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Almost all cancer therapies lead to a wide array of side effects, owing to the disruption of normal physiological processes and alteration of immunological responses. Of these, mucositis is one of the most commonly encountered side effects, presenting in about 20-40% of all patients receiving chemotherapy and 80% of those being treated with radiotherapy for head and neck malignancies. This article provides a brief introduction and comprehensive overview of the various treatment modalities used in managing this complication. The key to management is a multidisciplinary approach, revolving around pain control, oral hygiene, nutritional support and management of superimposed infection. The scarcity of therapeutic options for prevention or treatment of mucositis has resulted in clinical difficulty in controlling it, which, in turn, seriously affects the patient's quality of life and cancer management, contributing to patient morbidity and mortality.

Purpose: Mucositis is severely painful and often reported as one of the most distressing adverse effects of cancer therapy; it is a significant threat to quality of life as well as life itself. Anti-inflammatory agents may modulate physiologic mechanisms that perpetuate mucositis and be useful in prevention efforts. Because systemic anti-inflammatory agents are not appropriate for many patients, locally acting agents (mouthwashes) may be more feasible for use. This review and meta-analysis evaluates the role that anti-inflammatory mouthwashes have in preventing or reducing oral mucositis associated with chemotherapy and radiation therapy., Methods: A systematic literature review was conducted to identify studies evaluating the efficacy of anti-inflammatory mouthwashes to prevent therapy-associated mucositis. Meta-analysis was conducted to determine efficacy in preventing any mucositis and dose-limiting mucositis., Results: Eight peer-reviewed publications were identified; corticosteroid and nonsteroidal anti-inflammatory mouthwashes are effective in reducing overall incidence of mucositis and are associated with lower severity of mucositis. Meta-analysis reveals significant reduction in symptomatic mucositis incidence (OR 6.00, 95% CI 4.39-8.20, p < 0.0001) and reduction of dose-limiting mucositis (OR 2.12, 95% CI 1.07-4.28, p = 0.032)., Conclusion: Mouthwashes containing anti-inflammatory agents are a potential effective means to prevent or reduce mucositis associated with cancer therapy. There are limited adverse effects from these agents, and adherence is high, indicating safety and feasibility of use. Anti-inflammatory mouthwashes should be considered for supportive care in persons at risk for mucositis and must be further evaluated to investigate efficacy across multiple chemotherapy agents, adverse effects, and impacts on symptoms, pain, and quality of life., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The study aimed to evaluate the possible preventive effect of two concentrations (3 and 5% w/w) of Eugenia jambolana (EJ) extract against 5-FU-induced mucositis., Method: Sixteen adult rats were separated into four groups: two control and two preventive groups. Animals in Groups 1, 2, and 3 were injected intraperitoneally with 60 mg/kg/day of 5-FU on Day 1 followed by 150 mg/kg/day on Day 5. The rats in Group 4 (negative control) were given physiological saline at the same times and doses. Furthermore, on the fifth day of the study, the cheek and sublingual mucosa were irritated by external superficial scratches using the tip of an 18-G needle, followed by the application 15 µL of 20% acetic acid, after which 3 and 5% EJ w/w gels were applied topically for animals in Groups 2 and 3, respectively., Results: The weight and the mucositis scores were recorded. Antioxidant and anti-inflammatory markers and biochemical tests were analyzed. Significant differences were found between the study groups in weight loss, clinical mucositis scores, mortality rates, and antioxidant and anti-inflammatory parameters., Conclusion: The preventive effect of 3% gel was significant, with no mortality rate, making it an option for preventive strategies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Most patients with cancer treated with everolimus experience stomatitis, which seriously affects the quality of life. The salivary concentrations of everolimus may predict the incidence and severity of stomatitis. The authors aimed to examine