Semaglutide treatment for PRevention Of Toxicity in high-dosE Chemotherapy with autologous haematopoietic stem-cell Transplantation (PROTECT): study protocol for a randomised, double-blind, placebo-controlled, investigator-initiated study.

INTRODUCTION: Cancer treatment with high-dose chemotherapy damages the mucosal barrier of the gastrointestinal (GI) tract and is associated with severe toxicity involving mucositis, severe inflammation and organ dysfunction. Currently, there is no effective prophylaxis against this. Glucagon-like peptide 1 (GLP-1), a well-known regulator of blood glucose, has been suggested in mouse studies to possess trophic effects on gut epithelial cells as well as anti-inflammatory properties. In line with this, endogenous GLP-1 levels have been shown to be inversely correlated with toxicities after haematopoietic stem cell transplantation (HSCT) and treatment with a GLP-1 receptor agonist (GLP-1RA) was shown to limit chemotherapy-induced mucositis in rodents. This present study investigates the effects of the GLP-1RA semaglutide on GI mucositis severity score in patients with lymphoma undergoing high-dose chemotherapy followed by autologous (auto) HSCT. METHODS AND ANALYSIS: This is a randomised, double-blind, placebo-controlled, two-centre investigator-initiated clinical study. Forty adult patients with malignant lymphoma referred for auto-HSCT will be randomised in a 1:1 manner to receive either semaglutide or placebo once-weekly for 8 weeks. This includes a run-in period of 3-4 weeks with semaglutide 0.25 mg prior to high-dose chemotherapy treatment followed by a period of 4-5 weeks with semaglutide 0.5 mg including the 1 week of high-dose chemotherapy treatment. Clinical assessment of endpoint measurements and safety will be performed weekly during treatment and in a follow-up period of 10 weeks. The primary endpoint is GI mucositis severity (mean severity grade (0-II) during week 1-4 after auto-HSCT). Secondary endpoints include C-reactive protein increment, quality of life and safety. Fever, bacteraemia, antibiotic use, weight loss, morphine consumption, duration of hospitalisation, use of parenteral nutrition, change in muscle mass and clinical and laboratory evidence of organ toxicities will also be assessed. ETHICS AND DISSEMINATION: The study complies with Danish and European Union legislation and is approved by the Danish Medicines Agency, the Danish National Medical Research Ethics Committee (EU CT #2022-502139-20-00) and the Danish Data Protection Agency. The study is monitored by the Capital Region of Denmark's good clinical practice unit. All results, positive, negative and inconclusive, will be disseminated at national and international scientific meetings and in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT06449625.

Melatonin mitigates chemotherapy-induced small intestinal atrophy in rats and reduces cytotoxicity in murine intestinal organoids.

Cancer continues to pose a significant global health challenge, with gastrointestinal (GI) cancers among the most prevalent and deadly forms. These cancers often lead to high mortality rates and demand the use of potent cytotoxic chemotherapeutics. For example, 5-fluorouracil (5-FU) forms the backbone of chemotherapy regimens for various GI cancers, including colorectal cancer. While these chemotherapeutics efficiently kill cancer cells, they frequently cause off-target effects such as chemotherapy-induced mucositis (CIM), characterized by debilitating symptoms like pain, nausea, and diarrhoea, necessitating medical intervention. In this study, we elucidated the potential of melatonin and misoprostol to reduce 5-FU-induced small intestinal mucositis. Morphological and cellular changes in the jejunum, along with colonic faecal water content were quantified in rats as markers for CIM. Additionally, the effects of melatonin were investigated in vitro on 5-FU treated murine intestinal organoids. The results showed that melatonin prevented villus atrophy in the rat jejunal mucosa and upheld cell viability in murine intestinal organoids. In contrast, misoprostol alone or in combination with melatonin did not significantly affect CIM caused by 5-FU. These in vivo and in vitro experiments provided promising insights that melatonin may be used as a preventive and/or adjuvant combination therapy to prevent and reduce CIM, holding the potential to enhance cancer treatment outcomes and improve patient quality-of-life.

Fermented foods and probiotic consumption frequency as protective indicators for peri-implant diseases - a cross-sectional study.

