.oooo.2015.04.007DOI Listing
September 2015

Oral Medicine referrals at a hospital-based practice in the United States.

Oral Surg Oral Med Oral Pathol Oral Radiol 2015 Apr 20;119(4):423-9. Epub 2015 Jan 20.

Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, and Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA.

Objective: The objective of this study was to characterize the outpatient oral medicine (OM) clinic at Brigham and Women's Hospital (BWH), with particular emphasis on patient demographic characteristics and referral patterns.

Materials And Methods: A retrospective case record review of all initial consultations with OM experts at BWH from 2008 to 2010 was conducted. Data included demographic information, type of medical insurance, reason for referral, referring doctor's specialty, and distance between the patient's home and the referring doctor as well as BWH, number of prior doctors seen for the presenting problem (per patient report), tests ordered at the consultation visit, and clinical diagnoses.

Results: There were 1043 new outpatient consultation visits. Patients lived a median distance of 9.5 miles from the referring doctor and 18.9 miles from BWH and saw a median of one doctor (range 0-9) before consultation. Two thirds of patients were referred by physicians. The most common diagnoses included immune-mediated mucosal conditions (27.2%), orofacial pain disorders (25.1%), benign tumors or neoplasms (10.3%), and dysplasia and cancerous conditions (7.6%). Biopsy was the most frequent test performed at consultation.

Conclusions: Patients with oral conditions often see more than one doctor, before being referred to an OM expert and typically travel twice the distance to the expert compared with that between their home and the referring doctor. Equal efforts should be made to increase awareness of the importance of the specialty of OM among dentists, physicians, and the public.
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http://dx.doi.org/10.1016/j.oooo.2015.01.003DOI Listing
April 2015

Ensuring head and neck oncology patients receive recommended pretreatment dental evaluations.

J Oncol Pract 2015 Mar 27;11(2):151-4. Epub 2015 Jan 27.

Brigham and Women's Hospital; Dana-Farber Cancer Institute; Center for Clinical Excellence, Brigham and Women's Hospital, Boston, MA; and Center for Oncology Care at Erie County Medical Center, Buffalo, NY.

Purpose: Head and neck (H&N) cancer therapy can have a detrimental effect on oral health by increasing the risk of dry mouth, dental caries, dental infection, and osteonecrosis of the jaw. Pretreatment dental evaluations are recommended for patients with H&N cancer before radiation therapy to minimize the risk of acute and long-term adverse effects. In an earlier effort to educate patients and community dentists about the importance of pretreatment dental evaluations, we created a dental instructional guide (DIG) that outlines the necessary components of the preradiation dental evaluation. Yet our program did not have a system for documenting which patients received the DIG. The aim of this project was to create a reliable system to ensure that patients are given the DIG before radiation therapy and that such patients are readily identifiable, allowing us to confirm that their dental evaluations are complete before starting treatment.

Methods: We implemented a tracking template within the H&N oncology program at the Dana-Farber Cancer Institute that documents the date, patient, and clinician who gave the DIG. We used the Model for Improvement methodology and performed plan-do-study-act (PDSA) cycles to test and monitor the results of the template implementation.

Results: We showed a significant improvement in the rate of DIG documentation from a baseline of 0% (range, 0% to 0%) to a mean of 53% (range, 0% to 100%) over 3 months (P < .01).

Conclusion: This intervention was the first step in creating a sustainable system for ensuring timely preradiation dental evaluation, thereby decreasing the risk of dental complications from H&N cancer therapy.
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http://dx.doi.org/10.1200/JOP.2014.000414DOI Listing
March 2015

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report.

Biol Blood Marrow Transplant 2015 Mar 18;21(3):389-401.e1. Epub 2014 Dec 18.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Electronic address:

The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies.
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http://dx.doi.org/10.1016/j.bbmt.2014.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329079PMC
March 2015

Mammalian target of rapamycin inhibitor-associated stomatitis in hematopoietic stem cell transplantation patients receiving sirolimus prophylaxis for graft-versus-host disease.

Biol Blood Marrow Transplant 2015 Mar 5;21(3):503-8. Epub 2014 Dec 5.

Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, and Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts.

