Current concepts in targeted therapies for benign tumors of the jaw - A review of the literature.

The aim of our study was to review current concepts in targeted therapies for benign tumors of the jaw. Benign odontogenic and maxillofacial bone tumors often require radical surgery, with consequent morbidity that impacts patients' postsurgical quality of life. Currently, targeted therapies and novel nonsurgical therapeutics are being explored for management of non-resectable tumors, with the aim of avoiding surgery or minimizing surgical scope. However, data on clinical applications of targeted therapies for benign tumors of the jaw remain sparse. Therefore, a literature review was conducted, based on the PubMed database, which included in vivo human clinical studies describing clinical application of targeted therapy for benign tumor of the jaw. The review assessed the outcomes of BRAF and MEK inhibitors for treatment of ameloblastoma, RANKL monoclonal antibody for treatment of giant cell tumor, cherubism, aneurysmal bone cyst, and fibrous dysplasia, and tyrosine kinase inhibitor for treatment of odontogenic myxoma and cherubism. Targeted therapies decreased tumor size, slowed down tumor progression, and reduced bone pain. Surgery remains the gold standard, but targeted therapies are promising adjuvant or alternative treatment options for reducing tumor progression and morbidity of tumor surgery.

Prevalence and correlates of fear of recurrence among oral and oropharyngeal cancer survivors.

PURPOSE: Fear of recurrence (FoR) is a prevalent and difficult experience among cancer patients. Most research has focused on FoR among breast cancer patients, with less attention paid to characterizing levels and correlates of FoR among oral and oropharyngeal cancer survivors. The purpose was to characterize FoR with a measure assessing both global fears and the nature of specific worries as well as evaluate the role of sociodemographic and clinical factors, survivorship care transition practices, lifestyle factors, and depressive symptoms in FoR. METHODS: Three hundred eighty-nine oral and oropharyngeal survivors recruited from two cancer registries completed a survey assessing demographics, cancer treatment, symptoms, alcohol and tobacco use, survivorship care practices, depression, and FoR. RESULTS: Forty percent reported elevated global FoR, with similar percentages for death (46%) and health worries (40.3%). Younger, female survivors and survivors experiencing more physical and depressive symptoms reported more global fears and specific fears about the impact of recurrence on roles, health, and identity, and fears about death. Depression accounted for a large percent of the variance. Lower income was associated with more role and identity/sexuality worries, and financial hardship was associated with more role worries. CONCLUSIONS: FoR is a relatively common experience for oral and oropharyngeal cancer survivors. Many of its correlates are modifiable factors that could be addressed with multifocal, tailored survivorship care interventions. IMPLICATIONS FOR CANCER SURVIVORS: Assessing and addressing depressive symptoms, financial concerns, expected physical symptoms in the first several years of survivorship may impact FoR among oral and oropharyngeal cancer survivors.

Enhancing Self-care Among Oral Cancer Survivors: Protocol for the Empowered Survivor Trial.