BACKGROUND: Due to their modulatory effect on biofilm growth, bacterial gene expressions, and host-modulation effects, fermented foods and probiotic products could potentially have a protective role against peri-implant diseases. This cross-sectional study aimed to examine the association of consumption of fermented foods and products containing probiotics, with peri-implant health and diseases. METHODS: A total of 126 implants were included. The peri-implant health status (peri-implantitis, peri-implant mucositis, and peri-implant health) was assessed through Chicago's Classification of periodontal and peri-implant Diseases and Conditions. A questionnaire was used to evaluate the consumption patterns of fermented and probiotic foods and product. One-way ANOVA was employed to compare the 3 peri-implant conditions categories in terms of fermented food and probiotic consumption. RESULTS: There were significant differences in the daily and general consumption of yogurt, probiotic yogurt, kefir, ayran, vinegar, pomegranate syrup, whole meal bread, and homemade butter among peri-implantitis, peri-implant mucositis and peri-implant health (p < 0.05). The peri-implant health group consumed significantly more yogurt, kefir, ayran, vinegar, whole wheat bread, and homemade butter than peri-implant mucositis and peri-implantitis. CONCLUSION: A higher consumption of fermented and probiotic foods may be associated with peri-implant health. Fermented and probiotic products may be useful for prevention of peri-implant diseases in patients with implants.

Systemic Anti-Inflammatory Agents in the Prevention of Chemoradiation-Induced Mucositis: A Review of Randomised Controlled Trials.

Mucositis is a pathological condition characterised by inflammation and ulceration of the mucous membranes lining the alimentary canal, particularly in the mouth (oral mucositis) and the gastrointestinal tract. It is a common side effect of cancer treatments, including chemotherapy and radiotherapy, and it is sometimes responsible for treatment interruptions. Preventing mucositis throughout the alimentary tract is therefore crucial. However, current interventions mainly target either oral or gastrointestinal side effects. This review aimed to investigate the use of systemically administered anti-inflammatory agents to prevent mucositis in cancer patients undergoing cancer treatment. PubMed, Ovid, Scopus, Web of Science, WHO ICTRP and ClinicalTrials.gov were screened to identify eligible randomised controlled trials (RCTs). The published literature on anti-inflammatory agents provides mixed evidence regarding the degree of efficacy in preventing/reducing the severity of mucositis in most anticancer treatments; however, sample size continued to be a significant limitation, alongside others discussed. Our review yielded a list of several anti-inflammatory agents that exhibit potential mucositis-preventive effects in cancer patients undergoing cancer treatment, which can be used to inform clinical practice.

Evaluation of the efficacy of inter-dental brush and dental floss for peri-implant mucositis: A crossover randomized clinical trial.

OBJECTIVES: To evaluate the most effective method for mechanical inter-dental plaque removal between inter-dental brushes (IDB) and dental floss (DF), in addition to toothbrushing in patients affected by peri-implant mucositis (PIM); to identify possible factors related to the patient or to the single implant-supported element that could influence plaque accumulation and inflammation of peri-implant tissues. METHODS: Forty patients with PIM were recruited. They were randomly assigned to two different groups depending on inter-dental device used (IDB or DF). At baseline (T0), interproximal area (IA), interproximal emergence angle of the implant crown (A°) and manual dexterity (evaluated with Purdue Pegboard) have been recorded. At 14 days (T1), the inter-dental cleaning devices have been inverted between groups. After 14 days (T2), the Plaque Index (PI) and Gingival Index (GI) have been recorded. A questionnaire has been submitted to a patient for the analysis of preferences at T0, T1 and T2. RESULTS: Both inter-dental cleaning devices were effective in reducing PI and GI in the inter-dental area after 14 days of use. GI reduction was influenced by manual dexterity of the dominant hand. No significant differences were found for PI and GI at the variation of IA and A°. CONCLUSION: IDB was the most effective method for inter-dental plaque removal in all subjects regardless of their manual dexterity. DF seems to be more effective than IDB only in subjects with good dexterity.

A polyphenol-rich açaí seed extract protects against 5-fluorouracil-induced intestinal mucositis in mice through the TLR-4/MyD88/PI3K/mTOR/NF-κBp65 signaling pathway.

