MASCC/ISOO Clinical Practice Statement: Management of salivary gland hypofunction and xerostomia in cancer patients.

PURPOSE: A MASCC/ISOO Clinical Practice Statement (CPS) is aimed at generating a concise tool for clinicians that concentrates practical information needed for the management of oral complications of cancer patients. This CPS is focused on the management of salivary gland hypofunction and xerostomia in cancer patients. METHODS: This CPS was developed based on critical evaluation of the literature followed by a structured discussion of a group of leading experts, members of the Oral Care Study Group of MASCC/ISOO. The information is presented in the form of succinct bullets and tables to generate a short manual about the best standard of care. RESULTS: Salivary gland hypofunction and xerostomia in cancer patients are managed by (i) stimulating saliva production of salivary glands with residual secretory capacity or (ii) artificial wetting of the oral and lip surfaces which can be achieved by pharmacological or non-pharmacological interventions. Pharmacological interventions encompass the use of sialagogues and sialolytics, while non-pharmacological interventions involve the use of moistening agents, mechanical, gustatory, or electrostimulation of the salivary glands. Additional treatment modalities may be incorporated in practice based on local availability and the clinician's experience. CONCLUSION: The information presented in this CPS offers clinicians convenient access to the dosages and regimens of different interventions for managing salivary gland hypofunction or xerostomia to facilitate clinical efficiency and conserve valuable time for clinicians.

Impact of low-level laser therapy on the quality of life of patients with xerostomia undergoing head and neck radiotherapy: a systematic review.

PURPOSE: To carry out a systematic review to assess whether low-level laser therapy can improve the quality of life of patients with xerostomia undergoing head and neck radiotherapy. METHODS: A systematic search was performed through Embase, Medline/PubMed, Cochrane, Scopus, Web of Science, nonpeer-reviewed clinicaltrials.gov and LILACS. The strategy included clinical studies were selected that prospectively followed or evaluated the quality of life by directly comparing the use of low-level laser therapy for xerostomia induced by head and neck radiotherapy with alternative therapies without the use of a laser. The risk of bias in the studies was assessed by RoB 2.0 and Robins I. RESULTS: After all application of the predetermined criteria, four studies were included, dated between the years 2014 and 2023. Three studies described as randomized clinical trials were included, one of which was a randomized pilot study and only one was a prospective clinical trial. A total of 126 patients were evaluated, all four studies used the infrared wavelength, with two studies using the combination with the red wavelength. It was observed that low-level laser therapy can change the sensation of dry mouth, improving patients' quality of life. In addition, changes related to increased stimulated and unstimulated salivary flow were also identified. CONCLUSION: The use of low-level laser therapy has promising results on xerostomia, consequently improving the quality of life of patients undergoing radiotherapy in the head and neck region.

MASCC/ISOO Clinical Practice Statement: Management of oral manifestations of chronic graft-versus-host-disease.

PURPOSE: A MASCC/ISOO Clinical Practice Statement (CPS) is aimed at generating a concise tool for clinicians, which concentrates practical information needed for the management of oral complications of cancer patients. This CPS is focused on the management of oral manifestations of chronic graft-versus-host-disease (cGVHD). METHODS: This CPS was developed based on critical evaluation of the literature followed by a structured discussion of a group of leading experts, members of the Oral Care Study Group of MASCC/ISOO. The information is presented in the form of succinct bullets and table to generate a short manual about the best standard of care. RESULTS: The treatment goals in oral cGVHD are to relieve pain and xerostomia, improve oral function, prevent secondary infection, prevent deterioration of the dentition, and detect malignant transformation as early as possible. The prevention and treatment measures for oral mucosal lesions, hypofunction of the salivary glands, and sclerodermatous changes in the oral and perioral tissues are detailed, as well as the possible complications and side effects of these interventions. CONCLUSIONS: Patients post allogeneic hematopoietic cell transplantations, with cGVHD manifest in the oral and perioral tissues, should be regularly monitored and treated as needed by an oral care practitioner. This CPS provides the clinician with practical tools for examining, preventing, and treating the various sequalae that may affect the oral cavity in these patients.