BACKGROUND: Survivors of oral cavity and oropharyngeal cancer frequently experience difficulties in swallowing; tasting; speaking; chewing; and maintaining comfortable movements of the head, neck, and shoulder. Engagement in regular self-care can reduce further loss of function and mitigate late effects. Despite the substantial self-care requirements, there are no empirically based interventions to enhance the skills and confidence of these survivors in managing their ongoing care. OBJECTIVE: The aim of this study is to describe the rationale and methodology for a randomized controlled trial evaluating Empowered Survivor (ES) versus Springboard Beyond Cancer, a general web-based program for cancer survivors, on self-efficacy in managing care, preparedness for managing survivorship, and health-related quality of life (QOL). METHODS: This study will recruit a total of 600 individuals who were diagnosed with oral cavity or oropharyngeal cancer in the past 3 years and are currently cancer free primarily from state cancer registries; these individuals will be randomly assigned to either the ES or Springboard Beyond Cancer condition. The participants complete measures of self-efficacy in managing care, preparedness for survivorship, health-related QOL, and engagement in oral self-examination and head and neck strengthening and flexibility exercises at baseline and 2 and 6 months after baseline. The primary aim of this study is to evaluate the impact of ES versus Springboard Beyond Cancer on self-efficacy, preparedness, and health-related QOL. The secondary aim is to examine the mediators and moderators of ES's impact on self-efficacy in managing care, preparedness, and health-related QOL at 6 months. The exploratory aim is to conduct a process evaluation of ES to identify potential oncology or community settings for future implementation. RESULTS: Multilevel modeling will be used to examine whether there are significant differences between the ES and Springboard Beyond Cancer interventions over time. Mediational models will evaluate the indirect effects of ES on outcomes. Quantitative analyses will evaluate the predictors of ES use, and qualitative analyses will evaluate the preferred timing and settings for the implementation of ES. CONCLUSIONS: This randomized controlled trial evaluates a completely web-based intervention, ES, versus a general web-based program for cancer survivors, Springboard Beyond Cancer, on self-efficacy in managing care, preparedness for managing survivorship, and health-related QOL and identifies the putative mediators and moderators of the intervention's effects. If an effect on the primary outcomes is illustrated, the next step could be an implementation trial to evaluate the intervention's uptake in and impact on an oncology care setting or nonprofit organizations. TRIAL REGISTRATION: ClincalTrials.gov NCT04713449; https://clinicaltrials.gov/ct2/show/NCT04713449. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39996.

Feasibility and safety of the da Vinci Xi surgical robot for transoral robotic surgery.

The collective experience supporting the safety and efficacy of transoral robotic surgery continues to grow. The surgical robot da Vinci Xi has been used successfully off-label for head and neck surgery, including transoral robotic surgery. We evaluated operative outcomes and efficacy of the da Vinci Xi surgical robot for transoral surgery and compared our experience with the da Vinci Si and published da Vinci Xi experiences in transoral surgery. Nineteen total cases were retrospectively reviewed, six with the Si and thirteen with the Xi. Our experience with the da Vinci Xi showed similar peri- and postoperative outcomes to our Si experience the available da Vinci Xi literature. We advocate for careful patient selection while also considering the surgical team's experience with TORS. Transoral robotic surgery with the da Vinci Xi has specific advantages, and support is accumulating for its use in TORS. However, this indication remains off-label, and we do not anticipate the manufacturer will seek approval for this indication given the ongoing development and regulatory approvals of da Vinci Single Port for similar indications.

Self-efficacy in managing post-treatment care among oral and oropharyngeal cancer survivors.

OBJECTIVE: Physical and psychosocial effects of oral cancer result in long-term self-management needs. Little attention has been paid to survivors' self-efficacy in managing their care. Study goals were to characterise self-care self-efficacy and evaluate socio-demographics, disease, attitudinal factors and psychological correlates of self-efficacy and engagement in head and neck self-exams. METHODS: Two hundred thirty-two oral cancer survivors completed measures of socio-demographics, self-care self-efficacy, head and neck self-exams and attitudinal and psychological measures. Descriptive statistics characterised self-efficacy. Hierarchical regressions evaluated predictors of self-efficacy. RESULTS: Survivors felt moderately confident in the ability to manage self-care (M = 4.04, SD = 0.75). Survivors with more comorbidities (ß = -0.125), less preparedness (ß = 0.241), greater information (ß = -0.191), greater support needs (ß = -0.224) and higher depression (ß = -0.291) reported significantly lower self-efficacy. Head and neck self-exam engagement (44% past month) was relatively low. Higher preparedness (OR = 2.075) and self-exam self-efficacy (OR = 2.606) were associated with more engagement in self-exams. CONCLUSION: Many survivors report low confidence in their ability to engage in important self-care practices. Addressing unmet information and support needs, reducing depressive symptoms and providing skill training and support may boost confidence in managing self-care and optimise regular self-exams.

A Case of Sclerosing Polycystic Adenoma of the Parotid Gland.

