Salivary Electrostimulation in the Treatment of Radiation Therapy-Induced Xerostomia (LEONIDAS-2): A Multicenter, Randomized, Double-Masked, Sham-Controlled, Phase 3 Trial.

PURPOSE: Radiation therapy-induced xerostomia significantly affects quality of life in head and neck cancer survivors. Neuro-electrostimulation of the salivary glands may safely increase natural salivation and reduce dry mouth symptoms. METHODS AND MATERIALS: This multicenter, double-masked, randomized, sham-controlled clinical trial assessed the long-term effects of a commercially available intraoral neuro-electrostimulating device in lessening xerostomia symptoms, increasing salivary flow, and improving quality of life in individuals with radiation therapy-induced xerostomia. Using a computer-generated randomization list, participants were assigned (1:1) to an active intraoral custom-made removable electrostimulating device or a sham device to be used for 12 months. The primary outcome was the proportion of patients reporting a 30% improvement on the xerostomia visual analog scale at 12 months. A number of secondary and exploratory outcomes were also assessed through validated measurements (sialometry and visual analog scale) and quality-of-life questionnaires (EORTC QLQ-H&N35, OH-QoL16, and SF-36). RESULTS: As per protocol, 86 participants were recruited. Intention-to-treat analyses showed no statistical evidence of a difference between the study groups with respect to the primary outcome or for any of the secondary clinical or quality-of-life outcomes. Exploratory analyses showed a statistically significant difference in the changes over time of the dry mouth subscale score of the EORTC QLQ-H&N35 in favor of the active intervention. CONCLUSIONS: LEONIDAS-2 did not meet the primary and secondary outcomes.

Point-of-care Analysis for Non-invasive Diagnosis of Oral cancer (PANDORA): A technology-development proof of concept diagnostic accuracy study of dielectrophoresis in patients with oral squamous cell carcinoma and dysplasia.

BACKGROUND: Delays in the identification and referral of oral cancer remain frequent. An accurate and non-invasive diagnostic test to be performed in primary care may help identifying oral cancer at an early stage and reduce mortality. Point-of-care Analysis for Non-invasive Diagnosis of Oral cancer (PANDORA) was a proof-of-concept prospective diagnostic accuracy study aimed at advancing the development of a dielectrophoresis-based diagnostic platform for oral squamous cell carcinoma (OSCC) and epithelial dysplasia (OED) using a novel automated DEPtech 3DEP analyser. METHODS: The aim of PANDORA was to identify the set-up of the DEPtech 3DEP analyser associated with the highest diagnostic accuracy in identifying OSCC and OED from non-invasive brush biopsy samples, as compared to the gold standard test (histopathology). Measures of accuracy included sensitivity, specificity, positive and negative predictive value. Brush biopsies were collected from individuals with histologically proven OSCC and OED, histologically proven benign mucosal disease, and healthy mucosa (standard test), and analysed via dielectrophoresis (index test). RESULTS: 40 individuals with OSCC/OED and 79 with benign oral mucosal disease/healthy mucosa were recruited. Sensitivity and specificity of the index test was 86.8% (95% confidence interval [CI], 71.9%-95.6%) and 83.6% (95% CI, 73.0%-91.2%). Analysing OSCC samples separately led to higher diagnostic accuracy, with 92.0% (95% CI, 74.0%-99.0%) sensitivity and 94.5% (95% CI, 86.6%-98.5%) specificity. CONCLUSION: The DEPtech 3DEP analyser has the potential to identify OSCC and OED with notable diagnostic accuracy and warrants further investigation as a potential triage test in the primary care setting for patients who may need to progress along the diagnostic pathway and be offered a surgical biopsy.

MASCC/ISOO expert opinion on the management of oral problems in patients with advanced cancer.

