Characterization of orofacial features in sclerodermatous chronic graft-versus-host disease.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (alloHCT). The sclerodermatous form of cGVHD can be particularly debilitating; however, orofacial sclerodermatous involvement remains poorly described. OBJECTIVE: To characterize orofacial features of sclerodermatous cGVHD in a single center cohort of patients who underwent alloHCT. STUDY DESIGN: Retrospective data were collected from electronic medical records and analyzed descriptively. RESULTS: There were 39 patients who received alloHCT between 1993 and 2017 and developed orofacial sclerodermatous cGVHD. Concomitant cutaneous sclerodermatous cGVHD was common (n = 20, 51%). Orofacial sclerodermatous cGVHD features included fibrous bands of the buccal mucosa (n = 23, 59%), limited mouth opening (n = 19, 54%), perioral fibrosis (n = 8, 21%), and focal gingival recession (n = 4, 10%). Oral mucosal fibrosis was observed at the site of active or resolved chronic lichenoid inflammation in 30 patients, with all but two also presenting with a history of ulcerations. Management included jaw stretching exercises (n = 10; 6 stable/improved), surgery (n = 3; 2 improved), and intralesional corticosteroid injections (n = 2; 2 improved). CONCLUSIONS: Orofacial involvement with sclerodermatous cGVHD can present with multiple manifestations including fibrous banding, limited mouth opening, perioral fibrosis, and focal gingival recession. Surgical and non-surgical management strategies may improve clinical function and reduce morbidity.

Acromegaly: Overview and associated temporomandibular joint disorders.

OBJECTIVE: To provide a review on acromegaly and its orofacial manifestations, with a focus on associated arthropathies and temporomandibular joint disorders (TMD). METHODS: A review of current literature was performed through an electronic search of three databases: PubMed, ScienceDirect, and Google Scholar. The literature review was focused on the following topics of interest: etiology, diagnosis, and management of acromegaly, orofacial manifestations of acromegaly, acromegalic arthropathies, and acromegaly-associated TMD. RESULTS: Acromegaly is a chronic multisystem condition in which excessive production of growth hormone in adults, most commonly caused by benign pituitary adenomas, leads to somatic overgrowth. Orofacial changes are considered hallmarks of the disease. It is important for dentists to recognize signs and symptoms of acromegaly, as this may help to achieve early diagnosis and improve overall disease prognosis. Acromegalic arthropathies typically involve large joints, however, the temporomandibular joints (TMJ) can be affected. TMD associated with acromegaly is under-recognized and poorly characterized in current literature. CONCLUSION: In the appropriate clinical context, acromegaly should be considered as part of the differential diagnosis for patients presenting with TMD. Further studies are needed to better characterize the nature of TMD associated with acromegaly and to define the role of TMJ involvement in early diagnosis.

Hydroxychloroquine for the management of recalcitrant oral lichen planus.

OBJECTIVE: The objective of this study is to describe the efficacy of hydroxychloroquine (HCQ) in patients with oral lichen planus (OLP) refractory to conventional therapy. STUDY DESIGN: In this single-center retrospective study, patients were prescribed HCQ 200 mg twice daily. Pain, reticulation, erythema, and ulceration scores were recorded. Two-sample and paired t tests were used to evaluate mean and paired pain scores and paired t test to determine substantial differences in paired REU scores, at HCQ initiation visit and final follow-up at 12 to 24 months. RESULTS: Thirty-six patients (69.4% female) with a median age of 70 ± 12.0 (range 48-99) were initiated on HCQ. Only 30 patients were evaluable because pruritus developed in 5 patients (13.9%) and gastrointestinal symptoms in 1 (2.8%). The mean follow-up was 23.2 months (range 1-74). In 19 patients, there was a significant decline in the worst pain score from a mean of 3.9 (SD± 2.8, n = 19) to 1.9 (SD ± 2.4, n = 19) (t = 2.837, P < .006). Paired reticulation, erythema, and ulceration (REU scores) decreased from a weighted mean score of 16.0 (SD ± 8.0, n = 12) to 12.0 (SD ± 6.3, n = 12) (t = 2.07, P < .032). CONCLUSION: Hydroxychloroquine was a suitable option and effective in reducing symptoms and disease severity in patients with recalcitrant OLP who do not adequately respond to standard therapy.

Use of oral devices in the management of oral dysesthesia: case reports and literature review.