Açaí seed extract (ASE) is obtained from Euterpe oleracea Mart. (açaí) plant (Amazon region) has high nutritional and functional value. ASE is rich in polyphenolic compounds, mainly proanthocyanidins. Proanthocyanidins can modulate the immune system and oxidative stress by inhibiting the toll-like receptor-4 (TLR-4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) pathway. A great deal of evidence suggests that inflammatory cytokines and oxidative stress contribute to the pathogenesis of intestinal mucositis, and these events can lead to intestinal dysmotility. We hypothesized that ASE acts as an anti-inflammatory and antioxidant compound in intestinal mucositis induced by 5-fluorouracil (5-FU) through modulation of the TLR-4/MyD88/phosphatidylinositol-3-kinase α/mechanistic target of rapamycin/NF-κBp65 pathway. The animals were divided into linear 5-FU (450 mg/kg) and 5-FU + ASE (10, 30, and 100 mg/kg) groups. The weight loss of the animals was evaluated daily. Samples from duodenum, jejunum, and ileum were obtained for histopathological, biochemical, and functional analyses. ASE reduced weight loss, inflammatory parameters (interleukin-1ß; tumor necrosis factor-α; myeloperoxidase activity) and the gene expression of mediators involved in the TLR-2/MyD88/NF-κB pathway. ASE prevented histopathological changes with beneficial effects on gastrointestinal transit delay, gastric emptying, and intestinal absorption/permeability. In conclusion, ASE protects the integrity of the intestinal epithelial barrier by inhibiting the TLR/MyD88/PI3K/mechanistic target of rapamycin/NF-κBp65 pathway.

Lacticaseibacillus casei decrease long-chain fatty acids and most substances in an experimental model of intestinal mucositis.

PURPOSE: To evaluate the long-chain fatty acid and major compounds levels in the feces after prophylactic oral use of Lacticaseibacillus casei in an experimental model of intestinal mucositis. METHODS: Fifteen Swiss mice were randomly divided into three groups (n=5/group): The negative or positive control groups (n = 5) received saline orally for 18 days and an the intraperitoneal (i.p.) of saline or 5 Fluorouracil (450 mg/kg) in 15th day, respectability. L. casei group received oral concentration of L. casei (1x109 CFU/mL) for 18 days, the i.p. injection of 5-fluorouracil (450 mg/kg) in 15th days. Tissue samples from colon and each small intestine segment were collected for histopathological analysis. Stool samples were collected. Fecal composition of long-chain fatty acids and sterols were analysed by gas chromatography-mass spectrometry on the 15th and the 18th day. RESULTS: The mucosa layer of all small intestine segments of animals from L. casei showed well preserved epithelium and glands, without necrosis signs, but Goblet cells number decreased. Several long-chain fatty acids and sterols have been identified before and after in the groups. L. casei administration after 5-FU treatment reduced concentrations of linoleic acid (18:2) (p < 0.001) and oleic acid (18:1) (p < 0.001) in feces. CONCLUSIONS: L. casei prevented the mucosal damage associated with 5-FU-induced intestinal mucositis reduced long-chain fatty acid levels in the feces.

Efficacy of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine for the prevention of mucositis induced by platinum-based chemoradiation in head and neck cancer: A phase II study.

