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Background Intraglandular therapy with adipose-derived mesenchymal stromal cells (ASCs) for radiation-induced xerostomia and hyposalivation has shown promising effects on the salivary flow rate and in patient-reported outcomes. However, the mode of action is not fully understood, but changes in the salivary proteome have been observed. Methods This sub study, to the randomised, double-blinded, placebo-controlled trial investigating intraglandular mesenchymal stromal cells for radiation-induced hyposalivation (MESRIX-III), examines changes in the salivary proteome following intraglandular therapy into the submandibular glands with allogenic ASCs in unstimulated whole saliva (UWS) in previous head and neck cancer patients with radiation-induced hyposalivation. A total of 120 patients were included and randomised in a 1:1 ratio to receive intraglandular injections with either ASCs or placebo (CryoStor10, 10% dimethyl sulfoxide, Biolife Solutions). UWS samples was collected at baseline and at 4 months post transplantation. The main endpoint is comparison of the salivary human proteome evaluated by mass spectrometry analysis in the group receiving ASCs compared to placebo at 4 months. Secondary outcomes are comparison of the microbial proteome in the group receiving ASCs compared to placebo at 4 months; changes in the salivary proteome and microbial proteome in the group receiving ASCs from baseline to 4 months and evaluation of the salivary proteome and microbial proteome following radiation therapy at baseline in both groups. Discussion This study will gain insights into the potential mode of action of intraglandular ASC therapy for radiation-induced hyposalivation. The results may open avenues for a clinically applicable and disease-modifying treatment to ameliorate hyposalivation and restore salivary gland function following radiation therapy in previous head and neck cancer patients. Moreover, it will constitute the most extensive collection of data characterising the salivary proteome post-radiation therapy in the head and neck region. Trial registration The MESRIX-III study is approved by the Danish Data Protection Agency (protocol number P-2020–1164), the National Ethics Committee (protocol number: 1802872) and the Danish Medical Agency (2018–000348-24) and is registered at the ClinicalTrials.gov database (NCT04776538). First posted on clinicaltrials.gov 03-JAN-2021.

Introduction Radiotherapy-induced xerostomia (RIX) is one of the most common adverse effects of radiotherapy (RT) in head and neck cancer patients (HNC) and a major determinant of survivors’ quality of life. The primary objective was to evaluate the reduction of patients’ xerostomia symptoms after the utilisation of a sodium-hyaluronate mouthwash compared to a placebo solution. The secondary objectives were to evaluate the improvement of quality of life and to evaluate the patients’ satisfaction. Methods The protocol was approved by the ethical committee (Ref. 50,053/19) and registered at ClinicalTrials.gov (ID: NCT05103124). The study was a double-blind randomised clinical trial (RCT) with a crossover design and was conducted at the Fondazione Policlinico Universitario A. Gemelli, Rome. Results Thirty-two patients completed the study protocol. Lower values of the modified Xerostomia Questionnaire (XQ) were retrieved when comparing the baseline scores to the ones after the treatment, when compared with placebo (Mann–Whitney U test = 0.01); higher values of patients’ satisfaction (Likert scale) and modified XQ were retrieved for the sodium-hyaluronate mouthwash (Mann–Whitney U test = 0.001). Conclusions This RCT highlights the advantages of treating RIX with the sodium-hyaluronate mouthwash since it seems to be clinically effective in reducing its symptoms, without any reported adverse events. ClinicalTrials.gov: NCT05103124 in 17/10/2021.

Increased expression of B cell activating factor (BAFF or B lymphocyte stimulator) may explain the B cell activation characteristic of primary Sjögren's syndrome (pSS). To evaluate the efficacy and safety of belimumab, targeting BAFF, in patients with pSS. Patients were included in this bi-centric prospective 1-year open-label trial if they fulfilled American European Consensus group criteria, were anti-Sjögren's syndrome A-positive and had current systemic complications or salivary gland enlargement, or early disease (<5 years), or biomarkers of B cell activation. They received belimumab, 10 mg/kg, at weeks 0, 2 and 4 and then every 4 weeks to week 24. The primary end-point, assessed at week 28, was improvement in two of five items: reduction in ≥30% in dryness score on a visual analogue scale (VAS), ≥30% in fatigue VAS score, ≥30% in VAS pain score, ≥30% in systemic activity VAS assessed by the physician and/or >25% improvement in any B cell activation biomarker values. Among 30 patients included, the primary end-point was achieved in 18 (60%). The mean (SD) European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index decreased from 8.8 (7.4) to 6.3 (6.6) (p=0.0015) and EULAR) Sjögren's Syndrome Patient Reported Index from 6.4 (1.1) to 5.6 (2.0) (p=0.0174). The mean dryness, fatigue and pain VAS varied from 7.8 (1.8) to 6.2 (2.9) (p=0.0021), 6.9 (1.8) to 6.0 (2.2) (p=0.0606) and 4.6 (2.6) to 4.7 (2.4) (p=0.89), respectively. Salivary flow and Schirmer's test did not change. These encouraging results justify future randomised controlled trials of belimumab in a selected target population of pSS patients most likely to benefit from treatment.