Sclerosing polycystic adenoma (SPA) is a rare salivary gland tumor with about 100 cases reported in the literature. We describe a case of SPA in the parotid gland and review the diagnostic tools used for identifying SPA. A 24-year-old male with a two-year history of right-sided face mass, initially thought to be pleomorphic adenoma of the parotid gland after fine needle aspiration (FNA). Following superficial parotidectomy, histologic features were consistent with SPA. This case illustrates the challenge of pre-operative assessment for SPA. Recent study has suggested SPA is a neoplasm and definitive treatment is surgical excision.

Upregulation of IFN-Inducible and Damage-Response Pathways in Chronic Graft-versus-Host Disease.

Although chronic graft-versus-host disease (CGVHD) is the primary nonrelapse complication of allogeneic transplantation, understanding of its pathogenesis is limited. To identify the main operant pathways across the spectrum of CGVHD, we analyzed gene expression in circulating monocytes, chosen as in situ systemic reporter cells. Microarrays identified two interrelated pathways: 1) IFN-inducible genes, and 2) innate receptors for cellular damage. Corroborating these with multiplex RNA quantitation, we found that multiple IFN-inducible genes (affecting lymphocyte trafficking, differentiation, and Ag presentation) were concurrently upregulated in CGVHD monocytes compared with normal subjects and non-CGVHD control patients. IFN-inducible chemokines were elevated in both lichenoid and sclerotic CGHVD plasma and were linked to CXCR3+ lymphocyte trafficking. Furthermore, the levels of the IFN-inducible genes CXCL10 and TNFSF13B (BAFF) were correlated at both the gene and the plasma levels, implicating IFN induction as a factor in elevated BAFF levels in CGVHD. In the second pathway, damage-/pathogen-associated molecular pattern receptor genes capable of inducing type I IFN were upregulated. Type I IFN-inducible MxA was expressed in proportion to CGVHD activity in skin, mucosa, and glands, and expression of TLR7 and DDX58 receptor genes correlated with upregulation of type I IFN-inducible genes in monocytes. Finally, in serial analyses after transplant, IFN-inducible and damage-response genes were upregulated in monocytes at CGVHD onset and declined upon therapy and resolution in both lichenoid and sclerotic CGVHD patients. This interlocking analysis of IFN-inducible genes, plasma analytes, and tissue immunohistochemistry strongly supports a unifying hypothesis of induction of IFN by innate response to cellular damage as a mechanism for initiation and persistence of CGVHD.

Risk factors for residual obstructive sleep apnea after adenotonsillectomy in children.

OBJECTIVES/HYPOTHESIS: To determine the prevalence of residual obstructive sleep apnea (OSA) in children who had adenotonsillectomy (AT) and to identify the risk factors for residual OSA after AT. STUDY DESIGN: Retrospective chart review. METHODS: Children with OSA who had AT at a tertiary care children's hospital were reviewed. Data pertaining to demographics, past medical history, body mass index, tonsil and adenoid size, and polysomnography were obtained. Residual OSA was defined as apnea hypopnea index (AHI) greater than 2. The rate of residual OSA and risk factors for residual OSA were assessed. RESULTS: One hundred sixty-nine children with OSA underwent polysomnography before and after AT. The prevalence of residual OSA was 38%. The prevalence of residual OSA in obese patients (49%) was higher than that of nonobese patients (27%) (P = .02). Patients with neurological/developmental/craniofacial abnormalities had higher prevalence of residual OSA (44%) than patients without comorbidities (33%) (P < .05). The prevalence of residual OSA in patients with severe OSA (42%) was higher than patients with moderate (29%) or mild OSA (0%) (P = .03). Teenage patients (67%) had a higher prevalence of residual OSA than toddlers (27%), preschooler (33%), and middle childhood groups (29%) (P = .03). CONCLUSIONS: The majority of children had improvement in OSA after AT. The choice of AHI threshold used to define residual OSA influenced the prevalence of residual OSA. Teenagers and children with obesity, comorbidities including neurological/developmental/craniofacial abnormalities alone or in combination with asthma, or severe OSA have a high risk of residual OSA. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2624-2629, 2016.

Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes.