Effect of hyperbaric oxygen therapy on diabetes-related oral complications.

Background: Diabetes Mellitus is a chronic disease characterized by uncontrolled blood sugar levels, which lead to end-organ damage. While the diagnosis and treatment of its complications have been extensively studied, the effect of Hyperbaric Oxygen Therapy (HBO2) on diabetes-related oral complications remains unexplored. Aim: This prospective clinical study aims to investigate the effect of HBO2 on diabetes-related oral complications. Methods: Twenty patients diagnosed with diabetic foot ulcers and scheduled for HBO2 were included in this study. We recorded stimulated and unstimulated saliva pH, buffering capacity, flow rate, and subjective symptoms such as dry mouth, halitosis, taste loss, difficulty swallowing, and clinical examination findings before HBO2 and after the 21st session. Results: Upon comparing the findings, we observed a significant decrease in dry mouth and halitosis, periodontal disease severity, and healing of candida-related stomatitis and angular cheilitis. Despite not reaching statistical significance for other saliva parameters, the unstimulated salivary flow rate increased to normal limits (0.3-0.4 ml/min) in 6 out of 8 patients with a flow rate of less than 0.25 ml/min. Conclusion: Our study investigated the effect of HBO2 on diabetes-related oral complications for the first time, highlighting symptomatic relief for dry mouth and halitosis. Although our results are insufficient to report a definitive benefit, they underscore the need for further research on the oral health effects of HBO2.

Dental care professionals' awareness of oral dryness and its clinical management: a questionnaire-based study.

BACKGROUND: Despite the high prevalence of oral dryness and awareness of its complications, there is limited research on the clinical management of patients with oral dryness in general dental care. PURPOSE: To (1) describe and compare awareness among dental care professionals regarding saliva functions, potential causes and complications of oral dryness, and patient management (2) Investigate if the length of professional experience influences these aspects. METHODS: A digital self-administrated survey was sent to 2668 dental care professionals working in the general dental care, Public Dental Service, in Sweden. Twelve dental care professionals reviewed the questionnaire prior to its distribution. The questionnaire comprised 32 questions about patient management, awareness of saliva functions, causes and complications of oral dryness, and self-assessment queries. RESULTS: The response rate was 18.6% (241 dentists and 257 dental hygienists). Older adults (65+) were asked more often about dry mouth (93.0%) compared to those aged 18-23 years (50.0%) and those under 18 years (24.9%). Dental hygienists encountered individuals with oral dryness more frequently (61.1%) than dentists (48.5%) (p < 0.01), and more often asked individuals in the age groups 18-23 years (p = 0.003), 24-40 years (p = 0.045), and 41-65 years (p = 0.031) about dry mouth. A higher proportion of dental hygienists (88.3%) than dentists (51.0%) had measured salivary secretion rate, (p < 0.001) and more often suggested preventive dental care 3-4 times a year, (42.5% vs. 30.5%) (p < 0.007). Dentists had a higher awareness of saliva functions, while dental hygienists had a higher awareness about causes and complications of oral dryness. Higher proportions of dentists and dental hygienists with over 10 years of professional experience had measured salivary secretion rate (69.1% vs. 95.7%) compared to their counterparts with less than 10 years of professional experience (35.9% vs. 79.5%) (p < 0.001 for both). CONCLUSION: Compared to dentists, dental hygienists were more attentive to patients with oral dryness as they encountered these individuals more often, asked more age-groups, suggested frequent preventive measures, and had higher awareness of the causes and complications of oral dryness. Length of professional experience could improve both the management of patients with oral dryness and awareness of its causes, particularly for dental hygienists.