whether it was feasible to quantify the everolimus concentration in saliva and subsequently use it to predict stomatitis., Methods: Saliva and whole blood samples were taken from patients with cancer, who were treated with everolimus in the dosage of either 10 mg once a day or 5 mg twice a day. Everolimus concentrations in saliva samples were measured by liquid chromatography-tandem mass spectrometry. A published population pharmacokinetic model was extended with the everolimus concentration in saliva to assess any association between everolimus in the blood and saliva. Subsequently, the association between the occurrence of stomatitis and the everolimus concentration in saliva was studied., Results: Eleven patients were included in this study; saliva samples were available from 10 patients, including 3 patients with low-grade stomatitis. Everolimus concentrations were more than 100-fold lower in saliva than in whole blood (accumulation ratio 0.00801 and relative standard error 32.5%). Interindividual variability (67.7%) and residual unexplained variability (84.0%) were high. The salivary concentration of everolimus tended to be higher in patients with stomatitis, 1 hour postdose ( P = 0.14)., Conclusions: Quantification of the everolimus concentration in saliva was feasible and revealed a nonsignificant correlation between everolimus concentration in the saliva and the occurrence of stomatitis. If future research proves this relationship to be significant, the everolimus concentration in the saliva may be used as an early predictor of stomatitis without invasive sampling. Thereby, in patients with high salivary everolimus concentrations, precautions can be taken to decrease the incidence and severity of stomatitis., Competing Interests: J. H. Beijnen (partly) holds a patent on oral taxane formulations and is a part-time employee and stockholder of Modra Pharmaceuticals, a spin-out company developing oral taxanes. This is not related to the manuscript. N. Steeghs provided consultation or attended advisory boards for AIMM Therapeutics, Boehringer Ingelheim, and Ellipses Pharma and received research grants for the institute from AB Science, Abbvie, Actuate Therapeutics, Amgen, Array, AstraZeneca/MedImmune, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Cantargia, Cytovation, Deciphera, Genentech/Roche, GlaxoSmithKline, Incyte, InteRNA, Lilly, Merck Sharp & Dohme, Merus, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Taiho, and Takeda (outside the submitted work). R. B. Verheijen reports share ownership and employment at Johnson & Johnson, prior share ownership and employment at AstraZeneca, and share ownership of Galapagos and Chinook Tx (outside of the submitted work). The other authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: This prospective interventional study aimed to evaluate and analyse the efficacy of rhIL-11 mouthwash compared to Kangfuxin fluid in treatment and blank control in prevention of oral mucositis (OM) in patients receiving chemotherapy., Materials and Methods: In total, 50 patients in the treatment group and 62 patients in the prevention group were included. Subsequently, each group was divided into an experimental group and a control group. In the treatment group, the experimental patients received recombinant human interleukin-11 (rhIL-11) mouthwash, whereas the control group received Kangfuxin fluid. In the prevention group, experimental patients still received rhIL-11 mouthwash based on routine oral care, whereas the control group only received routine oral care. Meanwhile, we observed and recorded the efficacy in the treatment group, and the occurrence and grades of OM in the prevention group., Results: Through statistical analysis, the results showed that on the seventh day of treatment, the experimental group showed more improvement compared to the control group, and it was statistically significant (p = 0.032). The average healing time in the experimental group (3.59 ± 1.927 days) was shorter than that in the control group (4.96 ± 2.421 days; p = 0.031). In the prevention group, we observed the incidence of oral mucositis. No significant differences were found in the occurrence and grades of OM in the experimental and control groups (p = 0.175)., Conclusion: Our preliminary results indicate that rhIL-11 mouthwash may be a superior option to treat OM, especially in severe cases, compared to Kangfuxin fluid. However, there is no advantage in prevention., (© 2022. The Author(s).)