Purpose To analyse reliability in terms of concordance (agreement) and equivalence of the Patient Reported Outcome Measures (PROM) with an electronic modality (ePROM) of the recognised questionnaires assessing of xerostomia, dysphagia and quality of life (QoL) in Spanish patients with head and neck cancer (HNC). We hypothesised notable reliability and equivalence between the two modalities. Methods A total of 24 patients (median age 63.00 years, undergone radiotherapy, either alone or in combination with surgery and/or chemotherapy, and suffering xerostomia) were randomised to either paper-based (PROM) or ePROM in a two-arm crossover design with a within-subject comparison of the two modalities (washout period 90 min). Outcome measures of interest were xerostomia: severity itself (Xerostomia Inventory, XI), perceived xerostomia (visual analogue scale, VAS), regional oral dryness (Regional Oral Dryness Inventory, RODI) and dry mouth/sticky saliva (specific head and neck module European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module, EORTC QLQ-H&N35 and updated EORTC QLQ-H&N43); dysphagia: swallowing burden (Eating Assessment Tool-10, EAT-10) and swallowing (EORTC QLQ-H&N35 and EORTC QLQ-H&N43); and QoL: global health (EORTC QLQ-Core 30, EORTC QLQ-C30). Data concerning the concordance between modalities was evaluated using Spearman correlation coefficients, intraclass correlation coefficients (ICCs) and Bland Altman plots with limits of agreement. In addition, a two one-sided test to check equivalence with clinical importance changes. Finally, 1-week time span separated test and retest of ePROM (only electronic modality) using Wilcoxon test and ICCs. Results There was excellent concordance (PROM versus ePROM 0.79–0.96) with most differences fell within the limits of agreement. The equivalence analysis showed that the difference between both modalities was not more than a tolerably small amount ( P  < 0.05), except for dysphagia and QoL. Analysis over time exhibited from good to excellent (0.81–0.93) test–retest stability for the majority of outcome measures. Conclusion The newly developed ePROMs embedded into LAXER application have showed high level of reliability that supports their implementation in clinical practice, offering a convenient and efficient alternative to paper-based questionnaires. This study shows that electronic adaptations are possible despite the challenging older target population. Trial registration The study is part of the LAXER study (2021-11-04 / ClinicalTrials.gov: NCT05106608).

Objectives To validate the two recently developed disease activity indexes for assessment of primary Sjögren's syndrome (SS): the European League Against Rheumatism (EULAR) SS Patient Reported Index (ESSPRI) and the EULAR SS Disease Activity Index (ESSDAI). Methods A prospective international 6-month duration validation study was conducted in 15 countries. At each visit, physicians completed ESSDAI, SS disease activity index (SSDAI), Sjögren's Systemic Clinical Activity Index (SCAI) and physician global assessment (PhGA); and patients completed ESSPRI, Sicca Symptoms Inventory (SSI), Profile of Fatigue and Discomfort (PROFAD) and patient global assessment (PGA). Psychometric properties (construct validity, responsiveness and reliability) were evaluated and compared between scores. Results Of the 395 patients included, 145 (37%) and 251 (64%) had currently active or current or past systemic manifestations, respectively. EULAR scores had higher correlation with the gold standard than other scores (ESSDAI with PhGA: r=0.59; ESSRPI with PGA: r=0.70). Correlations between patient and systemic scores were very low (ranging from 0.07 to 0.29). All systemic scores had similar large responsiveness in improved patients. Responsiveness of patient scores was low but was significantly higher for ESSPRI compared with SSI and PROFAD. Reliability was very good for all scores. Conclusions ESSDAI and ESSPRI had good construct validity. All scores were reliable. Systemic scores had a large sensitivity to change in patients whose disease activity improves. Patient scores had a small sensitivity to change, however, significantly better for ESSPRI. Systemic and patient scores poorly correlated, suggesting that they are 2 complementary components that should be both evaluated, but separately.