PURPOSE: Current classification of head and neck squamous cell carcinomas (HNSCC) based on anatomic site and stage fails to capture biologic heterogeneity or adequately inform treatment. EXPERIMENTAL DESIGN: Here, we use gene expression-based consensus clustering, copy number profiling, and human papillomavirus (HPV) status on a clinically homogenous cohort of 134 locoregionally advanced HNSCCs with 44% HPV(+) tumors together with additional cohorts, which in total comprise 938 tumors, to identify HNSCC subtypes and discover several subtype-specific, translationally relevant characteristics. RESULTS: We identified five subtypes of HNSCC, including two biologically distinct HPV subtypes. One HPV(+) and one HPV(-) subtype show a prominent immune and mesenchymal phenotype. Prominent tumor infiltration with CD8(+) lymphocytes characterizes this inflamed/mesenchymal subtype, independent of HPV status. Compared with other subtypes, the two HPV subtypes show low expression and no copy number events for EGFR/HER ligands. In contrast, the basal subtype is uniquely characterized by a prominent EGFR/HER signaling phenotype, negative HPV-status, as well as strong hypoxic differentiation not seen in other subtypes. CONCLUSION: Our five-subtype classification provides a comprehensive overview of HPV(+) as well as HPV(-) HNSCC biology with significant translational implications for biomarker development and personalized care for patients with HNSCC.

A multicenter pilot evaluation of the National Institutes of Health chronic graft-versus-host disease (cGVHD) therapeutic response measures: feasibility, interrater reliability, and minimum detectable change.

The lack of standardized criteria for measuring therapeutic response is a major obstacle to the development of new therapeutic agents for chronic graft-versus-host disease (cGVHD). National Institutes of Health (NIH) consensus criteria for evaluating therapeutic response were published in 2006. We report the results of 4 consecutive pilot trials evaluating the feasibility and estimating the interrater reliability and minimum detectable change of these response criteria. Hematology-oncology clinicians with limited experience in applying the NIH cGVHD response criteria (n = 34) participated in a 2.5-hour training session on response evaluation in cGVHD. Feasibility and interrater reliability between subspecialty cGVHD experts and this panel of clinician raters were examined in a sample of 25 children and adults with cGVHD. The minimum detectable change was calculated using the standard error of measurement. Clinicians' impressions of the brief training session, the photo atlas, and the response criteria documentation tools were generally favorable. Performing and documenting the full set of response evaluations required a median of 21 minutes (range: 12-60 minutes) per rater. The Schirmer tear test required the greatest time of any single test (median: 9 minutes). Overall, interrater agreement for skin and oral manifestations was modest; however, in the third and fourth trials, the agreement between clinicians and experts for all dimensions except movable sclerosis approached satisfactory values. In the final 2 trials, the threshold for defining change exceeding measurement error was 19% to 22% body surface area (BSA) for erythema, 18% to 26% BSA for movable sclerosis, 17% to 21% BSA for nonmovable sclerosis, and 2.1 to 2.6 points on the 15-point NIH Oral cGHVD scale. Agreement between clinician-expert pairs was moderate to substantial for the measures of functional capacity and for the gastrointestinal and global cGVHD rating scales. These results suggest that the NIH response criteria are feasible for use, and these reliability estimates are encouraging, because they were observed following a single 2.5-hour training session given at multiple transplant centers, with no opportunity for iterative training and calibration. Research is needed to evaluate inter- and intrarater reliability in larger samples, and to evaluate these response criteria as predictors of outcomes in clinical trials.

Salivary gland involvement in chronic graft-versus-host disease: prevalence, clinical significance, and recommendations for evaluation.

Although xerostomia is a commonly reported complaint in patients with chronic graft-versus-host disease (cGVHD), criteria for evaluating the prevalence and characteristics of salivary gland involvement have not been well defined in this patient population. Previous studies also have made no distinction between salivary and mucosal oral cGVHD. We systematically evaluated signs and symptoms of sicca in a large cohort of patients with cGVHD (n = 101) using instruments widely used to study Sjogren's syndrome. Xerostomia was reported in 60 (77%) patients reporting ocular and 52 (67%) patients reporting oral complaints [corrected]. The salivary flow rate was < or =0.2 mL/min in 27%, and < or =0.1 mL/min in 16%. Histopathological changes, consisting of mononuclear infiltration and/or fibrosis/atrophy, were present in all patients with salivary dysfunction. Importantly, there was no correlation of salivary and oral mucosal involvement in cGVHD. Patients with cGVHD-associated salivary gland involvement had diminished oral cavity-specific quality of life and lower body mass index. Salivary gland involvement is a common and clinically distinct manifestation of cGVHD. Formal evaluation of salivary function using standardized criteria is needed, and this could be incorporated as an outcome measure in clinical trials of cGVHD.