Background and Objectives : One of the most debilitating side effects of chemotherapy is oral mucositis (OM). Photobiomodulation (PBM) demonstrates high efficacy in the management of OM. The aim of the study was to investigate the incidence of oral mucositis and evaluation of the effectiveness of PBM therapy. Materials and Methods : A total of 23 children diagnosed with leukaemia or lymphoma affected by chemotherapy-induced OM were enrolled in the study. OM grade was assessed with the World Health Organization (WHO) scale. Patients completed an approved questionnaire, and blood cell counts were read every 2 days. OM lesions were treated with class IV laser therapy with a frequency of every 48 h and density of 2, 4, 8, 16 or 30 J/cm 2 . The level of pain was measured with VAS scale. Results : The 23 patients developed a total of 41 OM episodes with a mean duration of 7.61 days ± 4.70. Laser therapy showed a great reduction regarding pain and a better function of patients even with neutropenia. Conclusions : Oral mucositis represents a significant burden to children. PBM brings positive aspects for patients; however, the optimal treatment parameters require further study.

Oral mucositis (OM) is one of the most common complications associated with chemotherapy. Here, we evaluated whether systemic dexamethasone (DEX) dosage in prophylactic antiemetics affected the incidence of OM in anthracycline-containing regimens. Patients receiving anthracycline-containing regimens for breast cancer were divided into high- and low-DEX dose groups and retrospectively evaluated. The incidence of all-grade OM in the first cycle in the high- and low-dose groups was 27.3% and 53.5%, respectively, and was significantly lowered by increasing the DEX dose (P < 0.01); thus, the study met its primary endpoint. The result in all treatment cycles was also significant (P = 0.02). In contrast, the incidence of dysgeusia was similar between the high- and low-dose groups in the first and all cycles (13.6% and 16.3% in the first cycle [P = 0.79] and 27.3% and 34.9% in all cycles [P = 0.42], respectively). Multivariate analysis revealed that low DEX dosage was an independent risk factor for all-grade OM development. In conclusion, our study suggests that DEX attenuates OM in anthracycline-containing regimens for breast cancer treatment in a dose-dependent manner. Further evaluation of OM prophylaxis, including DEX administration, is required for better control., (© 2022. The Author(s).)

Background: There is a need for studies that correlate the severity of oral mucositis (OM) with chemotherapy protocols, transient myelosuppression and oral health., Objective: To analyze the severity of OM among individuals with solid tumors during hospitalization and its correlation with the type of chemotherapy, myelosuppression and oral health condition., Design and Setting: Retrospective study at a public hospital in Bauru, state of São Paulo, Brazil, that is a regional referral center., Methods: Individuals diagnosed with solid malignant tumors who received chemotherapy during hospitalization for completion of the antineoplastic treatment cycle or who presented complications resulting from this were assessed., Results: Twenty-eight individuals (24.3%) manifested some degree of OM. The most prevalent degrees of OM according to the World Health Organization (WHO) and modified WHO classification were grades 2 (11.3%) and 5 (4.3%), respectively. It was observed that the higher the OM-WHO (P < 0.001; r = 0.306) and modified OM-WHO (P < 0.001; r = 0.295) classifications were, the greater the oral pain reported by the individuals was. Presence of mucositis in the upper lip and buccal mucosa contributed to increased severity of OM and worsening of swallowing during hospitalization. Thus, severe OM was associated with use of the FOLFIRI protocol (folinic acid, fluorouracil and irinotecan)., Conclusion: Individuals with tumors who presented severe OM had greater severity of oral pain and worse oral health. Use of the FOLFIRI protocol was associated with higher prevalence of severe OM, while use of 5-fluorouracil (5-FU) was correlated with worse oral condition.

Background: This study retrospectively analyzed the risk factors for transchemotherapy oral mucositis (OM)., Material and Methods: Before each chemotherapy cycle, patients were routinely evaluated for the presence/severity of OM based on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scale for adverse effects and graded as follows: However, specific conditions such as mucositis are graded on a five-point scale: 0, absence of mucositis, grade 1 (Asymptomatic or mild), 2 (Presence of pain and moderate ulceration, without interference with food intake), 3 (severe pain with interference with food intake) or 4 (Life-threatening with the need for urgent intervention). Information from 2 years of evaluations was collected and patient medical records were reviewed to obtain data on chemotherapy cycle, sex, age, body mass index, body surface area, primary tumor, chemotherapy protocol, and history of head and neck radiotherapy. The X² test and multinomial logistic regression were used for statistical analysis (SPSS 20.0, p<0.05)., Results: Among 19,000 total evaluations of 3,529 patients during 5.32±4.7 chemotherapy cycles (CT) the prevalence of OM was 6.3% (n=1,195). Chemotherapy duration (p<0.001), female sex (p=0.001), adjuvant intention (p=0.008) and the use of carboplatin (p=0.001), cisplatin (p=0.029), docetaxel (p<0.001) and bevacizumab (p=0.026) independently increased the risk of mucositis. In head and neck tumors, 2018 year (p=0.017), chemotherapy duration (p=0.018), BMI>30 (p=0.008), radiotherapy (p=0.037) and use of carboplatin (p=0.046) and cyclophosphamide (p=0.010) increased this prevalence., Conclusions: Cycles of chemotherapy, sex, cytotoxicity drugs, bevacizumab and head and neck radiotherapy increase the risk of OM in solid tumors.

