Cancer therapy-related salivary dysfunction.

Salivary gland dysfunction is a common side effect of cancer treatments. Salivary function plays key roles in critical daily activities. Consequently, changes in salivary function can profoundly impair quality of life for cancer patients. We discuss salivary gland anatomy and physiology to understand how anticancer therapies such as chemotherapy, bone marrow transplantation, immunotherapy, and radiation therapy impair salivary function. We discuss approaches to quantify xerostomia in the clinic, including the advantages and limitations of validated quality-of-life instruments and approaches to directly measuring salivary function. Current and emerging approaches to treat cancer therapy-induced dry mouth are presented using radiation-induced salivary dysfunction as a model. Limitations of current sialagogues and salivary analogues are presented. Emerging approaches, including cellular and gene therapy and novel pharmacologic approaches, are described.

[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.

Salivary gland organoid transplantation as a therapeutic option for radiation-induced xerostomia.

BACKGROUND: Xerostomia is a pathological condition characterized by decreased salivation due to salivary gland dysfunction and is frequently attributed to irreversible damage as a side effect of radiation therapy. Stem cell-derived organoid therapy has garnered attention as a promising avenue for resolving this issue. However, Matrigel, a hydrogel commonly used in organoid culture, is considered inappropriate for clinical use due to its undefined composition and immunogenicity. In this study, we aimed to develop a method for culturing collagen-based human salivary gland organoids (hSGOs) suitable for clinical applications and evaluated their therapeutic effectiveness. METHODS: Human salivary gland stem cells were isolated from the salivary gland tissues and cultured in both Matrigel and collagen. We compared the gene and protein expression patterns of salivary gland-specific markers and measured amylase activity in the two types of hSGOs. To evaluate the therapeutic effects, we performed xenogeneic and allogeneic transplantation using human and mouse salivary gland organoids (hSGOs and mSGOs), respectively, in a mouse model of radiation-induced xerostomia. RESULTS: hSGOs cultured in Matrigel exhibited self-renewal capacity and differentiated into acinar and ductal cell lineages. In collagen, they maintained a comparable self-renewal ability and more closely replicated the characteristics of salivary gland tissue following differentiation. Upon xenotransplantation of collagen-based hSGOs, we observed engraftment, which was verified by detecting human-specific nucleoli and E-cadherin expression. The expression of mucins, especially MUC5B, within the transplanted hSGOs suggested a potential improvement in the salivary composition. Moreover, the allograft procedure using mSGOs led to increased salivation, validating the efficacy of our approach. CONCLUSIONS: This study showed that collagen-based hSGOs can be used appropriately in clinical settings and demonstrated the effectiveness of an allograft procedure. Our research has laid the groundwork for the future application of collagen-based hSGOs in allogeneic clinical trials.

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.

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.

Acupuncture for Chronic Radiation-Induced Xerostomia in Head and Neck Cancer: A Multicenter Randomized Clinical Trial.

