Emerging pharmacotherapy trends in preventing and managing oral mucositis induced by chemoradiotherapy and targeted agents.

INTRODUCTION: The introduction of targeted therapy and immunotherapy has tremendously changed the clinical outcomes and prognosis of cancer patients. Despite innovative pharmacological therapies and improved radiotherapy (RT) techniques, patients continue to suffer from side effects, of which oral mucositis (OM) is still the most impactful, especially for quality of life. AREAS COVERED: We provide an overview of current advances in cancer pharmacotherapy and RT, in relation to their potential to cause OM, and of the less explored and more recent literature reports related to the best management of OM. We have analyzed natural/antioxidant agents, probiotics, mucosal protectants and healing coadjuvants, pharmacotherapies, immunomodulatory and anticancer agents, photobiomodulation and the impact of technology. EXPERT OPINION: The discovery of more precise pathophysiologic mechanisms of CT and RT-induced OM has outlined that OM has a multifactorial origin, including direct effects, oxidative damage, upregulation of immunologic factors, and effects on oral flora. A persistent upregulated immune response, associated with factors related to patients' characteristics, may contribute to more severe and long-lasting OM. The goal is strategies to conjugate individual patient, disease, and therapy-related factors to guide OM prevention or treatment. Despite further high-quality research is warranted, the issue of prevention is paramount in future strategies.

Preparing the Next Generation of Clinicians for Practice Using Augmented and Artificial Intelligence.

Artificial intelligence (AI) and Augmented Intelligence (AuI) have existed for decades but have only recently been applied to dentistry and incorporated into higher education for dental professionals. Early examples of the incorporation of AI into dental education suggest it can enhance students' learning and can be applied in pre-clinical and clinical instruction. AI can be used to support clinical decision-making for dental professionals, making radiographic interpretation more precise and consistent. This paper provides a brief overview of AI, highlights opportunities to improve higher education and provides brief case studies of individuals and organizations working to advance the quality of dental education using AI. Opportunities for the application of AI in dental education include the adoption of clinical decision support that can improve patient outcomes and overall quality of patient care; development of courses that assist students in learning enhanced radiographic interpretation, diagnosis and treatment planning; research collaborations with industry for product evaluation and future product developments; and practice administration in understanding the quality of the care being delivered at the school.

Immune checkpoint inhibitors in cancer therapy: Review of orofacial adverse events and role of the oral healthcare provider.

Immune checkpoint inhibitors (ICIs) are a revolutionary class of antineoplastic therapy that restore anti-tumor immunity. Consequences of this enhanced immune response include a multitude of immune related adverse events (irAEs) that can affect any body system, including the mouth. Orofacial irAEs reproduce features of numerous immune-mediated conditions, including oral lichen planus, mucous membrane pemphigoid, and Sjögren syndrome, among others. The aim of this review is to summarize known orofacial irAEs and to familiarize oral healthcare providers with how to identify and manage these toxicities as part of the care team for patients treated with ICIs.

Diagnosis and Management of Oral Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease.

ABSTRACT: Inflammatory bowel diseases (IBD) represent a group of chronic inflammatory disorders of the gastrointestinal tract that lead to impaired quality of life and substantial health care costs. Up to 50% of pediatric IBD cases present with manifestations in the oral cavity. These may develop in nearly every oral tissue, including the soft tissues, tongue, lips, teeth, and lymph nodes. The goal of this review is to offer a systematic approach to diagnose and manage commonly encountered oral manifestations of pediatric IBD. This knowledge is critical for enhancing the comprehensive care and quality of life of children with these debilitating diseases.

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.

Responding to a pandemic: Development of the Carolina Dentistry Virtual Oral Health Care Helpline.

BACKGROUND: A virtual oral health care help line was established to provide consultation and triage for people with dental questions and concerns. Its goal during a pandemic was to keep patients from seeking unnecessary in-person care from emergency departments and urgent care clinics, especially when dental practices were closed or limited to providing essential urgent and emergency oral health care. METHODS: The Adams School of Dentistry, University of North Carolina at Chapel Hill, developed the Carolina Dentistry Virtual Oral Health Care Helpline using a quality improvement framework with faculty and staff member feedback. The process included establishing infrastructure (phone, video, protocols, referrals, documentation), personnel (scheduling, training, calibration), and internal and external communication. The authors collected retrospective information for descriptive evaluation of the first month's operations. RESULTS: There were 337 telephone calls answered, of which 65 (19%) were administrative and 272 (81%) were related to dental concerns. Dental pain (54%) was the most prevalent reason for calling. Triage and Providers referred 107 of 175 callers (61%) to the school's urgent care center. Of the 79 callers who received teleconsultations from virtual providers, 33 (42%) did not require additional follow-up, and 7 (9%) needed a follow-up phone call. Overall, 4 people were referred to community clinics, and 4 were referred to the emergency department. CONCLUSIONS: The Helpline was launched quickly and improved through quality improvement cycles, and it provided a needed community dental service. The process resolved some patient concerns without their seeking urgent or emergency care. PRACTICAL IMPLICATIONS: The pandemic has increased teledentistry practice. The authors describe establishing a dental school's virtual oral health Helpline, which provides a framework for dental practices seeking to use this patient communication modality.