PURPOSE: The Palliative Care Study Group in conjunction with the Oral Care Study Group of the Multinational Association for Supportive Care in Cancer (MASCC) formed a sub-group to develop evidence-based guidance on the management of common oral problems in patients with advanced cancer. METHODS: This guidance was developed in accordance with the MASCC Guidelines Policy. A search strategy for Medline was developed, and the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials were explored for relevant reviews and trials, respectively. Guidance was categorised by the level of evidence, and "category of guideline" (i.e., "recommendation", "suggestion" or "no guideline possible"). RESULTS: Twelve generic suggestions (level of evidence - 5), three problem-specific recommendations and 14 problem-specific suggestions were generated. The generic suggestions relate to oral hygiene measures, assessment of problems, principles of management, re-assessment of problems and the role of dental/oral medicine professionals. CONCLUSIONS: This guidance provides a framework for the management of common oral problems in patients with advanced cancer, although every patient requires individualised management.

Salivary Gland Hypofunction and/or Xerostomia Induced by Nonsurgical Cancer Therapies: ISOO/MASCC/ASCO Guideline.

PURPOSE: To provide evidence-based recommendations for prevention and management of salivary gland hypofunction and xerostomia induced by nonsurgical cancer therapies. METHODS: Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library were searched for randomized controlled trials published between January 2009 and June 2020. The guideline also incorporated two previous systematic reviews conducted by MASCC/ISOO, which included studies published from 1990 through 2008. RESULTS: A total of 58 publications were identified: 46 addressed preventive interventions and 12 addressed therapeutic interventions. A majority of the evidence focused on the setting of radiation therapy for head and neck cancer. For the prevention of salivary gland hypofunction and/or xerostomia in patients with head and neck cancer, there is high-quality evidence for tissue-sparing radiation modalities. Evidence is weaker or insufficient for other interventions. For the management of salivary gland hypofunction and/or xerostomia, intermediate-quality evidence supports the use of topical mucosal lubricants, saliva substitutes, and agents that stimulate the salivary reflex. RECOMMENDATIONS: For patients who receive radiation therapy for head and neck cancer, tissue-sparing radiation modalities should be used when possible to reduce the risk of salivary gland hypofunction and xerostomia. Other risk-reducing interventions that may be offered during radiation therapy for head and neck cancer include bethanechol and acupuncture. For patients who develop salivary gland hypofunction and/or xerostomia, interventions include topical mucosal lubricants, saliva substitutes, and sugar-free lozenges or chewing gum. For patients with head and neck cancer, oral pilocarpine and oral cevimeline, acupuncture, or transcutaneous electrostimulation may be offered after radiation therapy.Additional information can be found at www.asco.org/supportive-care-guidelines.

Engineering Polymeric Nanosystems against Oral Diseases.

Nanotechnology and nanoparticles (NPs) are at the forefront of modern research, particularly in the case of healthcare therapeutic applications. Polymeric NPs, specifically, hold high promise for these purposes, including towards oral diseases. Careful optimisation of the production of polymeric NPs, however, is required to generate a product which can be easily translated from a laboratory environment to the actual clinical usage. Indeed, considerations such as biocompatibility, biodistribution, and biodegradability are paramount. Moreover, a pre-clinical assessment in adequate in vitro, ex vivo or in vivo model is also required. Last but not least, considerations for the scale-up are also important, together with an appropriate clinical testing pathway. This review aims to eviscerate the above topics, sourcing at examples from the recent literature to put in context the current most burdening oral diseases and the most promising polymeric NPs which would be suitable against them.

Oral lichen planus: A disease or a spectrum of tissue reactions? Types, causes, diagnostic algorhythms, prognosis, management strategies.

Oral lichen planus and lichenoid lesions comprise a group of disorders of the oral mucosa that likely represent a common reaction pattern to 1 or more unknown antigens. The coexistence of hyperkeratotic striation/reticulation, varying degrees of mucosal inflammation from mild erythema to severe widespread ulceration, and a band-like infiltrate of mononuclear inflammatory cells including activated T lymphocytes, macrophages, and dendritic cells, are considered suggestive of oral lichen planus and lichenoid lesions. Several classification systems of oral lichen planus and lichenoid lesions have been attempted, although none seem to be comprehensive. In this paper, we present a classification of oral lichen planus and lichenoid lesions that includes oral lichen planus, oral lichenoid contact lesions, oral lichenoid drug reactions, oral lichenoid lesions of graft vs. host disease, discoid lupus erythematosus, and systemic lupus erythematosus, lichen planus-like variant of paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome, chronic ulcerative stomatitis, lichen planus pemphigoides, solitary fixed drug eruptions, and lichen sclerosus. We present the clinical and diagnostic aspects of oral lichen planus and lichenoid lesions, and discuss related treatment options.