Objectives: To determine whether oral cryotherapy (OC) mitigates oral mucositis (OM) resulting from busulfan chemotherapy., Sample & Setting: Electronic health records of patients undergoing busulfan conditioning for blood and marrow transplantation were reviewed for this descriptive study. The post-OC group received OC with busulfan, but the pre-OC group did not., Methods & Variables: Demographic and disease characteristics for both groups were summarized using descriptive statistics. Wilcoxon rank-sum test was performed for continuous and ordinal measures, and chi-square tests were performed for categorical outcomes between the two groups., Results: This study found a decrease in the severity of OM as assessed by the World Health Organization OM scale. This study also found a reduction of total parenteral nutrition and opioid pain medication use, as well as a decrease in length of stay and airway protection-related intensive care unit transfers. An increase in day 11 methotrexate administration for graft-versus-host disease prophylaxis was observed in the post-OC group., Implications for Nursing: OC is a safe and easily implemented intervention that can decrease OM in patients receiving busulfan chemotherapy.

Radiotherapy and/or chemotherapy-induced oral mucositis (RIOM/CIOM) is a common complication in cancer patients, leading to negative clinical manifestations, reduced quality of life, and impacting compliance with anticancer treatment. The composition and metabolic function of the oral microbiome, as well as the innate immune response of the oral mucosa are severely altered during chemotherapy or radiotherapy, promoting the expression of inflammatory mediators by direct and indirect mechanisms. Commensal oral bacteria-mediated innate immune signaling via Toll-like receptors (TLRs) ambiguously shapes radiotherapy- and/or chemotherapy-induced oral damage. To date, there has been no comprehensive overview of the role of TLRs in RIOM/CIOM. This review aims to provide a narrative of the involvement of TLRs, including TLR2, TLR4, TLR5, and TLR9, in RIOM/CIOM, mainly by mediating the interaction between the host and microorganisms. As such, we suggest that these TLR signaling pathways are a novel mechanism of RIOM/CIOM with considerable potential for use in therapeutic interventions. More studies are needed in the future to investigate the role of different TLRs in RIOM/CIOM to provide a reference for the precise control of RIOM/CIOM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ji, Hao, Wang, Zou and Wang.)

Metformin (Met) is a first-line and essential treatment for type 2 diabetes, with anti-inflammatory effects. It has been reported Met could inhibit NF-κB activity and down-regulate the release of inflammatory factors. However, whether Met has a protective effect on chemotherapy-induced oral mucositis(CIOM) is unknown. The purpose of this study was to evaluate the protective effect of Metformin(Met) on chemotherapy-induced oral mucositis(CIOM) and further explore its possible mechanism. 5-Fu was used in the C57BL/6 mice to establish the model of CIOM. Our results showed Met could significantly improve 5-Fu-induced mucosal damage, apoptosis, ROS and releasing of inflammatory factors in the tongue tissue. In addition, Met could inhibit 5-Fu-induced high expression of endoplasmic reticulum stress(ERS)-related proteins GRP78 and CHOP. Further studies showed that the protective effect of ERS inhibitor 4-PBA on CIOM was similar to Met. Moreover, Met inhibited the phosphorylation of NF-κB in tongue tissue, independent of AMPK phosphorylation. The protective effect of PDTC, an inhibitor of NF-κB, on tongue tissue was similar to that of Met. This study confirmed the protective effect of Met on 5-Fu-induced CIOM, which was achieved by inhibiting ERS and reducing the activity of NF-κB., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Toothpastes are one of the most common personal care products among people of all ages. The various toothpaste types and their complex ingredients could cause irritation or allergic reactions. Allergic contact stomatitis has been often seen in clinical practice; however, desensitizing toothpastes as a trigger are often unrecognized. Here, we report three cases of allergic contact stomatitis due to stannous chloride-containing desensitizing toothpastes. General dentists and other professionals should pay more attention to the safety and adverse effects of toothpastes., (© 2022 Japanese Dermatological Association.)