BACKGROUND & AIMS: The current standard treatment modality for advanced head and neck squamous cell carcinoma (HNSCC), namely platinum-based (PB) concurrent chemoradiotherapy (CRT), is associated with frequent severe mucositis which is responsible for the multiple acute and late adverse events. So far, effective preventive methods for this CRT-induced mucositis are not identified. In the current study, we examined the prophylactic effects of beta-hydroxy-beta-methylbutyrate (HMB), arginine (Arg), and glutamine (Gln) (HMB/Arg/Gln) mixture. METHODS: Patients with HNSCC who were subject to PBCRT were randomly assigned to HMB/Arg/Gln intervention (Group I) and non-intervention (Group NI) cohort. The incidences of ≧ grade 3 mucositis (primary endpoint), ≧ grade 2 mucositis, and opioid usage and the degree of body weight loss (secondary endpoints) were compared between Group I and Group NI. RESULTS: A total of 75 patients were enrolled to this study and 38 patients were assigned to Group I, while 37 patients were to Group NI. After excluding patients who failed to complete CRT (3 in Group I and 2 in Group NI) or withdrew consents (11 in Group I and 1 in Group NI), 24 patients in Group I and 34 patients in Group NI were evaluated. HMB/Arg/Gln failed to reduce the incidences of ≧ grade 2 mucositis, but significantly (p = 0.0003) inhibited grade 3 mucositis in the late phase CRT, reducing the incidence from 64.6% (Group NI) to 25% (Group I) at 70Gy. The degree of body weight loss was significantly (p = 0.0038) lower in Group I (5.6%) compared to Group NI (8.9%), preventing the progression of PBCRT-induced cachexia. CONCLUSIONS: HMB/Arg/Gln administration demonstrated inhibitory effects on the progression of grade 3 mucositis and cancer cachexia in HNSCC patients treated with PBCRT. A larger scale phase III study is encouraged. CLINICAL TRIAL REGISTRATION: This study is registered to the UMIN Clinical Trial Registry: UMIN000050011.

Apocynin attenuates methotrexate-induced mucositis by regulating NF-κB, PPAR-γ and Bax/Bcl-2/Puma signals.

Oxidative stress, inflammation and apoptosis are the primary inducers of Methotrexate (MTX)-induced mucositis. This research aimed to determine whether apocynin (APO) could protect against MTX-induced mucositis. The antioxidants, anti-inflammatory and anti-apoptotic actions of APO in this model will be evaluated. The experiment was performed on 32 rats. A single dose (20 mg/kg) of MTX was injected i.p. to induce intestinal mucositis. APO was given orally once per day at a dose of 100mg/kg (five days prior to and five days following an MTX injection). APO safeguarded the histological structure of the duodenal mucosa, as observed by the conserved histology of goblet cells (villi and crypts). APO mitigated oxidative stress by reducing intestin MDA and raising GSH, SOD and GST, also suppressing NF-κB mRNA expression. Intestinal content of proinflammatory cytokines was reduced in APO-treated MTX rats, with downregulation of proinflammatory iNOS and upregulation of anti-inflammatory PPAR-γ proteins. The intestinal mucosa of rats treated with APO and MTX displayed weekly positive immune staining for cleaved caspase-3. APO upregulate the anti-apoptotic Bcl2 mRNA and down regulate the proapoptotic Bax and Puma mRNA in the duodenal mucosa. The results indicate the possibility of using APO as a novel therapeutic agent to prevent MTX-induced mucositis.

Efficacy of recombinant human interleukin-11 in preventing and treating oral mucositis after chemotherapy for patients with acute leukemia.

OBJECTIVE: This study aimed to investigate the clinical effects of recombinant human interleukin-11 (rhIL-11) gargle on preventing and treating oral mucositis (OM) after chemotherapy for acute leukemia. METHODS: This single-site, prospective, observer-blinded, nonrandomized controlled trial was conducted on 74 patients with acute leukemia, who were divided into the experimental and control groups. The patients in the experimental group were treated with IL-11 gargle, and those in the control group were treated with sodium bicarbonate gargle. We examined the time and severity of oral mucositis, severity and duration of associated pain, healing time of mucositis, effects of OM on eating, and levels of T-cell subset indicators before and after treatment to evaluate the effects of IL-11 treatment. RESULTS: The proportion of patients with severe OM was significantly lower in the experimental group than in the control group. Mucositis occurred later in the experimental group compared with the control group. The degree and duration of pain, ulcer healing time, and effects on eating were lower in the experimental group compared with the control group. Following treatment, the levels of all T-cell subset indicators improved in each of the two groups. However, the rate of improvement was significantly higher in the experimental group than in the control group. These differences were statistically significant (P < 0.05). CONCLUSIONS: IL-11 gargle reduced the severity of OM after chemotherapy for acute leukemia. Treatment with IL-11 relieved pain, promoted healing, and improved the curative effect of the condition, making it worthy of clinical promotion.

Investigation of the efficacy of systemic N-Acetyl Cysteine therapy preventing nasal mucositis following radiotherapy.