The effect of artificial saliva on the control of dry mouth: a semi-experimental study on COVID-19 patients under Non-invasive mechanical ventilation.

OBJECTIVES: Since maintaining oral hygiene is essential in nursing care, the present study was conducted to determine the effect of oral care using Mucosamin artificial saliva spray to control dry mouth in ICU patients with COVID-19. MATERIALS AND METHODS: The current semi-experimental research was conducted on eighty patients with COVID-19 selected using the available sampling method. The study tool was a Beck oral assessment scale (BOAS). The case and control groups were selected from two hospitals with relatively similar conditions and treatment procedures. For patients in the intervention group, mucosamin artificial saliva spray was used in addition to the common care, while control group patients received only common care. RESULTS: Eighty patients were randomly assigned to two groups named control and intervention (40 patients in each group). The intervention was very effective in reducing the BOAS score after four days in comparison with the control group (9.23 vs. 12.05, respectively; p-value < 0.001). Based on the adjusted model, the application of artificial saliva reduced the BOAS score, indicating improvement in mouth dryness. While the BOAS score was increased in the control group, it had a declining trend in the intervention one. CONCLUSION: The study's results showed that using artificial saliva spray could effectively reduce the symptoms of dry mouth in patients with COVID-19 treated with non-invasive mechanical ventilation. CLINICAL RELEVANCE: The present study introduced an applicable solution (artificial saliva) to treat mouth dryness in ICU patients under mechanical ventilation.

[Oral mucosa problems in palliative care]. / Mundschleimhautprobleme in der Palliative Care.

INTRODUCTION: Oral health problems appear in up to 80 % of palliative care patients. Almost all of these patients suffer from a dry mouth which is often the result of medication side effects. Even though a dry mouth is not a disease by itself, it enhances the risk of developing other more serious oral lesions and diseases. Stomatitis, an inflammatory response to radio- or oncological treatment induced lesions, is very painful and may interfere severely with the ingestion of food and fluids. Finally, oral fungal infections are very common in immunosuppressed patients. Each of these entities comes with specific symptoms and signs which may impair food and fluid intake but also have consequences on the quality of life in these patients. Hence, a systematic and standardized evaluation is essential and can be accomplished with little effort by all health care professionals.

Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction (MARSH): A pilot, first-in-human study of interferon gamma-stimulated marrow mesenchymal stromal cells for treatment of radiation-induced xerostomia.

BACKGROUND AIMS: Xerostomia, or the feeling of dry mouth, is a significant side effect of radiation therapy for patients with head and neck cancer (HNC). Preliminary data suggest that mesenchymal stromal/stem cells (MSCs) can improve salivary function. We performed a first-in-human pilot study of interferon gamma (IFNγ)-stimulated autologous bone marrow-derived MSCs, or MSC(M), for the treatment of radiation-induced xerostomia (RIX). Here we present the primary safety and secondary efficacy endpoints. METHODS: A single-center pilot clinical trial was conducted investigating the safety and tolerability of autologous IFNγ-stimulated MSC(M). The study was conducted under an approved Food and Drug Administration Investigational New Drug application using an institutional review board-approved protocol (NCT04489732). Patients underwent iliac crest bone marrow aspirate and MSC(M) were isolated, cultured, stimulated with IFNγ and cryopreserved for later use. Banked cells were thawed and allowed to recover in culture before patients received a single injection of 10 × 106 MSC(M) into the right submandibular gland under ultrasound guidance. The primary objective was determination of safety and tolerability by evaluating dose-limiting toxicity (DLT). A DLT was defined as submandibular pain >5 on a standard 10-point pain scale or any serious adverse event (SAE) within 1 month after injection. Secondary objectives included analysis of efficacy as measured by salivary quantification and using three validated quality of life instruments. Quantitative results are reported as mean and standard deviation. RESULTS: Six patients with radiation-induced xerostomia who had completed radiation at least 2 years previously (average 7.8 years previously) were enrolled in the pilot study. The median age was 71 (61-74) years. Five (83%) patients were male. Five patients (83%) were treated with chemoradiation and one patient (17%) with radiation alone. Grade 1 pain was seen in 50% of patients after submandibular gland injection; all pain resolved within 4 days. No patients reported pain 1 month after injection, with no SAE or other DLTs reported 1 month after injection. The analysis of secondary endpoints demonstrated a trend of increased salivary production. Three patients (50%) had an increase in unstimulated saliva at 1 and 3 months after MSC(M) injection. Quality of life surveys also showed a trend toward improvement. CONCLUSIONS: Injection of autologous IFNγ-stimulated MSC(M) into a singular submandibular gland of patients with RIX is safe and well tolerated in this pilot study. A trend toward an improvement in secondary endpoints of salivary quantity and quality of life was observed. This first-in-human study provides support for further investigation into IFNγ-stimulated MSC(M) injected in both submandibular glands as an innovative approach to treat RIX and improve quality of life for patients with HNC.