Oral dysesthesia (OD) is a diagnosis of exclusion that manifests as an unpleasant and abnormal sensation of the oral mucosa without any noticeable oral lesions. Burning sensation is one of the manifestations of OD which may advocate for similar pharmacotherapeutic options to burning mouth syndrome (BMS), resulting in possible adverse events. The aim of these case reports was to illustrate the significance and rationale for the use of oral devices as a mechanical/physical barrier and a safe approach in the management of OD, without experiencing any antagonistic effects from pharmacotherapeutic agents. Two patients with spontaneous and evoked (following dental procedures) OD symptoms in the right posterior mandibular quadrant and anterior hard palatal areas were evaluated. Additionally, their OD symptoms were associated with hyposalivation and taste changes. A thorough history and complete head and neck examination, with the exclusion of oral lesions and systemic conditions, were performed. These patients were previously prescribed topical clonazepam rinses. An in-office trial, with application of orthodontic wax to the affected area, was performed as a preliminary test in order to justify the fabrication of an oral device for possible symptomatic relief. Conclusion: The case reports demonstrated significant improvement of OD symptoms and amelioration of pain following fabrication of oral devices in two patients with no undesirable effects from pharmacotherapy. Additionally, the oral devices aided as a mechanical/physical barrier, potentially exerting a placebo effect while facilitating an improved quality of life. Furthermore, the cost-effectiveness and ease of fabricating the oral device has been advantageous over other systemic medications. This encourages the need for a detailed prospective study.

Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial.

Importance: Proliferative verrucous leukoplakia (PVL) is an aggressive oral precancerous disease characterized by a high risk of transformation to invasive oral squamous cell carcinoma (OSCC), and no therapies have been shown to affect its natural history. A recent study of the PVL immune landscape revealed a cytotoxic T-cell-rich microenvironment, providing strong rationale to investigate immune checkpoint therapy. Objective: To determine the safety and clinical activity of anti-programmed cell death 1 protein (PD-1) therapy to treat high-risk PVL. Design, Setting, and Participants: This nonrandomized, open-label, phase 2 clinical trial was conducted from January 2019 to December 2021 at a single academic medical center; median (range) follow-up was 21.1 (5.4-43.6) months. Participants were a population-based sample of patients with PVL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of dysplasia). Intervention: Patients underwent pretreatment biopsy (1-3 sites) and then received 4 doses of nivolumab (480 mg intravenously) every 28 days, followed by rebiopsy and intraoral photographs at each visit. Main Outcomes and Measures: The primary end point was the change in composite score (size and degree of dysplasia) from before to after treatment (major response [MR]: >80% decrease in score; partial response: 40%-80% decrease). Secondary analyses included immune-related adverse events, cancer-free survival (CFS), PD-1 ligand 1 (PD-L1) expression, 9p21.3 deletion, and other exploratory immunologic and genomic associations of response. Results: A total of 33 patients were enrolled (median [range] age, 63 [32-80] years; 18 [55%] were female), including 8 (24%) with previously resected early-stage OSCC. Twelve patients (36%) (95% CI, 20.4%-54.8%) had a response by composite score (3 MRs [9%]), 4 had progressive disease (>10% composite score increase, or cancer). Nine patients (27%) developed OSCC during the trial, with a 2-year CFS of 73% (95% CI, 53%-86%). Two patients (6%) discontinued because of toxic effects; 7 (21%) experienced grade 3 to 4 immune-related adverse events. PD-L1 combined positive scores were not associated with response or CFS. Of 20 whole-exome sequenced patients, all 6 patients who had progression to OSCC after nivolumab treatment exhibited 9p21.3 somatic copy-number loss on pretreatment biopsy, while only 4 of the 14 patients (29%) who did not develop OSCC had 9p21.3 loss. Conclusions and Relevance: This immune checkpoint therapy precancer nonrandomized clinical trial met its prespecified response end point, suggesting potential clinical activity for nivolumab in high-risk PVL. Findings identified immunogenomic associations to inform future trials in this precancerous disease with unmet medical need that has been difficult to study. Trial Registration: ClinicalTrials.gov Identifier: NCT03692325.

Dental evaluation and clearance prior to allogeneic hematopoietic cell transplantation.