Importance: Patients with head and neck cancer who undergo radiotherapy can develop chronic radiation-induced xerostomia. Prior acupuncture studies were single center and rated as having high risk of bias, making it difficult to know the benefits of acupuncture for treating radiation-induced xerostomia. Objective: To compare true acupuncture (TA), sham acupuncture (SA), and standard oral hygiene (SOH) for treating radiation-induced xerostomia. Design, Setting, and Participants: A randomized, blinded, 3-arm, placebo-controlled trial was conducted between July 29, 2013, and June 9, 2021. Data analysis was performed from March 9, 2022, through May 17, 2023. Patients reporting grade 2 or 3 radiation-induced xerostomia 12 months or more postradiotherapy for head and neck cancer were recruited from community-based cancer centers across the US that were part of the Wake Forest National Cancer Institute Community Oncology Research Program Research Base. Participants had received bilateral radiotherapy with no history of xerostomia. Interventions: Participants received SOH and were randomized to TA, SA, or SOH only. Participants in the TA and SA cohorts were treated 2 times per week for 4 weeks. Those experiencing a minor response received another 4 weeks of treatment. Main Outcomes and Measures: Patient-reported outcomes for xerostomia (Xerostomia Questionnaire, primary outcome) and quality of life (Functional Assessment of Cancer Therapy-General) were collected at baseline, 4 (primary time point), 8, 12, and 26 weeks. All analyses were intention to treat. Results: A total of 258 patients (201 men [77.9%]; mean [SD] age, 65.0 [9.16] years), participated from 33 sites across 13 states. Overall, 86 patients were assigned to each study arm. Mean (SD) years from diagnosis was 4.21 (3.74) years, 67.1% (n = 173) had stage IV disease. At week 4, Xerostomia Questionnaire scores revealed significant between-group differences, with lower Xerostomia Questionnaire scores with TA vs SOH (TA: 50.6; SOH: 57.3; difference, -6.67; 95% CI, -11.08 to -2.27; P = .003), and differences between TA and SA (TA: 50.6; SA: 55.0; difference, -4.41; 95% CI, -8.62 to -0.19; P = .04) yet did not reach statistical significance after adjustment for multiple comparisons. There was no significant difference between SA and SOH. Group differences in Functional Assessment of Cancer Therapy-General scores revealed statistically significant group differences at week 4, with higher scores with TA vs SOH (TA: 101.6; SOH: 97.7; difference, 3.91; 95% CI, 1.43-6.38; P = .002) and at week 12, with higher scores with TA vs SA (TA: 102.1; SA: 98.4; difference, 3.64; 95% CI, 1.10-6.18; P = .005) and TA vs SOH (TA: 102.1; SOH: 97.4; difference, 4.61; 95% CI, 1.99-7.23; P = .001). Conclusions and Relevance: The findings of this trial suggest that TA was more effective in treating chronic radiation-induced xerostomia 1 or more years after the end of radiotherapy than SA or SOH. Trial Registration: ClinicalTrials.gov Identifier: NCT02589938.

Long-Term Outcome Following Treatment With Allogeneic Mesenchymal Stem/Stromal Cells for Radiation-Induced Hyposalivation and Xerostomia.

BACKGROUND: Adipose-derived mesenchymal stem/stromal cells (ASCs) are proposed as a new xerostomia treatment. The study evaluated the long-term safety and effectiveness of allogeneic ASCs in radiation-induced xerostomia among patients with previous oropharyngeal cancer. METHODS: This study constitutes 3-year follow-up on the original 10 patients who received allogeneic ASCs injections to the submandibular and parotid glands as part of the MESRIX-II trial. The MESRIX-II trial included the preliminary 4-month follow-up. The primary endpoint was long-term safety. Secondary endpoints were effectiveness evaluated by changes in salivary flow rate and patient-reported outcomes (PROs). Immune response was evaluated by assessing the development of donor-specific antibodies (DSA). FINDINGS: All 10 MESRIX-II patients completed the long-term follow-up (ie, no missing data). During the long-term follow-up, 2 patients encountered a significant adverse event, which was determined to be unrelated to the treatment. No DSAs were detectable at 3 years. The stimulated salivary flow rate increased significantly from an average of 0.66 mL/minute at baseline to 0.86 mL/minute at follow-up, corresponding to an increase of 0.20 [95% CI 0.08 to 0.30] mL/minute, or approximately 30%. Among the PROs, sticky saliva symptoms were reduced, with a -20.0 [95% CI -37.3 to -2.7] units. INTERPRETATION: In conclusion, this study is the first to present long-term follow-up outcomes of allogeneic ASC treatment as a therapeutic option for radiation-induced xerostomia. The study found that ASC treatment appears safe, and there were no indications of adverse immune responses at the 3-year follow-up. Further studies are warranted to evaluate the findings in larger settings.

Mesenchymal Stromal/Stem Cell Therapy Improves Salivary Flow Rate in Radiation-Induced Salivary Gland Hypofunction in Preclinical in vivo Models: A Systematic Review and Meta-Analysis.