BACKGROUND: Radiotherapy (RT) is one of the main methods used in the treatment of head and neck cancers but may cause mucosal side effects in the tumor area and surrounding structures. These include nasal mucosal disorders and chronic rhinosinusitis due to disruption of the mucociliary system. This situation seriously affects the quality of life of the patients and there is no accepted effective method for its treatment yet. In our study, we aimed to examine the side effects of RT on the nasal mucosa and mucociliary system and to investigate histopathologically and immunohistochemically the effectiveness of N-acetyl cysteine (NAC) in preventing these side effects of RT. METHODOLOGY: The study was carried out with 30 female Sprague Dawley rats devided in three groups. No intervention was made in the control group. On the second day of the experiment, 30 Gy radiotherapy was applied to the head area in the RT group. NAC was administered intraperitoneally at a dose of 1 g/kg/day for 14 days from the first day of the study to the RT+ NAC group. On the second day, 30 Gy of radiotherapy was applied to the head area 1 hour after the NAC application. On the 14th day, 1 hour after NAC was applied to the RT+NAC group, all animals were sacrificed. The nasal mucosa samples were stained with hematoxylin-eosin, and the intensity and extent of staining sentan in the nasopharyngeal tissue samples were evaluated by immunohistochemical staining using anti-SNTN antibody. RESULTS: The loss of cilia in the nasal tissue was lower in the RT+NAC group than in the RT group. The intensity and extent of staining in the nasopharyngeal tissue of Sentan was higher in the RT+NAC group than in the RT group. Mucosal neutrophil and mononuclear inflammatory cell infiltration in the nasal tissue, vascular dilatation, hyperemia and hemorrhage, erosion and shedding of the mucosal epithelium, mucosal ulceration were found to be similar in the RT+NAC group and the control group. It was milder in the RT+NAC group than in the RT group, but not statistically significant. CONCLUSIONS: Radiotherapy caused pathological changes in the nasal mucosa, caused loss of cilia and a decrease in the level of Sentan, the cilia apical protein. The results of our study showed that NAC treatment can reduce the side effects of RT on the nasal mucosa. It also showed that NAC was effective in preventing the loss of cilia, which is the building block of the mucociliary system, and improving the expression of Sentan.

High molecular weight hyaluronic acid drastically reduces chemotherapy-induced mucositis and apoptotic cell death.

Oral and intestinal mucositis (OIM) are debilitating inflammatory diseases initiated by oxidative stress, resulting in epithelial cell death and are frequently observed in cancer patients undergoing chemo-radiotherapy. There are currently few preventative strategies for this debilitating condition. Therefore, the development of a safe and effective mucositis mitigating strategy is an unmet medical need. Hyaluronic acid (HA) preparations have been tentatively used in oral mucositis. However, the protective effects of HA in chemotherapy-induced mucositis and their underlying mechanisms remain to be fully elucidated. This study aimed to assess these mechanisms using multiple formulations of enriched HA (Mucosamin®), cross-linked (xl-), and non-crosslinked high molecular weight HA (H-MW-HA) in an oxidative stress-induced model of human oral mucosal injury in vitro and an in vivo murine model of 5-flurouracil (5-FU)-induced oral/intestinal mucositis. All tested HA formulations protected against oxidative stress-induced damage in vitro without inducing cytotoxicity, with H-MW-HA also significantly reducing ROS production. Daily supplementation with H-MW-HA in vivo drastically reduced the severity of 5-FU-induced OIM, prevented apoptotic damage and reduced COX-2 enzyme activity in both the oral and intestinal epithelium. In 5-FU-injected mice, HA supplementation also significantly reduced serum levels of IL-6 and the chemokine CXCL1/KC, while the serum antioxidant activity of superoxide dismutase was elevated. Our data suggest that H-MW-HA attenuates 5-FU-induced OIM, at least partly, by impeding apoptosis, inhibiting of oxidative stress and suppressing inflammatory cytokines. This study supports the development of H-MW-HA preparations for preventing OIM in patients receiving chemotherapy.

Thymoquinone protects against 5-Fluorouracil-induced mucositis by NF-κß and HIF-1 mechanisms in mice.