INTRODUCTION: Dental examination and stabilization are performed prior to allogeneic hematopoietic cell transplantation to decrease infection risk during neutropenia. Burden of dental disease and treatment need is not well characterized in this population. OBJECTIVES: This report describes the dental status of a cohort of patients within the Chronic Graft-versus-Host Disease Consortium and treatment rendered prior to transplant. METHODS: The cohort included 486 subjects (Fred Hutchinson: n = 245; Dana-Farber: n = 241). Both centers have institutional-based dental clearance programs. Data were retrospectively abstracted from medical records by calibrated oral health specialists. RESULTS: The median age at transplant was 55.9 years, 62.1% were male, and 88% were white. Thirteen patients were edentulous (2.7%). The mean teeth among dentate patients before clearance was 26.0 (SD, 4.6). Dental findings included untreated caries (31.2%), restorations (91.6%), endodontically treated teeth (48.1%), and dental implants (5.7%). Pretransplant procedures during clearance included endodontic therapy (3.6%; mean = 0.1 teeth), restorations (25.1%; mean = 0.7), dental prophylaxis (59.2%), scaling/root planing (5.1%), and extraction (13.2%; mean = 0.3). The mean teeth after clearance was 25.6 (SD, 5.0). CONCLUSIONS: Retrospective analysis of pre-AlloHCT dental data in subjects at two large transplant centers identified low levels of dental need. Findings suggest high access to care.

Oral Chronic Graft-Versus-Host Disease.

Chronic oral graft-versus-host disease (cGVHD) is a complex, frequent, and highly impactful complication of allogeneic hematopoietic cell transplantation (alloHCT). It represents the leading cause of morbidity and mortality in long-term alloHCT survivors. cGVHD can affect almost any visceral organ system and commonly affects the skin, eyes and mouth, manifesting with signs and symptoms similar to other known immune-mediated and autoimmune diseases. Oral manifestations of GVHD include inflammation, thinning, and ulceration of oral mucosal tissues (similar to lichen planus), lymphocyte-mediated salivary gland dysfunction (similar to Sjögren/Sicca Syndrome), and decreased oral opening (trismus) secondary to sclerosis of oral and perioral tissues (analogous to limitation in scleroderma). Potential sequelae include severe mucosal pain, compromised nutrition, weight loss, limitation in opening, and sometimes irreversible fibrosis of the salivary glands. While some cases can be managed with topical therapies, management may also require long-term targeted immunosuppressive and/or corticosteroid therapy with associated risk of local and systemic infection, hyperglycemia, kidney dysfunction, osteopenia/osteoporosis, and possibly secondary malignancies. The aim of this mini-review is to provide an up-to-date review of literature related to the diagnosis and management of oral cGVHD to aid dental and medical clinicians in optimizing oral cGVHD therapy while minimizing potential adverse effects.

Oral lichen planus: comparative efficacy and treatment costs-a systematic review.

OBJECTIVE: To compare the reported efficacy and costs of available interventions used for the management of oral lichen planus (OLP). MATERIALS AND METHODS: A systematic literature search was performed from database inception until March 2021 in MEDLINE via PubMed and the Cochrane library following PRISMA guidelines. Only randomized controlled trials (RCT) comparing an active intervention with placebo or different active interventions for OLP management were considered. RESULTS: Seventy (70) RCTs were included. The majority of evidence suggested efficacy of topical steroids (dexamethasone, clobetasol, fluocinonide, triamcinolone), topical calcineurin inhibitors (tacrolimus, pimecrolimus, cyclosporine), topical retinoids, intra-lesional triamcinolone, aloe-vera gel, photodynamic therapy, and low-level laser therapies for OLP management. Based on the estimated cost per month and evidence for efficacy and side-effects, topical steroids (fluocinonide > dexamethasone > clobetasol > triamcinolone) appear to be more cost-effective than topical calcineurin inhibitors (tacrolimus > pimecrolimus > cyclosporine) followed by intra-lesional triamcinolone. CONCLUSION: Of common treatment regimens for OLP, topical steroids appear to be the most economical and efficacious option followed by topical calcineurin inhibitors. Large-scale multi-modality, prospective trials in which head-to-head comparisons interventions are compared are required to definitely assess the cost-effectiveness of OLP treatments.

A Review of Oral Chronic Graft-Versus-Host Disease: Considerations for dental hygiene practice.

