Background: Radiation cystitis (RC) results from chronic inflammation, fibrosis, and vascular damage. The urinary symptoms it causes have a serious impact on patients’ quality of life. Despite the improvement in irradiation techniques, the incidence of radiation cystitis remains stable over time, and the therapeutic possibilities remain limited. Mesenchymal stem/stromal cells (MSC) appear to offer2 a promising therapeutic approach by promoting tissue repair through their paracrine action via extracellular vesicles (MSC-EVs) or conditioned medium from human mesenchymal stromal cells (MSC-CM). We assess the therapeutic potential of MSC-EVs or MSC-CM in an in vitro model of RC. Methods: In vitro RC was induced by irradiation of human bladder fibroblasts (HUBF) with the small-animal radiation research platform (SARRP). HUBF were induced towards an RC phenotype after 3 × 3.5 Gy irradiation in the presence of either MSC-EVs or MSC-CM, to assess their effect on fibrosis, angiogenesis, and inflammatory markers. Results: Our data revealed in vitro a higher therapeutic potential of MSC-EVs and MSC-CM in prevention of RC. This was confirmed by down-regulation of α-SMA and CTGF transcription, and the induction of the secretion of anti-fibrotic cytokines, such as IFNγ, IL10 and IL27 and the decrease in the secretion of pro-fibrotic cytokines, IGFBP2, IL1β, IL6, IL18, PDGF, TNFα, and HGF, by irradiated HUBFs, conditioned with MSC-EVs or MSC-CM. The secretome of MSC (MSC-CM) or its subsecretome (MSC-EVs) are proangiogenic, with the ability to induce vessels from HUVEC cells, ensuring the management of bladder vascular lesions induced by irradiation. Conclusion: MSC-EVs and MSC-CM appear to have promising therapeutic potential in the prevention of RC in vitro, by targeting the three main stages of RC: fibrosis, inflammation and vascular damage.
Background Despite improvements in radiation techniques, pelvic radiotherapy is responsible for acute and delayed bladder adverse events, defined as radiation cystitis. The initial symptoms of bladder injury secondary to pelvic irradiation are likely to occur during treatment or within 3 months of radiotherapy in approximately 50% of irradiated patients, and have a significant impact on their quality of life. The pathophysiology of radiation cystitis is not well understood, particularly because of the risk of complications associated with access to bladder tissue after irradiation, which limits our ability to study this process and develop treatments. Objective It is an original study combining digital data collection to monitor patients’ symptoms and biological markers during irradiation. The main objective of our study is to evaluate the correlation of biological biomarkers with the intensity of acute radiation cystitis and the quality of life of patients, assessed with the digital telemonitoring platform Cureety. Methods Patients with intermediate-risk localized prostate cancer who are eligible for localized radiotherapy will be included. Inflammatory biomarkers will be analyzed in urine and blood samples before the start of radiotherapy and at weeks 4, 12, and 48 of irradiation, through quantitative methods such as a multiplex Luminex assay, flow cytometry, and enzyme-linked immunosorbent assay. We will also characterize the patients’ gut and urine microbiota composition using 16S ribosomal RNA sequencing technology. Between sample collection visits, patients will complete various questionnaires related to radiation cystitis symptoms (using the International Prostate Symptom Score), adverse events, and quality of life (using the Functional Assessment of Cancer Therapy–Prostate questionnaire), using the Cureety digital remote monitoring platform. Upon receipt of the questionnaires, an algorithm will process the information and classify patients in accordance with the severity of symptoms and adverse events reported on the basis of Common Terminology Criteria for Adverse Events and International Prostate Symptom Score standards. This will allow us to correlate levels of urinary, blood, and fecal biomarkers with the severity of acute radiation cystitis symptoms and patient-reported quality of life. Results The study started in March 2022. We estimate a recruitment period of approximately 18 months, and the final results are expected in 2024. Conclusions This prospective study is the first to explore the overexpression of inflammatory proteins in fluid biopsies from patients with symptoms of acute radiation cystitis. In addition, the 1-year follow-up after treatment will allow us to predict which patients are at risk of late radiation cystitis and to refer them for radioprotective treatment. The results of this study will allow us to develop strategies to limit radiation damage to the bladder and improve the quality of life of patients. Trial Registration ClinicalTrials.gov NCT05246774; https://clinicaltrials.gov/ct2/show/NCT05246774?term=NCT05246774 International Registered Report Identifier (IRRID) DERR1-10.2196/38362
Although radiation therapy plays a crucial role in cancer treatment, and techniques have improved continuously, irradiation induces side effects in healthy tissue. Radiation cystitis is a potential complication following the therapeutic irradiation of pelvic cancers and negatively impacts patients’ quality of life (QoL). To date, no effective treatment is available, and this toxicity remains a therapeutic challenge. In recent times, stem cell-based therapy, particularly the use of mesenchymal stem cells (MSC), has gained attention in tissue repair and regeneration due to their easy accessibility and their ability to differentiate into several tissue types, modulate the immune system and secrete substances that help nearby cells grow and heal. In this review, we will summarize the pathophysiological mechanisms of radiation-induced injury to normal tissues, including radiation cystitis (RC). We will then discuss the therapeutic potential and limitations of MSCs and their derivatives, including packaged conditioned media and extracellular vesicles, in the management of radiotoxicity and RC.
BACKGROUND Despite advances in radiation techniques, radiation cystitis (RC) remains a significant cause of morbidity from pelvic radiotherapy, which may affect patients' quality of life (QoL). The pathophysiology of RC is not well understood, which limits the development of effective treatments. OBJECTIVE The RABBIO study aims to investigate the correlation between blood and urinary biomarkers and the intensity of acute RC symptoms and QoL in patients undergoing localized prostate cancer radiotherapy. METHODS The study included patients with low or intermediate-risk localized prostate cancer who were eligible for localized radiotherapy. Blood and urinary biomarkers were analyzed before radiotherapy was initiated and at weeks 4 and 12 of radiation therapy. Patients completed questionnaires related to radiation cystitis symptoms and QoL using a digital remote monitoring platform. The information was processed by means of an algorithm which classified patients according to the severity of symptoms and adverse events reported. Levels of blood and urinary biomarkers were correlated with the severity of acute RC symptoms and patient-reported QoL. RESULTS 401 adverse events’ questionnaires were collected over the duration of the study. The most frequently reported adverse events at week 4 were pollakiuria, constipation, and diarrhea. In comparison with baseline, the mean Functional Assessment of Cancer Therapy-Prostate (FACT-P) score decreased at week 4. A significant polarization of M2-phenotype macrophages and increase in serum and urine levels of M-CSF, HGF, and MIP-1α over baseline were observed at week 12. Baseline serum and urine M-CSF concentrations showed a significant negative correlation with FACT–P scores at weeks 4 and 12. CONCLUSIONS The RABBIO study is the first to explore the overexpression of inflammatory proteins in fluid biopsies from patients with symptoms of acute RC. These preliminary findings suggest that serum and urine HGF, M-CSF, MIP-1α, as well as macrophage polarization are potential biomarkers of cystitis after prostate radiotherapy. The elevated M-CSF levels in serum and urine at baseline were associated with the deterioration of QoL during radiotherapy. The results of this study may help to develop mitigation strategies to limit radiation damage to the bladder. CLINICALTRIAL NCT05246774
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