Background and Objectives : Oral mucositis, a severe non-hematological complication, can be induced by chemoradiotherapy. It is associated with severe local dysfunction, severely affecting the patient's quality of life; it increases the risk of oral infections and interrupts oncological treatment, thus prolonging the duration and cost of hospitalization. Besides all of the agents used in the prevention and treatment of oral mucositis induced by oncological treatment, can there be found an easier one to administer, with an effective preparation, high addressability, both for adults and paediatric patients, without side effects, and at the same time cheap and easy to purchase? The aim of the present paper is to demonstrate the existence of this product, which is available to everyone, having multiple benefits. Materials and Methods : For the purpose of writing this article, materials were searched in electronic databases in between 2019 and 2021, taking into consideration papers where authors have demonstrated the effectiveness of this product through its topical or systemic use. Results : Numerous studies have highlighted the benefits of honey on oral mucositis. Through its analgesic, anti-inflammatory, anti-cancerous and antibacterial action, honey has proved to have a major impact on the patient's quality of life and nutritional status by promoting tissue epithelialization and healing of the chemoradiotherapy-induced lesions. Conclusions : Superior to many natural agents, bee honey can be successfully used in both preventing and treating oral mucositis. There are currently numerous studies supporting and recommending the use of bee honey in the management of this oncological toxicity.

Oral mucositis (OM) is a common complication during chemotherapy characterized by ulceration, mucosa atrophy, and necrosis, which seriously interferes with nutritional intake and oncotherapy procedures among patients. However, the efficacy of current treatments for OM remains limited. Cannabidiol (CBD) is a natural cannabinoid with multiple biological activities, including antioxidant and anti-inflammatory potential. In this study, we aimed to investigate the chemopreventive effects and mechanisms of CBD in protecting C57BL/6N mice and human oral keratinocytes (HOK) from 5-fluorouracil- (5-FU-) induced OM. Here, we found that CBD alleviated the severity of 5-FU-induced OM in mice, including improved survival, decreased body weight loss, reduced ulcer sizes, and improved clinical scores. Histologically, CBD restored epithelial thickness and normal structure in tongue tissues. Meanwhile, CBD attenuated reactive oxygen species (ROS) overproduction and improved the antioxidant response, suppressed the inflammatory response, promoted the proliferation of epithelial cells, and inhibited 5-FU-induced apoptosis. In vitro , consistent outcomes showed that CBD suppressed cellular ROS levels, enhanced antioxidant ability, reduced inflammatory response, promoted proliferation, and inhibited apoptosis in 5-FU-treated HOK cells. In particular, CBD upregulated the expression levels of antioxidant enzymes, heme oxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase 1 (NQO1), by increasing the expression and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and decreasing Kelch-like ECH-associated protein 1 (Keap1). Notably, the Nrf2 inhibitor ML385 reversed the protective effect of CBD. Nrf2-siRNA transfection also significantly blunted the antioxidant effect of CBD in in vitro OM model. Collectively, our findings suggested that CBD protected against 5-FU-induced OM injury at least partially via the Nrf2/Keap1/ARE signaling pathways, highlighting the therapeutic prospects of CBD as a novel strategy for chemotherapy-induced OM., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Lin Li et al.)

Objectives: Oral mucositis (OM) is an acute toxicity related to cancer treatment. This systematic review aimed to identify potential risk factors associated with the development of OM in pediatric cancer patients., Methods: A search was performed in four electronic databases to identify studies that analyzed risk factors for OM in pediatric cancer patients., Results: Nineteen articles were included. The incidence of OM ranged from 20% to 80.4%. Chemotherapeutic agents were potential risk factors for OM in eight (42%) studies. Hematological, hepatic, and renal parameters were also considered in eight (42%) studies, while specific individual factors were reported in five (26.3%) studies. Baseline disease, oral microbiota, genetic profile, and biomarkers were reported in four (21.5%) studies each. Meta-analysis showed that groups submitted to high-risk chemotherapy for OM had a 2.79-fold increased risk of OM., Conclusions: Identifying risk factors for OM is essential in order to allow individualized and early prevention treatment., (© 2021 Wiley Periodicals LLC.)