Mucositis is among the most common side effects of 5-Fluorouracil (5-FU) and other cancer therapeutic drugs. Thymoquinone (TQ), a bioactive constituent extracted from Nigella sativa, has antioxidant and anti-inflammatory properties and can modify acute gastrointestinal injury. To investigate the effects of TQ on mucositis induced by 5-FU, studied animals were divided into four groups: control, 5-FU unit dose (300 mg/kg) to cause oral and intestinal mucositis (OM and IM), TQ (2.5 mg/kg) and TQ (2.5 mg/kg) plus 5-FU. Due to The molecular mechanisms, it was confirmed that the expression of NF-κß and HIF-1 increases in OM. The serum levels of malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD), as well as pathological parameters, were assessed. Based on our results, the nuclear factor-kappa ß gene expression in the tongue was downregulated significantly in the 5-FU + TQ compared to the 5-FU. TQ treatment can diminish MDA, and a reduction in oxidative stress was shown. TQ could also reduce the severity of tissue destruction and damaging effects induced by 5-FU on the tongue and intestine. We also observed lower villus length and width in the intestine of the 5-FU group compared to the control group. According to our research's pathological, biochemical, and molecular results, treatment with TQ as an anti-inflammatory and antioxidant compound may be the potential to improve and treat 5-FU-induced OM and IM, and TQ could be used against cancer treatment drugs and exhibit fewer adverse effects.

Synergistic synbiotic containing fructooligosaccharides and Lactobacillus delbrueckii CIDCA 133 alleviates chemotherapy-induced intestinal mucositis in mice.

Intestinal mucositis is a commonly reported side effect in oncology patients undergoing chemotherapy and radiotherapy. Probiotics, prebiotics, and synbiotics have been investigated as alternative therapeutic approaches against intestinal mucositis due to their well-known anti-inflammatory properties and health benefits to the host. Previous studies showed that the potential probiotic Lactobacillus delbrueckii CIDCA 133 and the prebiotic Fructooligosaccharides (FOS) alleviated the 5-Fluorouracil (5-FU) chemotherapy-induced intestinal mucosa damage. Based on these previous beneficial effects, this work evaluated the anti-inflammatory property of the synbiotic formulation containing L. delbrueckii CIDCA 133 and FOS in mice intestinal mucosa inflammation induced by 5-FU. This work showed that the synbiotic formulation was able to modulate inflammatory parameters, including reduction of cellular inflammatory infiltration, gene expression downregulation of Tlr2, Nfkb1, and Tnf, and upregulation of the immunoregulatory Il10 cytokine, thus protecting the intestinal mucosa from epithelial damage caused by the 5-FU. The synbiotic also improved the epithelial barrier function by upregulating mRNA transcript levels of the short chain fatty acid (SCFA)-associated GPR43 receptor and the occludin tight junction protein, with the subsequent reduction of paracellular intestinal permeability. The data obtained showed that this synbiotic formulation could be a promising adjuvant treatment to be explored against inflammatory damage caused by 5-FU chemotherapy.

Tacrolimus/methotrexate vs tacrolimus/reduced-dose methotrexate/mycophenolate for graft-versus-host disease prevention.

Tacrolimus (Tac)/methotrexate (MTX) is standard graft-versus-host disease (GVHD) prophylaxis; however, is associated with several toxicities. Tac, reduced-dose MTX (mini-MTX), and mycophenolate mofetil (MMF) have been used but never compared with standard MTX. We performed a randomized trial comparing Tac/MTX (full-MTX) with Tac/mini-MTX/MMF (mini-MTX/MMF) for GVHD prevention after allogeneic hematopoietic cell transplantation (HCT). Patients (pts) receiving first myeloablative HCT using an 8/8 HLA-matched donor were eligible. Primary end points were incidence of acute GVHD (aGVHD), mucositis, and engraftment. Secondary end points included chronic GVHD (cGVHD), organ toxicity, infection, relapse, nonrelapse mortality (NRM), and overall survival (OS). Ninety-six pts were randomly assigned to full-MTX (N = 49) or mini-MTX (N = 47). The majority (86%) used bone marrow grafts. There was no significant difference in grade 2-4 aGVHD (28% mini-MTX/MMF vs 27% full-MTX; P = .41); however higher incidence of grade 3-4 aGVHD (13% vs 4%; P = .07) with mini-MTX/MMF. Pts receiving mini-MTX/MMF had lower grade 3 or 4 mucositis and faster engraftment. There were no differences in moderate-to-severe cGVHD at 1 year or infections. Pts receiving mini-MTX/MMF experienced less nephrotoxicity and respiratory failure. There was no difference in the 1-year relapse (19% vs 21%; P = .89) and OS (72% vs 71%; P = .08), and mini-MTX/MMF was associated with lower but nonsignificant NRM (11% vs 22%; P = .06). Compared with full-MTX, mini-MTX/MMF was associated with no difference in grade 2-4 aGVHD and a more favorable toxicity profile. The higher severe aGVHD warrants further study to optimize this regimen. The trial was registered at www.clinicaltrials.gov as #NCT01951885.