BACKGROUND: Mesenchymal stromal/stem cells (MSCs) have been suggested for salivary gland (SG) restoration following radio-induced salivary gland damage. This study aimed to determine the safety and effectiveness of MSC therapy on radio-induced SG damage and hypofunction in preclinical in vivo studies. METHODS: PubMed and EMBASE were systematically searched for preclinical in vivo interventional studies evaluating efficacy and safety of MSC treatment following radio-induced salivary gland damage published before 10th of January 2022. The primary endpoint was salivary flow rate (SFR) evaluated in a meta-analysis. The study protocol was published and registered on PROSPERO ( www.crd.ac.uk/prospero ), registration number CRD42021227336. RESULTS: A total of 16 preclinical in vivo studies were included for qualitative analysis (858 experimental animals) and 13 in the meta-analysis (404 experimental animals). MSCs originated from bone marrow (four studies), adipose tissue (10 studies) and salivary gland tissue (two studies) and were administered intravenously (three studies), intra-glandularly (11 studies) or subcutaneously (one study). No serious adverse events were reported. The overall effect on SFR was significantly increased with a standardized mean difference (SMD) of 6.99 (95% CI: 2.55-11.42). Studies reported improvements in acinar tissue, vascular areas and paracrine factors. CONCLUSION: In conclusion, this systematic review and meta-analysis showed a significant effect of MSC therapy for restoring SG functioning and regenerating SG tissue following radiotherapy in preclinical in vivo studies without serious adverse events. MSC therapy holds significant therapeutic potential in the treatment of radio-induced xerostomia, but comprehensive, randomized, clinical trials in humans are required to ascertain their efficacy in a clinical setting.

Mesenchymal Stem/Stromal Cell Therapy for Radiation-Induced Xerostomia in Previous Head and Neck Cancer Patients: A Phase II Randomized, Placebo-Controlled Trial.

PURPOSE: No effective treatment exists for radiation-induced xerostomia. The objective of this study was to compare the effect of adipose-derived mesenchymal stem/stromal cell (ASC) injection, relative to placebo, on salivary gland function in patients with radiation-induced xerostomia. PATIENT AND METHODS: In this single-centre, double-blind, placebo-controlled trial, patients with hyposalivation were randomised to receive ultrasound-guided injections of allogeneic ASCs or placebo into the submandibular glands. Patients were followed for 4 months. We evaluated unstimulated whole salivary flow rate (UWS), stimulated salivary flow rate, and patient-reported outcomes. Adverse events were recorded and immune response determined in blood samples. RESULTS: We enrolled 120 patients. ASC treatment resulted in a statistically significant UWS increase of 0.04 [95% confidence interval (CI), 0.02-0.06] mL/min (38%) compared with pretreatment baseline whereas placebo treatment did not cause a significant increase [0.01 (95% CI, -0.01 to 0.04) mL/min (21%)]. Both the ASC and placebo treatment yielded notable symptom reductions, with dry mouth decreasing by 13.6 and 7.7 units, sticky saliva decreased by 14.8 and 9.3 units, swallowing difficulties decreased by 7.9 and 8.0 units, and the summary score of the Xerostomia Questionnaire decreased 5.9 and 5.1 units for the ASC and placebo arms, respectively. We found no statistically significant group difference between the ASC and placebo arms for any of the outcomes. CONCLUSIONS: We could not confirm superiority of the ASC relative to placebo. ASC therapy significantly improved UWS in previous patients with head and neck cancer, whereas placebo resulted in an insignificant increase.

Randomized Double-Blind Placebo-Controlled Study of Salivary Substitute with Enzymatic System for Xerostomia in Patients Irradiated in Head and Neck Region.