Long-term effectiveness of a novel intra-oral electro-stimulator for the treatment of dry mouth in patients with Sjogren's syndrome: A randomised sham-controlled feasibility study (LEONIDAS-1).

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.

Use and efficacy of dry-mouth interventions in Sjögren's disease patients and possible association with perceived oral dryness and patients' discomfort.

OBJECTIVES: Sjögren's disease (SjD) patients use various interventions to relief their oral dryness. However, the use and efficacy of these interventions have only partially been evaluated. The present study aims to investigate whether there is an association between the perceived oral dryness and discomfort of SjD patients and their use of specific interventions. MATERIALS AND METHODS: A cross-sectional study was performed among SjD patients, who completed several questionnaires to assess the severity of their oral dryness and an inventory of dry-mouth interventions. The perceived efficacy of each intervention was reported on a 5-point Likert-scale. RESULTS: The questionnaires were returned by 92 SjD patients. For relief of oral dryness, they mostly used "eating fruit", "drinking tea", "moistening the lips", "drinking water, and "drinking small volumes" (> 50%). Three interventions had a frequency of use ranging from 2-6 times/day, whereas, "drinking water" and "drinking small volumes" showed higher frequencies (> 14). The highest overall efficacy (≥ 3.5) was reported for "chewing gum" and "using a mouth gel". Furthermore, various dry-mouth interventions showed significant associations with oral dryness scores and/or patients' discomfort. For example, "drinking small volumes" and "using XyliMelts" were associated with the Bother Index score. CONCLUSION: Great variation was found in the use of dry-mouth interventions by the participants and the severity of the oral dryness and/or patients' discomfort seemed to affect their choice of intervention. Notably, the mostly used interventions did not show the highest reported efficacy. CLINICAL RELEVANCE: These findings might help SjD patients and clinicians in their choice of effective dry-mouth interventions.

Efficacy of auricular acupuncture in improving dry mouth among an institutionalised older population: A randomised controlled study.

AIMS: To investigate the efficacy of applying auricular acupuncture (AA) treatment in improving dry mouth in institution-dwelling older adults. BACKGROUND: Dry mouth (xerostomia) is a common distressing problem in older populations, especially for institution-dwelling older adults that can affect oral health and quality of life. DESIGN: A randomised controlled trial was conducted from December 2020 to March 2021 and performed according to STRICTA guidelines extended from the CONSORT statement. METHODS: Older adults aged more than 65 years were randomly allocated to an AA group (n = 37) with an 8-week actual auricular points treatment or a control group (n = 38) receiving sham auricular point acupuncture. Measurements comprised a subjective assessment of the level of dry mouth as assessed by a visual analogue scale in a xerostomia questionnaire, and an objective assessment of the physiological wetness of the lingual mucosa measured with a moisture-checking device. A generalised estimating equation model was used for data analyses. RESULTS: After completing an 8-week AA intervention stimulating the Shenmen, Point Zero and Salivary Gland 2-prime points, the AA group exhibited significantly improved subjective symptoms of dry mouth comprised of difficulty speaking (B = -6.47, p < .001), difficulty swallowing (B = -6.73, p < .001), the amount of oral saliva (B = -5.38, p < .001), a dry throat (B = -7.53, p < .001) and thirst (B = -8.06, p < .001) compared with the control group. Moreover, the AA group had higher objective oral saliva flow than the control group (B = 4.73, p < .001). CONCLUSION: AA is an effective non-pharmacological method for improving subjective symptoms of dry mouth and objective saliva secretion in older populations living in nursing homes. RELEVANT TO CLINICAL PRACTICE: Performing regular AA on the Shenmen, Point Zero and Salivary Gland 2-prime auricular points can be considered an alternative treatment approach to improve dry mouth in institution-dwelling older adults.