Chemoradiation-induced mucositis is a debilitating condition of the gastrointestinal tract eventuating from antineoplastic treatment. It is believed to occur primarily due to oxidative stress mechanisms, which generate Reactive Oxygen Species (ROS). The aim of this scoping review was to assess the role of oxidative stress in the development of Oral Mucositis (OM). Studies from the literature, published in MEDLINE and SCOPUS, that evaluated the oxidative stress pathways or antioxidant interventions for OM, were retrieved to elucidate the current understanding of their relationship. Studies failing inclusion criteria were excluded, and those suitable underwent data extraction, using a predefined data extraction table. Eighty-nine articles fulfilled criteria, and these were sub-stratified into models of study (in vitro, in vivo, or clinical) for evaluation. Thirty-five clinical studies evaluated antioxidant interventions on OM's severity, duration, and pain, amongst other attributes. A number of clinical studies sought to elucidate the protective or therapeutic effects of compounds that had been pre-determined to have antioxidant properties, without directly assessing oxidative stress parameters (these were deemed "indirect evidence"). Forty-seven in vivo studies assessed the capacity of various compounds to prevent OM. Findings were mostly consistent, reporting reduced OM severity associated with a reduction in ROS, malondialdehyde (MDA), myeloperoxidase (MPO), but higher glutathione (GSH) and superoxide dismutase (SOD) activity or expression. Twenty-one in vitro studies assessed potential OM therapeutic interventions. The majority demonstrated successful a reduction in ROS, and in select studies, secondary molecules were assessed to identify the mechanism. In summary, this review highlighted numerous oxidative stress pathways involved in OM pathogenesis, which may inform the development of novel therapeutic targets.

Background: Oral mucositis (OM) is known to be the most common and challenging side effect of conditioning chemotherapy in haematopoietic cell transplant (HCT). This side effect causes significant morbidity and may delay the treatment plan, as well as increase therapeutic expenses. There are few clinical trials in the literature that indicate any kind of treatment or prevention methods are effective. Therefore, the aim of this study is to perform a systematic review of literature and examine the effectiveness of oral cryotherapy (OC) in management of chemotherapy-induced OM in patients with haematological malignancies undergoing a HCT., Methods: A systematic literature search was conducted, using the electronic databases PubMed, Embase, MEDLINE and Scopus. A total of 322 papers were identified and 9 papers were analysed based on defined inclusion and exclusion criteria. The quality of the chosen primary studies was appraised using the COCHRANE risk of bias assessment tool., Results: Nine randomized controlled trials, analysing 658 participants; control group (n = 289, age mean ± SD; 41.15 ± 21) and treatment group (n = 369, age mean ± SD; 39.15 ± 20), were included in this systematic review. Seven studies had significantly addressed the effectiveness of OC (p value < 0.05), in reducing the incidence of developing severe OM in the adult population undergoing HCT, especially when the conditioning regimen protocols included high dose of alkylating agent such as melphalan., Conclusion: This review supports the use of OC for prevention of OM in patients undergoing HCT, with high-dose of melphalan conditioning protocols. It is recommended that more studies be conducted to compare efficacy and duration of OC with other chemotherapeutic agents with relatively short plasma half-lives. The heterogeneity of the trials demonstrated the need to regulate the validated assessment tools and similar interventions that would enable comparisons and analyses of treatment effects based on well-designed RCTs., (© 2022. The Author(s).)