This study aims to compare whether the use of a salivary substitute including an enzymatic system clinically reduces the intensity of xerostomia, as well as exploring the impact that this has on the quality of life, in patients who had received radiotherapy in the head and neck (HNC) region. Forty patients who had completed radiotherapy treatment within 6 months to 1 year previously were allocated into an Enzymatic Spray group (n = 21) or a Placebo arm (n = 19). It should be noted that two patients in the Placebo arm declined to participate during phase 2 of the study. All patients were randomized and used both products three times a day for 30 days. For analysis, xerostomia grade, unstimulated (UWS) and stimulated (SWS) salivary flow rate, and quality of life through the University of Washington Quality of Life Questionnaire validated in Portuguese (UW-QoL) were assessed in two phases: Phase 1 (before the use of the products) and Phase 2 (after 30 days of using the products). All clinical data were collected from medical records. Analyzing the salivary substitute with the enzymatic system, an improvement in xerostomia complaints was observed 30 days after using the product; however, this difference was not statistically significant (p > 0.05). Regarding quality of life, no significant differences were observed in relation to the UW-QoL and saliva domain between the groups in the two phases of the study (p > 0.05). The salivary substitute with the enzymatic system may be effective in reducing radio-induced xerostomia symptoms; however, further research is necessary to evaluate the efficacy of this salivary substitute on oral health.

Functionality of bone marrow mesenchymal stromal cells derived from head and neck cancer patients - A FDA-IND enabling study regarding MSC-based treatments for radiation-induced xerostomia.

PURPOSE: Salivary dysfunction is a significant side effect of radiation therapy for head and neck cancer (HNC). Preliminary data suggests that mesenchymal stromal cells (MSCs) can improve salivary function. Whether MSCs from HNC patients who have completed chemoradiation are functionally similar to those from healthy patients is unknown. We performed a pilot clinical study to determine whether bone marrow-derived MSCs [MSC(M)] from HNC patients could be used for the treatment of RT-induced salivary dysfunction. METHODS: An IRB-approved pilot clinical study was undertaken on HNC patients with xerostomia who had completed treatment two or more years prior. Patients underwent iliac crest bone marrow aspirate and MSC(M) were isolated and cultured. Culture-expanded MSC(M) were stimulated with IFNγ and cryopreserved prior to reanimation and profiling for functional markers by flow cytometry and ELISA. MSC(M) were additionally injected into mice with radiation-induced xerostomia and the changes in salivary gland histology and salivary production were examined. RESULTS: A total of six subjects were enrolled. MSC(M) from all subjects were culture expanded to > 20 million cells in a median of 15.5 days (range 8-20 days). Flow cytometry confirmed that cultured cells from HNC patients were MSC(M). Functional flow cytometry demonstrated that these IFNγ-stimulated MSC(M) acquired an immunosuppressive phenotype. IFNγ-stimulated MSC(M) from HNC patients were found to express GDNF, WNT1, and R-spondin 1 as well as pro-angiogenesis and immunomodulatory cytokines. In mice, IFNγ-stimulated MSC(M) injection after radiation decreased the loss of acinar cells, decreased the formation of fibrosis, and increased salivary production. CONCLUSIONS: MSC (M) from previously treated HNC patients can be expanded for auto-transplantation and are functionally active. Furthermore IFNγ-stimulated MSC(M) express proteins implicated in salivary gland regeneration. This study provides preliminary data supporting the feasibility of using autologous MSC(M) from HNC patients to treat RT-induced salivary dysfunction.

Efficacy of photobiomodulation therapy combined with mobile health education in patients with head and neck cancer suffering from chronic xerostomia after radiotherapy: protocol for a three-arm, randomised, placebo-controlled, double-blinded study.

INTRODUCTION: The role of photobiomodulation (PBM) therapy for oral tissue damage induced by cancer treatment is currently unclear, and there is low-quality to moderate-quality evidence supporting the use of this approach for treating xerostomia and/or hyposalivation. Consequently, patients with head and neck cancer increasingly turn to basic oral hygiene to alleviate salivary gland dysfunction, and their adherence can be improved by mobile health (mHealth) education. The primary objective of this study will be to analyse the effects of different doses of PBM therapy (7.5 J/cm2 vs 3 J/cm2) plus mHealth education on quality of life (QoL), oral health, salivary secretion and salivary gland ultrasound assessment at postintervention and at the 6-month follow-up in patients with head and neck cancer after radiotherapy compared with those in control group. METHODS AND ANALYSIS: A prospective, three-arm, randomised, placebo-controlled, double-blinded study will be conducted among patients with head and neck cancer suffering from chronic xerostomia. A total of 20 patients per arm will be included and randomly assigned to receive 7.5 J/cm2 of PBM, 3 J/cm2 of PBM or placebo therapy. PBM therapy will be applied during 24 sessions at 22 points extra and intraorally two times per week for 3 months, combined with a mobile application (https://www.laxer.es). The assessments will be recorded at the beginning of the study, at postintervention and at the 6-month follow-up. The primary outcomes will be QoL, oral health, salivary secretion and salivary gland ultrasound. The pain pressure threshold, functional performance, mood and sleep quality will be secondary indicators. ETHICS AND DISSEMINATION: This study received ethics approval from the Andalusian Biomedical Research Ethics Portal (2402-N-21 CEIM/CEI Provincial de Granada) according to the Declaration of Helsinki for Biomedical Research. The results of this study will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT05106608.