Protective Effect of Electroacupuncture on Chemotherapy-Induced Salivary Gland Hypofunction in a Mouse Model.

Radiotherapy and chemotherapy can impair salivary gland (SG) function, which causes xerostomia and exacerbate other side effects of chemotherapy and oral infection, reducing patients' quality of life. This animal study aimed to assess the efficacy of electroacupuncture (EA) as a means of preventing xerostomia induced by 5-fluorouracil (5-FU). A xerostomia mouse model was induced via four tail vein injections of 5-FU (80 mg/kg/dose). EA was performed at LI4 and LI11 for 7 days. The pilocarpine-stimulated salivary flow rate (SFR) and salivary glands weight (SGW) were recorded. Salivary immunoglobulin A (SIgA) and lysozyme were determined via enzyme-linked immunosorbent assay (ELISA). SG was collected for hematoxylin and eosin staining to measure acini number and acinar cell size. Tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and aquaporin 5 (AQP5) mRNA expressions in SG were quantified via RT-qPCR. 5-FU caused significant decreases in SFR, SGW, SIgA, lysozyme, AQP5 expression, and acini number, while TNF-α and IL-1ß expressions and acinar cell size were significantly increased. EA treatment can prevent 5-FU damage to the salivary gland, while pilocarpine treatment can only elevate SFR and AQP5 expression. These findings provide significant evidence to support the use of EA as an alternative treatment for chemotherapy-induced salivary gland hypofunction and xerostomia.

Dental Pulp Stem Cells for Salivary Gland Regeneration-Where Are We Today?

Xerostomia is the phenomenon of dry mouth and is mostly caused by hypofunction of the salivary glands. This hypofunction can be caused by tumors, head and neck irradiation, hormonal changes, inflammation or autoimmune disease such as Sjögren's syndrome. It is associated with a tremendous decrease in health-related quality of life due to impairment of articulation, ingestion and oral immune defenses. Current treatment concepts mainly consist of saliva substitutes and parasympathomimetic drugs, but the outcome of these therapies is deficient. Regenerative medicine is a promising approach for the treatment of compromised tissue. For this purpose, stem cells can be utilized due to their ability to differentiate into various cell types. Dental pulp stem cells are adult stem cells that can be easily harvested from extracted teeth. They can form tissues of all three germ layers and are therefore becoming more and more popular for tissue engineering. Another potential benefit of these cells is their immunomodulatory effect. They suppress proinflammatory pathways of lymphocytes and could therefore probably be used for the treatment of chronic inflammation and autoimmune disease. These attributes make dental pulp stem cells an interesting tool for the regeneration of salivary glands and the treatment of xerostomia. Nevertheless, clinical studies are still missing. This review will highlight the current strategies for using dental pulp stem cells in the regeneration of salivary gland tissue.

The effect of gum chewing on xerostomia and salivary flow rate in elderly and medically compromised subjects: a systematic review and meta-analysis.