Purpose: Allogeneic hematopoietic cell transplantation (alloHCT), also known as stem cell or bone marrow transplantation, is a cellular therapy performed to treat a variety of malignant and non-malignant hematologic diseases. Chronic graft-versus-host disease (cGVHD) is a common immune-mediated complication of alloHCT that can affect various organs of the body, with approximately 70% of affected patients presenting with oral features. Oral manifestations of cGVHD include lichenoid lesions (diagnostic feature), erythema, pseudomembranous ulcerations, superficial mucoceles, salivary gland hypofunction, xerostomia, orofacial sclerosis, trismus, and increased sensitivity to spicy, acidic, hard, and crunchy foods. Patients with oral cGVHD are also at increased risk for developing secondary conditions, such as oral candidiasis, dental caries, and oral squamous cell carcinoma. Given these complex oral health challenges, the dental hygienist can play a key role in optimizing patients' oral health care from pre-stem cell transplantation through survivorship. Optimal care includes a comprehensive health history assessment, thorough extraoral and intraoral examinations, detailed hard and soft tissue evaluations, oral hygiene, and dietary assessment, along with the delivery of patient-centered, oral health instruction and preventive therapies. Appropriate monitoring and management of oral cGVHD require a collaborative care approach between dental, oncology, and oral medicine providers. As part of a multidisciplinary care team, dental hygienists play an important role in the management of patients with oral cGVHD. The purpose of this review is to provide an overview of alloHCT and its oral health considerations, with a focus on oral cGVHD etiology, signs and symptoms, and management considerations for the dental team.

Detection of circulating tumor human papillomavirus DNA before diagnosis of HPV-positive head and neck cancer.

Human papillomavirus (HPV), most commonly HPV16, causes a growing subset of head and neck squamous cell carcinomas (HNSCCs), including the overwhelming majority of oropharynx squamous cell carcinomas in many developed countries. Circulating biomarkers for HPV-positive HNSCC may allow for earlier diagnosis, with potential to decrease morbidity and mortality. This case-control study evaluated whether circulating tumor HPV DNA (ctHPVDNA) is detectable in prediagnostic plasma from individuals later diagnosed with HPV-positive HNSCC. Cases were participants in a hospital-based research biobank with archived plasma collected ≥6 months before HNSCC diagnosis, and available archival tumor tissue for HPV testing. Controls were biobank participants without cancer or HPV-related diagnoses, matched 10:1 to cases by sex, race, age and year of plasma collection. HPV DNA was detected in plasma and tumor tissue using a previously validated digital droplet PCR-based assay that quantifies tumor-tissue-modified viral (TTMV) HPV DNA. Twelve HNSCC patients with median age of 68.5 years (range, 51-87 years) were included. Ten (83.3%) had HPV16 DNA-positive tumors. ctHPV16DNA was detected in prediagnostic plasma from 3 of 10 (30%) patients with HPV16-positive tumors, including 3 of 7 (43%) patients with HPV16-positive oropharynx tumors. The timing of the plasma collection was 19, 34 and 43 months before cancer diagnosis. None of the 100 matched controls had detectable ctHPV16DNA. This is the first report that ctHPV16 DNA is detectable at least several years before diagnosis of HPV16-positive HNSCC for a subset of patients. Further investigation of ctHPV16DNA as a biomarker for early diagnosis of HPV16-positive HNSCC is warranted.

Effect of COVID-19 on training and mental health of oral medicine residents in North America.

OBJECTIVE: The objective of this study was to assess resident and faculty perception of the effect of the coronavirus disease 2019 pandemic on the training experience, education, and psychological well-being of oral medicine (OM) residents. STUDY DESIGN: An anonymous 16-item online questionnaire was e-mailed to faculty and residents of all Commission on Dental Accreditation-accredited OM residency programs in North America. Survey questions asked about the pandemic's effect on resident educational, clinical, and research activities and the well-being of the residents. Survey data were collected using Qualtrics XM. RESULTS: Forty participants (52.5% residents and 47.5% faculty members) responded to the survey. Regarding the effect on clinical activities, 67.5% reported 50% or less reduction in patient volume seen by residents at its worst during the pandemic. With respect to educational activities, most reported a complete switch of didactic training (85.3%), academic examinations (60%), and off-site resident rotations (45%) to a virtual platform. Research activities were affected the most; 55% reported complete cessation for some time. Thirty-three percent perceived a negative effect, 18% perceived no effect, 11% perceived a positive effect, and 38% were unsure regarding the effect of coronavirus disease 2019 on resident morale. Despite the interruptions in the clinical, research, and educational activities, 62.5% expected on-time resident graduation. CONCLUSION: Despite constraints due to the pandemic, OM residency programs successfully continued clinical activities, didactic training, and research productivity through virtual means and a hybrid delivery care model while supporting their residents' morale.