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.

Evaluation and management of dry mouth and its complications in rheumatology practice.

INTRODUCTION: The symptom of dry mouth has multiple potential etiologies and can be a diagnostic clue to the presence of common systemic diseases encountered in rheumatology practice. The presence of decreased saliva flow (i.e. salivary hypofunction) defines a subset of dry mouth patients in whom there may be reversible drug effects, an iatrogenic insult such as head and neck irradiation, or a disease that directly involves the salivary glands (e.g. Sjögren's disease). The assessment of salivary hypofunction includes sialometry, salivary gland imaging, salivary gland biopsy, and an assessment for relevant systemic diseases. Optimal management of dry mouth requires accurate definition of its cause, followed by general measures that serve to alleviate its symptoms and prevent its complications. AREAS COVERED: Through a literature search on xerostomia and salivary hypofunction, we provide an overview of the causes of dry mouth, highlight the potential impact of salivary hypofunction on oral and systemic health, detail routine evaluation methods and treatment strategies, and emphasize the importance of collaboration with oral health care providers. EXPERT OPINION: Our Expert Opinion is provided on unmet needs in the management of dry mouth and relevant research progress in the field.

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.

Post-radiation xerostomia therapy with allogeneic mesenchymal stromal stem cells in patients with head and neck cancer: study protocol for phase I clinical trial.

BACKGROUND: Xerostomia is a common side effect of radiotherapy in patients with head and neck tumors that negatively affects quality of life. There is no known effective standard treatment for xerostomia. Here, we present the study protocol used to evaluate the safety and preliminary efficacy of allogeneic mesenchymal stromal stem cells (MSCs) derived from umbilical cord tissue. PATIENTS AND METHODS: Ten oropharyngeal cancer patients with post-radiation xerostomia and no evidence of disease recurrence 2 or more years after (chemo)irradiation (intervention group) and 10 healthy volunteers (control group) will be enrolled in this nonrandomized, open-label, phase I exploratory study. MSCs from umbilical cord tissue will be inserted under ultrasound guidance into both parotid glands and both submandibular glands of the patients. Toxicity of the procedure will be assessed according to CTCAE v5.0 criteria at days 0, 1, 5, 28, and 120. Efficacy will be assessed by measuring salivary flow and analyzing its composition, scintigraphic evaluation of MSC grafting, retention, and migration, and questionnaires measuring subjective xerostomia and quality of life. In addition, the radiological, functional, and morphological characteristics of the salivary tissue will be assessed before, at 4 weeks, and at 4 months after the procedure. In the control group subjects, only salivary flow rate and salivary composition will be determined. DISCUSSION: The use of allogeneic MSCs from umbilical cord tissue represents an innovative approach for the treatment of xerostomia after radiation. Due to the noninvasive collection procedure, flexibility of cryobanking, and biological advantages, xerostomia therapy using allogeneic MSCs from umbilical cord tissue may have an advantage over other similar therapies.

Oral micro-electronic platform for temperature and humidity monitoring.