Viable Bifidobacterium tablets for the prevention of chemotherapy-/radiation-induced mucositis in patients undergoing haematopoietic stem cell transplantation.

PURPOSE: Mucositis is a frequent and severe complication in haematopoietic stem cell transplantation (HSCT). The effectiveness of probiotics in mucositis has been indicated by several clinical trials, but the results are still controversial. To date, studies on the influence of probiotics in HSCT are limited. Therefore, we conducted this retrospective study to evaluate the impact of viable Bifidobacterium tablets on the incidence and duration of chemotherapy-/radiation-induced mucositis in patients undergoing HSCT. METHODS: Clinical data of 278 patients who underwent HSCT between May 2020 and November 2021 were retrospectively analysed. They were divided into a control group (138) and a probiotic group (140) according to whether they took viable Bifidobacterium tablets. First, we analysed the baseline data of the two groups. Then, we compared the incidence, severity and duration of mucositis between the two groups by using Mann-Whitney U test, chi-square test and Fisher's exact test according to the type of data. In order to exclude the influence of confounding factors, we further evaluated the efficacy of oral probiotics in preventing oral mucositis by Binary logistic regression analysis. RESULTS: The use of viable Bifidobacterium tablets markedly reduced the incidence of oral mucositis (OM) (62.9% vs. 81.2%, p = 0.001) and mainly reduced the incidence of grades 1-2 OM (74.6% vs. 58.6%, p = 0.005). There was no significant difference in the incidence of severe (grades 3-4) OM between the two groups (6.5% vs. 4.3%, p = 0.409). The median duration of OM was shorter in the probiotic group (10 vs. 12 days, p = 0.037). The incidence and duration of diarrhoea did not differ between the two groups. Moreover, the use of viable Bifidobacterium tablets had no influence on engraftment. CONCLUSIONS: Our results suggested that viable Bifidobacterium tablets could effectively reduce the incidence of grades 1-2 OM and duration of OM during the transplant process without affecting the outcome of HSCT.

Anakinra and dexamethasone treatment of idarubicin-induced mucositis and diarrhoea in rats.

Chemotherapy-induced mucositis, characterized by diarrhoea and villous atrophy, is a severe side effect contributing to reduced quality of life and premature death in cancer patients treated with cytostatics. Despite its high incidence, there is no effective supportive therapy available. The main objective of this study was to determine if the anti-inflammatory drugs anakinra and/or dexamethasone-which have different mechanisms-of-action-might be used to effectively treat idarubicin-induced mucositis in rats. Mucositis was induced through a single injection with 2 mg/kg idarubicin (with saline as control), followed by daily treatments of anakinra (100 mg/kg/day), dexamethasone (10 mg/kg/day) or both for 3 days. After 72 h, jejunal tissue was collected for morphological, apoptotic and proliferative analyses, and colonic faecal water content and body weight change were determined. The diarrhoea that was induced by idarubicin (from 63.5% to 78.6% water content in faeces) was completely reversed by anakinra alone, and the jejunal villus height reduction by 36% was prevented by a combination of anakinra and dexamethasone. Dexamethasone reduced apoptosis in the jejunal crypts, both alone and in combination with anakinra. These positive effects encouraged further investigations into the use of anakinra and dexamethasone as supportive therapies for chemotherapy-induced intestinal mucositis and diarrhoea.