BACKGROUND: Xerostomia negatively affects quality of life. Symptoms include oral dryness; thirst; difficulty speaking, chewing, and swallowing food; oral discomfort; mouth soft tissue soreness and infections; and rampant tooth decay. The objective of this systematic review and meta-analysis was to investigate if gum chewing is an intervention that results in objective improvements in salivary flow rates and subjective relief from xerostomia. METHOD: We searched electronic databases including Medline, Scopus, Web of Science, Embase, Cochrane Library (CDSR and Central), Google Scholar and the citations of review papers (last searched 31/03/23). The study populations included: 1) elderly people with xerostomia (> 60 years old, any gender, and severity of xerostomia), and 2) medically compromised people with xerostomia. The intervention of interest was gum chewing. Comparisons included gum chewing vs. no gum chewing. The outcomes included salivary flow rate, self-reported xerostomia, and thirst. All settings and study designs were included. We conducted a meta-analysis on studies where measurements of unstimulated whole salivary flow rate for both a gum chewing, and no gum chewing intervention (daily chewing of gum for two weeks or longer) were reported. We assessed risk of bias using Cochrane's RoB 2 and ROBINS-I tools. RESULTS: Nine thousand six hundred and two studies were screened and 0.26% (n = 25) met the inclusion criteria for the systematic review. Two of the 25 papers had a high overall risk of bias. Of the 25 papers selected for the systematic review, six met the criteria to be included in the meta-analysis which confirmed a significant overall effect of gum on saliva flow outcomes compared to control (SMD = 0.44, 95% CI: 0.22-0.66; p = 0.00008; I2 = 46.53%). CONCLUSIONS: Chewing gum can increase unstimulated salivary flow rate in elderly and medically compromised people with xerostomia. Increasing the number of days over which gum is chewed increases the improvement in the rate of salivation. Gum chewing is linked with improvements in self-reported levels of xerostomia (although it is noted that no significant effects were detected in five of the studies reviewed). Future studies should eliminate sources of bias, standardise methods to measure salivary flow rate, and use a common instrument to measure subjective relief from xerostomia. STUDY REGISTRATION: PROSPERO CRD42021254485.

A scoping review on hyposalivation associated with systemic conditions: the role of physical stimulation in the treatment approaches.

BACKGROUND: Several systemic conditions can result in distinct degrees of salivary gland damage and consequent hypofunction. The development of successful management schemes is highly challenging due to the complexity of saliva. This study aimed to systematically map the literature on the physical stimulation of salivary glands for hyposalivation management and the response of individuals according to different systemic conditions causing salivary impairment. METHODS: A systematic search in the literature was performed. Two reviewers independently selected clinical trials, randomized or not, that used physical stimulation to treat hyposalivation caused by systemic conditions. Studies evaluating healthy subjects without hyposalivation were included as controls. Single-arm clinical studies or case series were also included for protocol mapping (PRISMA extension for scoping reviews). RESULTS: Out of 24 included studies, 10 evaluated healthy subjects, from which 9 tested transcutaneous electrical nerve stimulation (TENS) and 1 tested acupuncture and electroacupuncture. Fourteen studies evaluated individuals with hyposalivation: 6 applied TENS, 6 applied low-level laser therapy (LLLT), and 2 applied acupuncture, carried out in post-chemotherapy, medication use, postmenopausal women, hemodialysis patients, smokers, diabetics, Sjögren's syndrome (SS). All showed increased salivation after treatment, except for two LLLT studies in individuals with SS. CONCLUSIONS: Among the different patient groups, individuals with Sjögren's syndrome (SS) exhibited the poorest responses, while those with medication-induced hyposalivation demonstrated the most favorable treatment outcomes, independently of the management strategy for saliva stimulation. It means that physical stimulation of salivary glands holds promise as an alternative for managing hyposalivation in cases of reversible gland damage. However, to make informed decisions in current practice, it is necessary to conduct new well-designed randomized clinical trials with appropriate methodologies.