Actinium-225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC). We aimed to report the safety and antitumour activity of 225Ac-PSMA RLT of mCRPC in a large cohort of patients treated at multiple centres across the world. This retrospective study included patients treated at seven centres in Australia, India, Germany, and South Africa. We pooled data of consecutive patients of any age and Eastern Cooperative Oncology Group performance status with histopathologically confirmed adenocarcinoma of the prostate who were treated with one or more cycles of 8 MBq 225Ac-PSMA RLT administered intravenously for mCRPC. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium-177 (177Lu) PSMA RLT, and radium-223 dichloride. The primary outcomes were overall survival and progression-free survival. Between Jan 1, 2016, and May 31, 2023, 488 men with mCRPC received 1174 cycles of 225Ac-PSMA RLT (median two cycles, IQR 2–4). The mean age of the patients was 68·1 years (SD 8·8), and the median baseline prostate-specific antigen was 169·5 ng/mL (IQR 34·6–519·8). Previous lines of treatment were docetaxel in 324 (66%) patients, cabazitaxel in 103 (21%) patients, abiraterone in 191 (39%) patients, enzalutamide in 188 (39%) patients, 177Lu-PSMA RLT in 154 (32%) patients, and radium-223 dichloride in 18 (4%) patients. The median follow-up duration was 9·0 months (IQR 5·0–17·5). The median overall survival was 15·5 months (95% CI 13·4–18·3) and median progression-free survival was 7·9 months (6·8–8·9). In 347 (71%) of 488 patients, information regarding treatment-induced xerostomia was available, and 236 (68%) of the 347 patients reported xerostomia after the first cycle of 225Ac-PSMA RLT. All patients who received more than seven cycles of 225Ac-PSMA RLT reported xerostomia. Grade 3 or higher anaemia occurred in 64 (13%) of 488 patients, leukopenia in 19 (4%), thrombocytopenia in 32 (7%), and renal toxicity in 22 (5%). No serious adverse events or treatment-related deaths were recorded. 225Ac-PSMA RLT shows a substantial antitumour effect in mCRPC and represents a viable therapy option in patients treated with previous lines of approved agents. Xerostomia is a common side-effect. Severe bone marrow and renal toxicity are less common adverse events. None.

Xerostomia, generally addressed as dry mouth, poses significant challenges to patients’ quality of life, particularly in the context of cancer treatment. Although various medications and interventions, including salivary substitutes and stimulants, muscarinic agonists, antineoplastic detoxifying agents, anti-inflammatory agents, superoxide dismutase mimetics, mesenchymal stem cells, submandibular gland transfer, intensity-modulated radiation therapy, dose fractionation, transcutaneous electrical nerve stimulation, hyperbaric oxygen therapy, photobiomodulation, acupuncture, and nutritional interventions, have been proposed for this condition, no approved or definite treatments are currently available. Moreover, the evidence supporting the efficacy of proposed interventions remains limited and subject to controversy in terms of safety, efficacy, and optimal protocol. This review provides a comprehensive insight into cancer treatment-related xerostomia, underlying its pathophysiology, etiology, clinical manifestation, and therapeutic options, providing a clinical guide for clinicians to adopt a patient-tailored approach to cancer treatment-related xerostomia and offering vision on current ongoing and future studies in the field.

Background The impact of poor oral health on older adults’ quality of life is a public health problem. In this study, the mediating effects of dental status, occlusal condition, dysphagia, and masticatory performance on the association between xerostomia and oral health-related quality of life (OHRQoL) were assessed in the older adult population. Methods Stratified cluster sampling was used to recruit 1076 community-dwelling adults aged 65 years and older from Kaohsiung, Taiwan. Community care centers were randomly selected according to their geographic classifications (urban, rural, or mountainous areas). Assessments of dental status and occlusal condition were performed by dentists. Information on demographics, physical function, xerostomia, dysphagia and depression was collected through face-to-face interviews. Masticatory performance was evaluated using color-changeable chewing gum. OHRQoL was measured using the Geriatric Oral Health Assessment Index. Hierarchical regression models were used to assess the relationships between OHRQoL and physical function, dental status and oral function in older adults. Path analysis was used to estimate direct and indirect pathways between xerostomia and OHRQoL. Results Participants with xerostomia exhibited a 0.20 OHRQoL reduction ( p  < .001) compared with patients with no xerostomia, and the direct effect accounted for 83.3% of the total effect. Dysphagia and masticatory performance were found to exert significant mediating effects on the association between xerostomia and OHRQoL (βs = 0.20 and − 0.12, respectively; both p  < .001; βs = 0.06 and − 0.09, respectively; both p  < .05). Moreover, potential mediating effects of the number of functional teeth (βs = − 0.11 and − 0.43, respectively; both p  < .001) and occlusal condition (βs = 0.09 and 0.13, respectively; both p  < .05) on the relationship between xerostomia and masticatory performance were noted. Conclusions Dysphagia and masticatory performance may serve as pathways through which xerostomia affects quality of life. Early oral function intervention may be a valuable and actionable target for older adults to maintain quality of life. Our results further suggest that checkup and screening for oral dysfunction are essential to prevent or delay the onset of complications.

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.