Polysaccharide Fraction from Campomanesia adamantium and Campomanesia pubescens Attenuates 5-Fluorouracil-Induced Intestinal Mucosal Inflammation in Mice.

Gastrointestinal toxicity, including diarrhea and inflammation, is commonly observed with the use of 5-fluorouracil (5-FU). Several studies have shown that polysaccharides are interesting bioactive macromolecules for the treatment or prevention of gastrointestinal diseases. Therefore, in this study, the effect of a polysaccharide fraction from a mixture of two Guavira species (Campomanesia adamantium and Campomanesia pubescens), referred to here as CPW, on the development of intestinal mucositis was investigated. Intestinal mucositis was induced by a single injection of 5-FU (450 mg/kg), and various doses of CPW (3-100 mg/kg) were tested. CPW attenuated disease development and prevented small bowel dysmotility and colon shortening. CPW prevented the increase in villi width, crypt depth, and mucosal thickness in the duodenum, but not in the colon. Preservation of mucus, reduction of oxidative stress, inflammation, and prevention of the 5-FU-induced enlargement and swelling of the spleen were observed. In conclusion, this study demonstrated for the first time that CPW alleviates the intestinal damage induced by 5-FU and could be used as an adjuvant strategy during chemotherapy.

NF-κB as a Potential Target for the Treatment and Prevention of Mucositis.

Mucositis is a debilitating and severe side effect of chemotherapy and radiotherapy. It is responsible for reducing the patient's quality of life and represents a significant economic burden in oncology. Currently, there is no definitive and definite treatment for this disease. Intracellular signalling pathways have provided excellent drug development resources, particularly cancer therapeutic development. In recent decades, active research has been conducted to describe the pathogenesis of mucositis and the role of nuclear factor-kappa B (NF-κB) signalling pathways in mucositis development. Insights into the mechanisms of mucositis are creating new approaches for effective targeted treatment and their success in clinical use. Several studies have concentrated on elucidating the functional significance of NF-kB activation and its signalling mechanisms in mucositis in recent decades. Also, evidence indicates that NF-κB is the primary node for the development and progression of mucositis. Its altered expression is associated with increased mucosal injury in mucositis. Hence, regulating the activation of NF-κB could be a powerful strategy for the clinical management of mucositis. Thus, this review examines the role of NF-κB as a potential therapeutic target for chemotherapy and radiation-induced mucositis therapy.

Efficacy of Prophylactic High-Dose Gabapentin and Venlafaxine on Reducing Oral Mucositis Pain Among Patients Treated With Chemoradiation for Head and Neck Cancer: A Single-Institution, Phase 2, Randomized Clinical Trial.

PURPOSE: Given the paucity of level 1 evidence, the optimal regimen to control oral mucositis pain remains unclear. Although national guidelines allow consideration of prophylactic gabapentin, prior trials showed improved pain control with venlafaxine among patients with diabetic neuropathy. We sought to investigate the role of prophylactic high-dose gabapentin with venlafaxine to reduce oral mucositis pain among patients with head and neck cancer. METHODS AND MATERIALS: We performed a single-institution, phase 2 randomized trial on nonmetastatic squamous cell carcinoma of the head and neck treated with chemoradiation. Patients were randomized to either prophylactic gabapentin (3600 mg daily) with or without venlafaxine (150 mg daily). Primary endpoint was differences in pain levels at the end of chemoradiation. Secondary endpoint was toxicity profiles, quality of life changes, opioid use, and feeding tube placement. Differences between the 2 arms at multiple time points were evaluated using a generalized linear mixed regression model with Sidak correction. RESULTS: Between May 2018 and March 2021, a total of 62 patients were enrolled and evaluable for analysis (n = 32 for the gabapentin alone arm, n = 30 for the gabapentin + venlafaxine arm). Over 90% of patients tolerated gabapentin well. Head and neck pain level showed a mean value of 45 (standard deviation, 23) and 43 (standard deviation, 21) for the gabapentin alone and the gabapentin + venlafaxine arms, respectively (P = .65). No statistically significant differences were observed in adverse events, opioid use, feeding tube placement, or quality of life. CONCLUSIONS: The addition of venlafaxine to prophylactic gabapentin did not result in improvements in pain control and quality of life among patients with head and neck cancer.