Increased T-bet+ cytotoxic effectors and type I interferon-mediated processes in chronic graft-versus-host disease of the oral mucosa.

Although chronic graft-versus-host disease (cGVHD) is a major long-term complication of allogeneic hematopoietic stem cell transplantation, little is known of its pathogenesis. We have systematically examined oral mucosa among cGVHD patients and determined that the clinical severity of oral cGVHD was correlated with apoptotic epithelial cells, often found adjacent to infiltrating effector-memory T cells expressing markers of cytotoxicity and type I cytokine polarization. Accumulation of T-bet(+) T-cell effectors was associated with both increased proliferation and the expression of the type I chemokine receptor CXCR3. Concurrently, in both infiltrating cells and keratinocytes, we observed increased expression of the CXCR3 ligand MIG (CXCL9) and interleukin-15 (IL-15), type I interferon (IFN)-inducible factors that support the migration, type I differentiation, and expansion of alloreactive effectors. In severely affected mucosa, we observed high levels of MxA, a protein specifically induced by type I IFN, and signal transducer and activator of transcription 1 (STAT1) phosphorylation, a critical step in the IFN-signaling pathway, along with increased numbers of plasmacytoid dendritic cells. These data challenge the current paradigm of cGVHD as a type II cytokine-driven disorder and support the model that oral cGVHD results from type I IFN-driven immigration, proliferation, and differentiation of T-bet(+) type I T effectors. The clinical trials are registered at http://www.clinicaltrials.gov as NCT00331968.

Changes in salivary proteome following allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is frequently complicated by severe infections and graft-vs-host disease (GVHD). Saliva contains many components of adaptive and innate immune response crucial for local host defenses. Changes in salivary constituents could reflect systemic processes such as immune reconstitution and development of GVHD that occur posttransplant. This study was an initial evaluation of salivary protein changes that occur after allo-HCT. PATIENTS AND METHODS: Serially collected saliva samples from 41 patients undergoing allo-HCT were evaluated. Changes in salivary proteome were initially examined by SELDI-TOF mass spectrometry. Individual protein changes were identified by 2-dimensional differential in-gel electrophoresis (2D-DIGE) with subsequent MS/MS sequencing and ELISA. RESULTS: Significant increases and decreases in multiple salivary proteins that lasted at least 2 months posttransplant were detected by SELDI-TOF mass spectrometry. Lactoferrin and secretory leukocyte protease inhibitor demonstrated elevations 1 month post-HCT that persisted at least 6 months. Secretory IgA (sIgA) levels were decreased 1 month posttransplant, with recovery at approximately 6 months. Levels of salivary beta(2)-microglobulin were elevated at 6 months and correlated with sIgA levels. CONCLUSION: Allo-HCT is associated with long-term changes in several salivary proteins important for innate immune responses. These results support further studies on the association of salivary proteins with posttransplant complications including infections and GVHD.

Chronic graft versus host disease of oral mucosa: review of available therapies.

The use of hematopoetic stem cell transplantation (HSCT) has greatly expanded in the recent years for many neoplastic and hematological disorders. Chronic graft versus host disease (cGVHD) is a major complication of allogeneic HSCT and a major cause of morbidity and mortality. Oral mucosal involvement is frequent in cGVHD and contributes significantly to the overall burden of the condition. Oral medicine professionals should be familiar with various treatment options for oral cGVHD. This review discusses treatment modalities available for the management of oral mucosal manifestations of cGVHD. Available evidence for efficacy and safety of various systemic and topical agents, including corticosteroids, calcineurin antagonists, mycophenolate mofetil, and extracorporeal photopheresis, is reviewed.