Salivary stimulatory effect of novel low level transcutaneous electro neurostimulator in geriatric patients with xerostomia.

BACKGROUND: Xerostomia (dryness of the mouth) is one of the most common long-term consequences of ageing, and it causes a tremendous impact on the function and morphology of the salivary ductal system. As a consequence, it leads to a decrease in the amount of salivary output and also affects the overall quality of life. The purpose of this study was to determine whether electrostimulation using a custom designed transcutaneous electrical nerve stimulation (TENS) device will help to improve the quality of secreted saliva following electrostimulation. METHODS: One hundred thirty-five participants underwent the intervention for three months, twice daily (80 Hz). Pre-intervention and post-intervention unstimulated saliva were collected. Parameters such as salivary pH, cortisol level, salivary antioxidants, total protein, the viscosity of saliva, and microbial carriage were analysed. RESULTS: Salivary pH, cortisol, microbial cultures, viscosity, and antioxidants showed a significant difference at the end of the 3rd month (p < 0.05). Irrespective of the patient's age, gender, and common underlying systemic illnesses (diabetes and hypertension), a significant change in the quality of the salivary analytes was observed. CONCLUSION: The study emphasises the use of a custom designed TENS device in improving the quality of secreted saliva among old patients with oral dryness.

Chewing Gum May Alleviate Degree of Thirst in Patients on Hemodialysis.

Background and Objectives: Fluid restriction commonly causes dry mouth in patients on hemodialysis (HD). The observed effects of chewing gum on the amount of saliva, interdialytic weight gain (IDWG), and degree of thirst in patients on HD have been inconsistent. We investigated whether chewing gum can modulate these three parameters in patients on HD. Materials and Methods: We used purposive sampling to enroll 37 patients on HD who were then randomly divided into the chewing gum group (n = 19) and the control (non-chewing gum) group (n = 18). The degree of thirst was assessed using a self-rated visual analog scale (VAS) and a summated xerostomia inventory (SXI), respectively. Results: The degree of thirst after dialysis was significantly lower in the chewing gum group than in the control group. The amount of saliva was higher in the chewing gum group than in the control group before dialysis, but the saliva amount was comparable between the groups after dialysis. Furthermore, the amount of saliva was not associated with IDWG in patients on HD before or after dialysis. Conclusions: Chewing gum may alleviate the feeling of thirst but may not affect the amount of saliva and IDWG in patients on HD. Therefore, we suggest that chewing gum may be a useful approach to improve dry mouth and thirst in patients on HD.

A New Model of Salivary Pacemaker-A Proof of Concept and First Clinical Use.

Background and Objectives: Saliva is of utmost importance for maintaining oral health. Management of saliva flow rate deficiency recently includes salivary neuro-electrostimulation. The aim of this paper is to present a new model of salivary pacemaker-the MICROSAL device (MD), an intelligent, miniaturized, and implant-supported oral device used for salivary stimulation. Materials and Methods: This report presents the development, calibration, and first clinical tests which involved the MD. The novel features of this device are the pH sensor and the fact that it communicates with the patient's smartphone, where oral wetness and pH are graphically exposed. Saliva samples were taken before and after the MD was used on a 68-year-old patient suffering from post-irradiation xerostomia, and albumin and total protein were analyzed. Results: The device uses up to 3 V and time intervals of 2 s seconds for stimulation. The total volume of all saliva samples collected during the clinical trial was almost seven times higher after the device was used. Albumin decreased from a maximum of 0.15 g/dL to 0.04 g/dL, and total proteins from 0.65 g/dL to 0.21 g/dL, after salivary stimulation. Conclusions: The MD increased saliva secretion of the patient, and we are confident it will be a good solution for future management of salivary gland hypofunction.

Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction (MARSH): Study protocol for a phase 1 dose-escalation trial of patients with xerostomia after radiation therapy for head and neck cancer: MARSH: Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction.