Intraoral theranostics, the integration of diagnostics and therapeutics within the oral cavity, is gaining significant traction. This pioneering approach primarily addresses issues like xerostomia (dry mouth), commonly resulting from cancer treatment, with a specific focus on monitoring temperature and humidity. This paper introduces the innovative Intra-Oral Portable Micro-Electronic (IOPM) fluidic theranostic device platform. It leverages conventional dental spoons by incorporating advanced sensors for precise measurements of oral temperature and humidity. Personalization options include a microfluidic chip and a tooth model, enabling targeted delivery of therapeutic agents to optimize treatment outcomes. The electronic control system simplifies the administration of fluid dosages, intelligently adjusted based on real-time oral cavity temperature and humidity readings. Rigorous experimental evaluations validate the platform's precision in delivering fluid volumes at predefined intervals. This platform represents a transformative advancement for individuals contending with oral health challenges such as xerostomia (dry mouth). Furthermore, it has the potential to elevate oral healthcare standards by providing advanced diagnostics and tailored therapeutic solutions, benefiting both patients and dental professionals alike.

CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration after radiation-induced injury.

The salivary glands often become damaged in individuals receiving radiotherapy for head and neck cancer, resulting in chronic dry mouth. This leads to detrimental effects on their health and quality of life, for which there is no regenerative therapy. Macrophages are the predominant immune cell in the salivary glands and are attractive therapeutic targets due to their unrivaled capacity to drive tissue repair. Yet, the nature and role of macrophages in salivary gland homeostasis and how they may contribute to tissue repair after injury are not well understood. Here, we show that at least two phenotypically and transcriptionally distinct CX3CR1+ macrophage populations are present in the adult salivary gland, which occupy anatomically distinct niches. CD11c+CD206-CD163- macrophages typically associate with gland epithelium, whereas CD11c-CD206+CD163+ macrophages associate with blood vessels and nerves. Using a suite of complementary fate mapping systems, we show that there are highly dynamic changes in the ontogeny and composition of salivary gland macrophages with age. Using an in vivo model of radiation-induced salivary gland injury combined with genetic or antibody-mediated depletion of macrophages, we demonstrate an essential role for macrophages in clearance of cells with DNA damage. Furthermore, we show that epithelial-associated macrophages are indispensable for effective tissue repair and gland function after radiation-induced injury, with their depletion resulting in reduced saliva production. Our data, therefore, provide a strong case for exploring the therapeutic potential of manipulating macrophages to promote tissue repair and thus minimize salivary gland dysfunction after radiotherapy.

Fibrin hydrogels fortified with FGF-7/10 and laminin-1 peptides promote regeneration of irradiated salivary glands.

Ionizing radiation, commonly used for head and neck cancer treatment, typically damages the salivary glands, resulting in hyposalivation. The development of treatments to restore this lost function is crucial for improving the quality of life for patients suffering from this condition. To address this clinical need, we have developed an innovative hydrogel by chemically conjugating laminin-1 peptides (A99 and YIGSR) and growth factors, FGF-7 and FGF-10, to fibrin hydrogels. Our results demonstrate that FGF-7/10 and laminin-1 peptides fortified fibrin hydrogel [enhanced laminin-1 peptides fibrin hydrogel (Ep-FH)] promotes salivary gland regeneration and functionality by improving epithelial tissue organization, establishing a healthy network of blood vessels and nerves, while reducing fibrosis in a head and neck irradiated mouse model. These results indicate that fibrin hydrogel-based implantable scaffolds containing pro-regenerative signals promote sustained secretory function of irradiated salivary glands, offering a potential alternative treatment for hyposalivation in head and neck cancer patients undergoing radiation treatment. These unique findings emphasize the potential of fibrin hydrogel-based implantable scaffolds enriched with pro-regenerative signals in sustaining the secretory function of irradiated salivary glands and offer a promising alternative treatment for addressing hyposalivation in head and neck cancer patients undergoing radiation therapy. STATEMENT OF SIGNIFICANCE: Radiation therapies used to treat head and neck cancers often result in damaged salivary gland, leading to severe dryness of the oral cavity. In this study, we engineered FGF-7 and FGF-10 and immobilized them into L1p-FH. The resulting hydrogel, Ep-FH, restored irradiated salivary gland functionality by enhancing epithelial tissue organization, promoting the development of a healthy network of blood vessels and nerves as well as reduction of fibrosis.