The mammalian target of rapamycin (mTOR) inhibitor sirolimus is effective in reducing incidence of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Agents that inhibit the mTOR pathway are known to be associated with significant and potentially dose-limiting toxicities, including stomatitis. The objective of this study was to report the clinical features and management outcomes of sirolimus-associated oral ulcers in the context of post-HSCT prophylaxis of GVHD. Seventeen patients, from a study cohort of 967, who were treated with sirolimus as prophylaxis for GVHD after allogeneic HSCT at the Dana-Farber/Brigham and Women's Cancer Center developed oral ulcers and were referred to the oral medicine clinic for evaluation and treatment over a period of 6 years. Clinical characteristics (appearance, anatomic site, size) and therapeutic outcomes (time to complete resolution) were documented. Median time to onset of oral ulceration was 55 days after allogeneic HSCT (range, 6 to 387 days); 92.9% of ulcers were located on nonkeratinized mucosa, with the ventrolateral tongue the most common site of involvement. Thirteen patients were treated with topical corticosteroid therapy; 12 of these patients also required intralesional corticosteroid injections. Clinical improvement (resolution of the lesions and improvement of symptoms) was noted in all cases, with no reported adverse events. Median time to complete resolution after onset of therapy was 14 days (range, 2 to 70 days). Patients receiving sirolimus for GVHD prophylaxis may develop painful oral ulcerations, which can be effectively managed with topical steroid treatment. Further prospective studies are needed to better elucidate the incidence of this complication, identify risk factors, and evaluate the effectiveness of interventions.
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http://dx.doi.org/10.1016/j.bbmt.2014.11.680DOI Listing
March 2015

Effect of prophylactic low level laser therapy on oral mucositis: a systematic review and meta-analysis.

PLoS One 2014 8;9(9):e107418. Epub 2014 Sep 8.

Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada; Program in Child Health Evaluative Sciences, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, Canada.

Background: Objective was to determine whether prophylactic low level laser therapy (LLLT) reduces the risk of severe mucositis as compared to placebo or no therapy.

Methods: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched until February 2014 for randomized controlled trials (RCTs) comparing prophylactic LLLT with placebo or no therapy in patients with cancer or undergoing hematopoietic stem cell transplantation (HSCT). All analyses used random effects models.

Results: Eighteen RCTs (1144 patients) were included. Prophylactic LLLT reduced the overall risk of severe mucositis (risk ratio (RR) 0.37, 95% confidence interval (CI) 0.20 to 0.67; P = 0.001). LLLT also reduced the following outcomes when compared to placebo/no therapy: severe mucositis at the time of anticipated maximal mucositis (RR 0.34, 95% CI 0.20 to 0.59), overall mean grade of mucositis (standardized mean difference -1.49, 95% CI -2.02 to -0.95), duration of severe mucositis (weighted mean difference -5.32, 95% CI -9.45 to -1.19) and incidence of severe pain (RR 0.26, 95% CI 0.18 to 0.37).

Conclusion: Prophylactic LLLT reduced severe mucositis and pain in patients with cancer and HSCT recipients. Future research should identify the optimal characteristics of LLLT and determine feasibility in the clinical setting.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107418PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157876PMC
December 2015

Characterization of oral involvement in acute graft-versus-host disease.

Biol Blood Marrow Transplant 2014 Nov 27;20(11):1717-21. Epub 2014 Jun 27.

Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, Massachusetts; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts. Electronic address:

Acute graft-versus-host-disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). The purpose of this study was to characterize the oral features associated with aGVHD in patients who underwent HSCT between 1995 and 2010 and developed prominent oral aGVHD. Data was collected from patient medical records and analyzed descriptively. Twenty-one cases were identified, of which 5 (24%) demonstrated only oral features; the remaining 16 had variable involvement of skin (n = 14), liver (n = 7), and gut (n = 5). The median time to onset of any sign of aGVHD was 22 days (range, 8 to 154 days), and that for onset of oral aGVHD was 35 days (range, 11 to 159 days). Sites affected by nonspecific erythema and ulcerations included buccal mucosa (19 of 21; 90%) tongue (18 of 21; 86%; dorsum in 8), labial mucosa (16 of 21; 76%), palatal mucosa (15 of 21; 71%; hard palate in 7), and floor of mouth (7 of 21; 33%). Eight cases (38%) presented with lip ulceration and crusting. In addition to systemic therapies, topical solutions of dexamethasone, tacrolimus, and morphine were used for ancillary support. Oral features of aGVHD may be the initial manifestation and include nonspecific erythema and ulcerations of keratinized and nonkeratinized mucosa and lips. Intensive topical therapies may help reduce symptoms and promote healing.
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http://dx.doi.org/10.1016/j.bbmt.2014.06.031DOI Listing
November 2014

Oral graft-versus-host disease.

Dent Clin North Am 2014 Apr;58(2):351-68

Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, 1620 Tremont Street, 3rd Floor, Boston, MA 02115, USA. Electronic address:

Allogeneic hematopoietic cell transplantation (allo-HCT) is used for the treatment of a variety of disorders, primarily hematologic malignancies. Graft-versus-host disease (GVHD) is a significant complication following allo-HCT and a major cause of morbidity and mortality. The oral cavity is frequently involved in GVHD, leading to pain, functional impairment, and reduced quality of life. Early diagnosis, management, and long-term follow-up of oral GVHD are important components of overall patient care.
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http://dx.doi.org/10.1016/j.cden.2013.12.007DOI Listing
April 2014