STAT3-Deficient hyperimmunoglobulin E syndrome: report of a case with orofacial granulomatosis-like disease.

Hyperimmunoglobulin E syndrome (HIES) is a rare heterogeneous primary immunodeficiency disorder characterized by infections of the lung and skin, elevated serum immunoglobulin E, and involvement of soft and bony tissues. Autosomal dominant HIES and related disorders are caused by defects in the Janus activated kinase-signal transducer and activator of transcription signaling pathway, leading to reduced numbers of T helper cell type 17 and impaired production of interleukin (IL)-17 A, IL-17 F, and IL-22. In addition, neutrophils have chemotactic defects, resulting in impaired responses at skin and lung sites. We report here a case of orofacial granulomatosis-like disease in a teenage boy ultimately found to have autosomal dominant HIES caused by a heterozygous mutation in the STAT3 gene.

Interventions for the management of radiotherapy-induced xerostomia and hyposalivation: A systematic review and meta-analysis.

INTRODUCTION: Salivary gland hypofunction is a common and permanent adverse effect of radiotherapy to the head and neck. Randomised trials of available treatment modalities have produced unclear results and offer little reliable guidance for clinicians to inform evidence-based therapy. We have undertaken this systematic review and meta-analysis to estimate the effectiveness of available interventions for radiotherapy-induced xerostomia and hyposalivation. METHODS: We searched MEDLINE, Cochrane Central, EMBASE, AMED, and CINAHL database through July 2016 for randomised controlled trials comparing any topical or systemic intervention to active and/or non-active controls for the treatment of radiotherapy-induced xerostomia. The results of clinically and statistically homogenous studies were pooled and meta-analyzed. RESULTS: 1732 patients from twenty studies were included in the systematic review. Interventions included systemic or topical pilocarpine, systemic cevimeline, saliva substitutes/mouthcare systems, hyperthermic humidification, acupuncture, acupuncture-like transcutaneous electrical nerve stimulation, low-level laser therapy and herbal medicine. Results from the meta-analysis, which included six studies, suggest that both cevimeline and pilocarpine can reduce xerostomia symptoms and increase salivary flow compared to placebo, although some aspects of the relevant effect size, duration of the benefit, and clinical meaningfulness remain unclear. With regard to interventions not included in the meta-analysis, we found no evidence, or very weak evidence, that they can reduce xerostomia symptoms or increase salivary flow in this population. CONCLUSIONS: Pilocarpine and cevimeline should represent the first line of therapy in head and neck cancer survivors with radiotherapy-induced xerostomia and hyposalivation. The use of other treatment modalities cannot be supported on the basis of current evidence.

Novel non-invasive adjunctive techniques for early oral cancer diagnosis and oral lesions examination.

Oral cancer is a potentially fatal disease with an increasing incidence and an unchanged 5-year mortality rate. Unfortunately, oral cancer is often still late diagnosed, which leads to an increase in the likelihood of functional impairment due to treatment and mortality rate. Definitive diagnosis of oral cancer must be confirmed by scalpel biopsy and histological assessment. However despite its benefits, scalpel biopsy is invasive and it is burdened by a potential morbidity. Furthermore, previous studies have suggested a high degree of intraobserver and interobserver variability regarding the histological evaluation of malignancy. As a consequence, in recent years there has been a growing and persisting demand towards developing new non-invasive, practical diagnostic tools that might facilitate the early detection of oral cancer. The most investigated non-invasive adjunctive techniques are vital staining, autofluorescence, chemiluminescence, narrow band imaging, and exfoliative cytology. Aim of the review is to critically describe these adjunctive aids and, after considering the literature data, an expert opinion on the effectiveness and the possible use of each technique will be provided.