Oral manifestations of immune-related adverse events in cancer patients treated with immune checkpoint inhibitors.

Immunotherapy with immune checkpoint inhibitors (ICIs) has transformed cancer treatment over the past decade, improving survival rates in numerous advanced cancers. Immune-related adverse events (irAEs) are common and can affect any organ system, with many of these toxicities being well-characterized with clear grading criteria and management approaches. There has been less emphasis on oral manifestations of irAEs. This review provides an overview of oral manifestations of irAEs, including mucosal and salivary gland toxicities, and proposes a grading system and management guidelines. irAEs are common treatment-related toxicities in patients treated with ICIs. Oral irAEs can range from asymptomatic white reticulations to life-threatening mucocutaneous reactions requiring aggressive management with corticosteroids and/or permanent discontinuation of ICIs. Oral healthcare providers should be prepared to identify and manage oral irAEs in collaboration with oncologists and other specialists.

Oral myeloid sarcoma as an uncommon manifestation of acute myeloid leukemia: A case series and review of the literature.

BACKGROUND AND OVERVIEW: Oral myeloid sarcoma (MS) is an extramedullary tumor that can occur in the setting of acute myeloid leukemia, either as the first sign of an underlying disease or later in the course of disease. The authors' aim was to present the clinical features of oral MS and review the literature. CASE DESCRIPTION: Case 1 was an 82-year-old woman with an asymptomatic erythematous swelling on the maxillary gingiva and no history of hematologic malignancy. Case 2, a 65-year-old man, and case 3, a 58-year-old woman, each had a history of acute myeloid leukemia and a painful ulcer on the palatal mucosa and an asymptomatic ulcer on the lower lip mucosa, respectively. Case 1 was treated with focal radiation then chemotherapy and achieved complete remission initially, but died of relapse 2 years after diagnosis. Case 2 received radiotherapy and immunotherapy and had a complete response. Case 3 received chemotherapy and achieved remission initially, but relapsed and is undergoing investigational targeted therapies. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Oral MS can manifest as gingival or mucosal swelling or ulceration and can indicate onset or relapse of associated hematologic malignancies, which often have a poor prognosis. Because patients with oral findings are likely to seek treatment from their dentists first, oral clinicians should maintain a broad differential diagnosis list when evaluating oral lesions, especially if treatment prescribed for a more common diagnosis fails to resolve the lesion.

Use of Prescription Sialagogues for Management of Xerostomia in Chronic Graft-versus-Host-Disease.

The aim of this study is to analyze utilization patterns of prescription sialagogues for management of xerostomia in patients with chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (alloHSCT). There have been several small reports describing the clinical use of sialagogue therapy in the management of patients with cGVHD. While these reports suggest that sialagogue therapy is safe and effective in this unique patient population, the numbers of patients reported, and overall evidence base, remain limited. The objective of this study was to characterize medication utilization and treatment outcomes in a cohort of patients with cGVHD and xerostomia who were prescribed sialagogue therapy. A retrospective chart review was conducted of patients who were diagnosed with cGVHD and prescribed sialagogue therapy for xerostomia from 2005 to 2019. Data collected included patient demographics, date of alloHSCT, date of oral cGVHD diagnosis, concurrent immunosuppressive medications, sialagogue regimen, worst xerostomia score (on a 1 to 10 scale), and patient-reported outcomes. The study included 70 patients managed with pilocarpine (n = 57) and cevimeline (n = 13), with a median age of 62 years (range: 24 to 82). Overall median duration of therapy was 7 months (range: 1 to 154). The baseline median self-reported worst xerostomia score was 6 of 10. Median percent reported improvement was 10%, 40%, and 50% for FU1 (<6 months), FU2 (6 to 12 months), and FU3 (>12 months) accordingly. Most patients who reported lower percentage improvement utilized the medication for less than 6 months, and those with moderate response were compliant for longer than 6 months. When all patients were considered, there was a significant reduction (median of 1.5 points; range: 0 to 7) in the xerostomia score from pre (median: 6.5; range: 1 to 10) to post (median: 5; range: 0 to 10) (P< .001). Most common side effects were nausea (2.9%) and diarrhea (1.4%). Patients with cGVHD and xerostomia reported improvement in symptoms with sialagogue therapy and remained on medication for a median of 7 months with infrequent side effects. The sustained duration of therapy suggests perceived benefits, though prospective, blinded, and randomized studies are needed.