Background: Cancer patients usually suffer from intensive chemotherapy-related oral mucositis (OM), yet limited effective treatment can rapidly alleviate OM severity., Methods: This prospective study examined the efficacy of Reishimmune-S containing one fungal immunomodulatory protein, GMI on OM in patients with head and neck cancer. Patients with head and neck cancer and the diagnosis of chemotherapy-related OM were enrolled randomizedly to receive standard supportive care with/without Reishimmune-S 500 mg/day orally for consecutive 14 days. Due to intolerance to standard supportive care alone in the control arm, only the experimental arm with Reishimmune-S supplementation was analyzed in our trial. OM grading was evaluated as the primary outcome on day 1, 8, and 15. Secondary outcomes were absolute neutrophil counts and quality of life assessed by the EORTC-QLQ-H&N 35 questionnaire on day 1, 8, and 15., Results: Reishimmune-S supplement significantly reduced OM grading both at day 8 and 15. Trouble with social contact and weight loss conditions were also improved by Reishimmune-S. Reishimmune-S did not significantly affect absolute neutrophil counts during the 15-day follow-up., Conclusion: Reishimmune-S supplement potentially alleviates the severity of chemotherapy-mediated OM., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Methotrexate (MTX), a chemotherapeutic agent, is known to cause oral mucositis. Chitosan has been shown to have a protective effect in inflammatory animal models. This research aimed to examine the protective effect of chitosan against oral mucositis caused by MTX., Methods and Results: Wistar albino rats were randomly divided into three groups. Control (n = 8), (saline via oral gavage for 5 days), MTX (n = 8), (60 mg/kg single dose MTX intraperitoneally on the 1st day and for the following 4 days saline via oral gavage), and MTX + chitosan (n = 8), (1st day single dose 60 mg/kg MTX intraperitoneally and followed with 200 mg/kg chitosan via oral gavage for 4 days). After 24 h of the last dose, the animals were euthanised. Blood, tongue, buccal and palatal mucosa tissues were collected. Serum interleukin 1-beta (IL1-β), tumour necrosis factor-alpha (TNF-α), matrix metalloproteinase (MMP-1, and MMP-2) activities, tissue bcl-2/bax ratio and the expression of caspase-3 (casp-3), and casp-9 were detected. The tissues were also examined histologically. Serum TNF-α, IL1-β, MMP-1 and MMP-2 activities and tissue casp-3 and casp-9 activities significantly increased but the bcl-2/bax ratio significantly decreased in the MTX group compared those of the control group. Histologically, diffuse inflammatory cells were observed in MTX group. However, In the MTX + chitosan group, all the values were close to those of the control group., Conclusion: It was demonstrated that chitosan has a protective effect against oral mucosal damage caused by MTX. Thus, it may be a candidate agent against MTX induced oral mucositis., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: Oral mucositis (OM) is a painful inflammatory oral condition that affects children who undergo chemotherapy. Oxidative stress is a known OM mediator and pro-inflammatory cytokines contribute to the amplification of the immune response. To investigate the possible associations of rs4880 (superoxide dismutase 2, SOD2 47 C/T), rs7943316 (catalase, CAT -21 A/T), rs1800629 (tumor necrosis factor α, TNF- α -308 G/A), and rs1800795 (interleukin 6, IL-6 -174 G/C) polymorphisms with chemo-induced OM occurrence and severity in oncopediatric patients., Methodology: We conducted a single-center, observational cross-sectional study with sample collection of oral epithelial cells from 95 children and adolescents with hematological cancers who underwent chemotherapy, followed by genomic DNA extraction. Single-nucleotide polymorphisms (SNPs) were assessed with PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism). Demographic data and information concerning OM occurrence were obtained from dental charts of the multidisciplinary oral care team. Information on OM severity was obtained from appropriately-filled Oral Assessment Guide records. Descriptive and inferential statistics were conducted with Student's T test, chi-squared test, and Fisher's exact test, with p≤0.05., Results: The mean age was 10 years-old and most patients were male individuals (57.89%). Female sex was considered a protective factor for OM occurrence (OR=4.83; CI=[1.14; 16.57]). The AA genotype for CAT was the most frequent amongst individuals with severe OM (p=0.04). The GA genotype for TNF- α was the most frequent amongst individuals without severe OM (p=0.03). For SOD2 and IL-6 , the most frequent genotypes were CT and GG respectively for all groups (p>0.05)., Conclusion: The AA genotype for CAT -21 A/T was a tendency among the group with severe OM. Data on TNF- α -308 G/A were inconclusive. No associations were detected for SOD2 47 C/T and IL-6 -174 G/C polymorphisms in oncopediatric patients with chemo-induced oral mucositis.