BACKGROUND: Xerostomia, or dry mouth, is a common side effect of head and neck radiation. Current treatment options for radiation-induced xerostomia are generally supportive in nature. Adult stem cells are the ultimate source for replenishment of salivary gland tissue. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are a viable cell-based therapy for xerostomia. We have undertaken studies enabling U.S. Food and Drug Administration Investigational New Drug status, demonstrating the normal phenotype, intact functionality, and pro-growth secretome of interferon-γ (IFNγ)-stimulated BM-MSCs taken from patients with head and neck cancer who have undergone radiation ± chemotherapy. Here we present the protocol of MARSH, a first-in-human clinical trial of bone marrow-derived, IFNγ-activated BM-MSCs for the treatment of radiation-induced xerostomia. METHODS: This single-center phase 1 dose-escalation with expansion cohort, non-placebo-controlled study will assess the safety and tolerability of BM-MSCs for the treatment of radiation-induced xerostomia in patients who had head and neck cancer. The phase 1 dose-escalation study will be a 3 + 3 design with staggered enrollment. A total of 21 to 30 subjects (9 to 18 in phase 1 study, 12 in expansion cohort) will be enrolled. The primary endpoint is determining the recommended phase 2 dose (RP2D) of IFNγ-stimulated BM-MSCs to enable further studies on the efficacy of BM-MSCs. Patients' bone marrow will be aspirated, and BM-MSCs will be expanded, stimulated with IFNγ, and injected into the submandibular gland. The RP2D will be determined by dose-limiting toxicities occurring within 1 month of BM-MSC injection. Secondary outcomes of saliva amounts and composition, ultrasound of salivary glands, and quality of life surveys will be taken at 3-, 6-, 12-, and 24-month visits. DISCUSSION: Autotransplantation of IFNγ-stimulated BM-MSCs in salivary glands after radiation therapy or chemoradiation therapy may provide an innovative remedy to treat xerostomia and restore quality of life. This is the first therapy for radiation-induced xerostomia that may be curative. TRIAL REGISTRATION: World Health Organization International Clinical Trials Registry Platform: NCT04489732.

Primary dental care treatment in primary Sjögren's syndrome: a possible role in improving salivary flow rate.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is an inflammatory chronic disorder that mainly affects exocrine glands. Additionally, oral infections can aggravate the glandular dysfunction. However, data on primary dental care (PDC) treatment in pSS are scarce. This study aimed to appraise the impact of PDC on the Xerostomia Inventory (XI), unstimulated/stimulated salivary flow rates and salivary cytokine profile in pSS. METHODS: Fifty-two pSS patients and 52 sex- and age-matched control participants without systemic autoimmune diseases were included in a prospective study. At inclusion, all participants were assessed through a standardised protocol, measurement of salivary pro-inflammatory cytokines, and underwent PDC. Dental procedures included: oral hygiene guidance, restorative treatment of caries, surgical removal of residual roots and impacted or partially erupted teeth, cysts, supra and subgingival periodontal scaling and treatment of soft tissue disorders (removal of lesions and treatment of opportunistic infections). After 3 months, the clinical/laboratorial assessments were repeated. RESULTS: At inclusion, the Decayed, Missing and Filled Teeth (DMFT) index was higher in the pSS patients than in the control group (13.3±8.2 vs. 8.6±6.2, p=0.002), whereas periodontal parameters were comparable in both groups (p>0.05). After PDC, 26.9% of pSS patients showed a reduction of at least 6 points (clinical improvement) in XI, but mean XI remained unchanged (p=0.285). PDC resulted in an increase in mean unstimulated (p<0.001) and stimulated (p=0.001) salivary flow rates in pSS, with no change in salivary cytokine profile (p≥0.05). CONCLUSIONS: PDC promoted improvement in unstimulated and stimulated salivary flow rates in pSS. This novel finding reinforces the recommendation of this strategy for pSS patients. CLINICALTRIALS: gov (Identifier: NCT03711214).