Valeria Mercadante

Purpose: This systematic review aimed to assess the updated literature for the prevention of salivary gland hypofunction and xerostomia induced by non-surgical cancer therapies. Methods: Electronic databases of MEDLINE/PubMed, EMBASE, and Cochrane Library were searched for randomized controlled trials (RCT) that investigated interventions to prevent salivary gland hypofunction and/or xerostomia. Literature search began from the 2010 systematic review publications from the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) up to February 2024. Two independent reviewers extracted information regarding study design, study population, cancer treatment modality, interventions, outcome measures, methods, results, risk of bias (RoB version 2), and conclusions for each article. Results: A total of 51 publications addressing preventive interventions were included. Eight RCTs on tissue-sparing radiation modalities were included showing significant lower prevalence of xerostomia, with unclear effect on salivary gland hypofunction. Three RCTs on preventive acupuncture showed reduced prevalence of xerostomia but not of salivary gland hypofunction. Two RCTs on muscarinic agonist stimulation with bethanechol suggested a preventive effect on saliva flow rate and xerostomia in patients undergoing head and neck radiation or radioactive iodine therapy. Two studies on submandibular gland transfer showed higher salivary flow rates compared to pilocarpine and lower prevalence of xerostomia compared to no active intervention. There is insufficient evidence on the effectiveness of vitamin E, amifostine, photobiomodulation, and miscellaneous preventive interventions. Conclusion: This systematic review continues to support the potential of tissue-sparing tecniques and intensity-modulated radiation therapy (IMRT) to preserve salivary gland function in patients with head and neck cancer, with limited evidence on other preventive strategies, including acupuncture and bethanecol. Preventive focus should be on optimized and new approaches developed to further reduce radiation dose to the parotid, the submandibular, and minor salivary glands. As these glands are major contributors to moistening of the oral cavity, limiting the radiation dose to the salivary glands through various modalities has demonstrated reduction in prevalence and severity of salivary gland hypofunction and xerostomia. There remains no evidence on preventive approaches for checkpoint inhibitors and other biologicals due to the lack of RCTs.

Background: Effective treatments for dry mouth of Sjogren's syndrome are limited and hampered by adverse effects. The aim of LEONIDAS‐1 was to explore the feasibility of salivary electrostimulation in individuals with primary Sjogren's syndrome, as well as parameters required to inform the design of a future phase III trial.Methods: Multicentre, parallel‐group, double‐blind, randomised sham‐controlled trial in two UK centres. Participants were randomised (1:1, computer‐generated) to active or sham electrostimulation. The feasibility outcomes included screening/eligibility ratio, consent, and recruitment and drop‐out rates. Preliminary efficacy outcome included dry mouth visual analogue scale, Xerostomia Inventory, the EULAR Sjögren's syndrome patient reported index‐Q1, and unstimulated sialometry.Results: Forty‐two individuals were screened, of whom 30 (71.4%) met the eligibility criteria. All eligible individuals consented to recruitment. Out of the 30 randomised participants (active n = 15, sham n = 15), 4 dropped out and 26 (13 vs. 13) completed all study visits as per protocol. Recruitment rate was 2.73 participants/month. At 6‐month post‐randomisation the difference in mean reduction in visual analogue scale, xerostomia inventory and EULAR Sjögren's syndrome patient reported index‐Q1 scores between groups were 0.36 (95% CI: −0.84, 1.56), 3.31 (0.43, 6.18), and 0.23 (−1.17, 1.63), respectively; unstimulated salivary flow increased by a mean of 0.98 mL/15 min, all in favour of the active group. No adverse events were reported.Conclusion: LEONIDAS‐1 results support progression to a phase III definitive randomised controlled trial of salivary electrostimulation in individuals with Sjogren's syndrome. Xerostomia inventory could be considered the primary patient‐centred outcome measure and the corresponding observed treatment effect could inform the sample size of a future trial.

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.

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 .

Objective: To preliminary evaluate the clinical effects of probiotics in individuals with symptomatic oral lichen planus and the possible mechanisms of action.Subjects and Methods: A group of 30 individuals with symptomatic oral lichen planus were recruited in a randomised double‐blind parallel group controlled (1:1) proof‐of‐concept pilot trial of probiotic VSL#3 vs placebo. Efficacy outcomes included changes in pain numeric rating scale, oral disease severity score and the chronic oral mucosal disease questionnaire. Adverse effects, home diary and withdrawals were assessed as feasibility outcomes. Mechanistic outcomes included changes in salivary and serum levels of CXCL10 and IFN‐γ and in oral microbial composition.Results: The probiotic VSL#3 was safe and well tolerated. We observed no statistically significant change in pain, disease activity, quality of life, serum/salivary CXCL10 or oral microbial composition with respect to placebo. Salivary IFN‐γ levels demonstrate a trend for a reduced level in the active group (p = 0.082) after 30 days of probiotic consumption.Conclusions: The present proof‐of‐concept study provides some weak not convincing indication of biological and clinical effects of probiotic VSL#3 in individuals with painful oral lichen planus. Further research in this field is needed, with the current study providing useful information to the design of future clinical trials.

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.

Objectives: Systematic review with meta‐analysis of interventions for dry mouth symptoms and hyposalivation of Sjögren's syndrome (SS).Materials and Methods: We searched MEDLINE, Cochrane Central and EMBASE up to February 2018 for randomized trials of interventions for dry mouth and hyposalivation of SS. The primary outcome was the mean change in xerostomia symptoms. The secondary outcomes included changes in salivary flow and quality of life. We used the Cochrane risk of bias tool for individual studies and the GRADE method to summarize the quality of evidence across studies for the included outcomes.Results: Thirty‐six studies (3,274 patients) were included in the systematic review. Results from the meta‐analyses showed high‐quality evidence that pilocarpine was superior to placebo in reducing dry mouth symptoms. We found moderate quality of evidence that pilocarpine, rituximab and interferon‐alpha were more effective than placebo in increasing salivary flow, with the relevant effect size being large for pilocarpine, and notably smaller for rituximab and interferon‐alpha.Conclusion: Clinicians should be very confident in the beneficial effects of pilocarpine upon dry mouth symptoms of SS and moderately confident that pilocarpine, rituximab and interferon‐alpha can have beneficial effects upon salivary flow. Adverse events are common. The use of other treatment modalities cannot be supported on the basis of current evidence.