Oral immune-related adverse events associated with PD-1 inhibitor therapy: A case series.

OBJECTIVE: The aim of this study was to characterize clinical and histopathological features, and management outcomes of patients with oral immune-related adverse events (irAEs) secondary to programmed cell death-1 (PD-1) inhibitors. METHODS: This was a case series of cancer patients receiving PD-1 inhibitor therapy who were referred to oral medicine for the development of oral irAEs. Demographic, clinical, and histopathological data were collected from electronic medical records. RESULTS: There were 13 patients (7 males) with a median age of 68 years (range: 39-82) who were treated with nivolumab (n = 7) or pembrolizumab (n = 6). Oral irAEs included lichenoid lesions (n = 10), erythema multiforme (EM) (n = 2), and acute graft-versus-host disease reactivation (n = 1), with or without ulcerations (n = 8). Four patients (31%) presented with only oral irAEs. Oral biopsies showed lichenoid mucositis (n = 4). Management with topical and systemic steroids led to complete symptomatic response in most patients (n = 12). PD-1 inhibitor therapy was temporarily discontinued (n = 3) and discontinued indefinitely (n = 2) due to severe oral irAEs. CONCLUSION: Patients receiving PD-1 inhibitors may develop oral irAEs characterized by lichenoid lesions, ulcers, or EM. Topical and systemic steroids appear to be effective in managing oral lesions although the severity of irAEs may necessitate PD-1 inhibitor therapy dose modification.

Long-Term Utilization Patterns of Topical Therapy and Clinical Outcomes of Oral Chronic Graft-versus-Host Disease.

An open-label phase 2 study of topical dexamethasone versus tacrolimus solutions in new-onset oral chronic graft-versus-host disease (cGVHD) revealed the superior efficacy of dexamethasone. The objective of this study was to report long-term patterns of topical therapy utilization and clinical outcomes in this cohort after completing the 30-day trial. A retrospective record review was performed from the date of study completion to January 2017. Topical therapies, systemic immunosuppressive therapies, objective measurements (National Institutes of Health severity score, oral mucosal scores), patient- reported outcomes (dryness, sensitivity, pain), and adverse events were recorded for oral cGVHD-related outpatient visits. Follow-up (FU) periods were defined as FU1 (0-1 month), FU2 (1-3 months), FU3 (3-6 months), FU4 (6-12 months), FU5 (12-18 months), and FU6 (18-24 months). Forty patients (52.5% males, median age, 56 years) completed the clinical trial and were included in the analysis. Topical therapies used were dexamethasone, tacrolimus, clobetasol, or a combination of these agents. At FU1, all 40 patients were receiving topical therapy, which decreased to 54.5% (12 out of 22) at FU6. Clinician-reported oral mucosal scores (0-12) and patient-reported sensitivity scores (0-10) decreased over time from FU1 (median mucosal score, 3; sensitivity, 3) to FU6 (mucosal score, 1; sensitivity, 2). Intralesional steroid therapy was provided to 6 patients for management of refractory oral ulcerations, all within the first year of follow-up. Patients with de novo symptomatic oral cGVHD may require long-term care with topical immunomodulatory therapy for up to 2 years, if not longer. Topical steroid and tacrolimus therapies are safe and effective in managing symptomatic oral cGVHD. Second-line topical therapy for refractory oral cGVHD requires further investigation.

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

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.

Casein Kinase II: an attractive target for anti-cancer drug design.

Casein Kinase II (CK2) is a ubiquitous serine/threonine kinase that is highly conserved in eukaryotic cells. CK2 has been shown to impact cell growth and proliferation, as numerous growth-related proteins are substrates of CK2. More importantly, experimental evidence linking increased expression and activity of CK2 to human cancers underscores the relevance of CK2 biology to cellular transformation and carcinogenesis. Due to the critical regulatory role CK2 plays in cell fate determination in cancer cells, there is a tremendous interest in the development of CK2-specific therapies. Supporting this, recent reports have demonstrated that genetic manipulation of CK2 expression as well as pharmacological inhibition of its enzymatic activity sensitizes cancers to apoptotic stimuli. Here we provide a succinct account of the biology of CK2, its cellular substrates, its pro-survival and pro-proliferation activity, and highlight evidence for its involvement in human cancer.