5-Fluorouracil (5-FU)-induced oral mucositis has a severe negative impact on the patient's quality of life. This study aimed to investigate the role of endoplasmic reticulum stress (ERS) in the occurrence of 5-FU-induced oral mucositis in vivo and in the clinic. In vivo, 5-FU-induced oral mucositis model mice showed a higher level of glucose-regulated protein 78 kD (GRP78, a marker of ERS) than control mice. The inhibition of ERS could effectively reduce 5-FU-induced oxidative stress, inflammatory factor mRNA and cell apoptosis. Moreover, inhibition of ERS significantly decreased the activation of nuclear factor kappa-B (NF-κB) in 5-FU-induced oral mucositis model mice following tissue damage reduction. In the clinic, 5-FU could increase cell apoptosis and cause oral mucosa damage while increasing the expression of the ERS marker genes GRP78 and C/EBP-homologous protein (CHOP). Our study found that 5-FU could induce severe ERS, upregulate the expression of GRP78 and CHOP, raise oxidative stress and increase the expression of inflammatory factors by activating the NF-κB pathway, thus causing cell apoptosis and finally leading to oral mucosal injury., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The objective of this study was to evaluate the effect of topical chamomile in the prevention and/or treatment of oral mucositis (OM) in cancer patients. It was a systematic review, which sought articles of the randomized clinical trial according to the PRISMA parameters, registered in the PROSPERO. The databases used were PubMed, Cochrane Library, and Bireme. Descriptors were selected from DeCs/MeSH and the PICO strategy was applied. The search found 148 publications. After all the steps, six articles were selected. The total sample included 492 patients and all studies used the same OM measurement scale. The results showed that the application of topical chamomile was effective in the prevention and/or treatment of OM in four of the six studies, with a dose ranging from 1% to 2.5% and duration that ranged from single to 4 times a day. Some limitations were observed: the minimum age of the patients was not informed, and there was no specification of the sites involved or the chemotherapies used. The application of topical chamomile in the preventive/therapeutic of chemo-induced OM seems to be recommended. In addition, scientific production should be encouraged, as it aims to determine useful protocols for this phytotherapy for the oncology population., (© 2022 John Wiley & Sons, Ltd.)

Purpose: This study aimed to evaluate the effects and mechanisms of action of royal jelly (RJ) and propolis compared to photobiomodulation therapy (PBMT) in an animal model of 5-fluorouracil-related oral mucositis (OM)., Methods: Seventy-two male Wistar rats were randomly allocated to four groups (n = 18 each): control (no treatment), PBMT (intraoral laser, 6 J/cm 2 ), RJ, and propolis. On days 0 and 2, the animals received an injection of 5-fluorouracil (5-FU). The buccal mucosa was scratched (days 3 and 4) and the treatments were initiated on day 5. Six animals of each group were euthanized on days 8, 10, and 14. Phytochemical analysis (thin-layer chromatography, TLC) and clinical, histopathological, and immunohistochemical analysis of pS6, pAKT, and NF-κB were performed, and oxidative stress markers were also investigated., Results: TLC revealed the presence of large amounts of sucrose (Rf 0.34) in RJ and of flavonoids in propolis. Lower clinical OM scores were observed on day 8, and improved morphological data were observed on day 10 in the PBMT, RJ, and propolis groups (p < 0.05). On day 8, immunoexpression of pS6, pAKT, and NF-κB was increased compared to control. On day 14, reduced glutathione (GSH) antioxidant levels were increased in the propolis group compared to control (p < 0.05)., Conclusions: Our results showed that RJ and propolis, as well as PBMT, are effective in the treatment of OM. Considering that some patients who develop OM do not have access to PBMT, the present study demonstrated that topical application of RJ and propolis may be an important alternative for the treatment of OM., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Sapanisertib is an oral, highly selective inhibitor of mammalian target of rapamycin complexes 1 and 2., Objective: The aim of this study was to assess the safety, tolerability, pharmacokinetics, preliminary efficacy, and to establish the recommended phase 2 dose (RP2D) of sapanisertib., Patients and Methods: In this dose-escalation and expansion study, East Asian patients with nonhematologic malignancies received increasing sapanisertib doses once-daily (QD; starting at 2 mg) or once-weekly (QW; starting at 20 mg) in 28-day cycles., Results: Among 28 patients (QD dosing, n = 22; QW dosing, n = 6), three dose-limiting toxicities were reported (stomatitis [n = 2], gastrointestinal inflammation, gingivitis, and acute myocardial infarction [all n = 1]), all in the 4 mg QD cohort. The RP2D of sapanisertib was 3 mg QD. The most common adverse events were stomatitis (64%), nausea (50%), and decreased appetite (50%) in the QD arm, and nausea (100%), blood alkaline phosphatase increased (67%), and hyperglycemia (67%) in the QW arm. The T max of sapanisertib was ~ 0.5-2.6 h and the T 1/2 was ~ 5.9-7.6 h. Three patients achieved stable disease for ≥ 6 months (1 each in 3 mg QD, 4 mg QD and 20 mg QW cohorts, respectively); the clinical benefit rate was 45% and 67% in the QD and QW arms, respectively., Conclusions: The RP2D of sapanisertib in East Asian patients (3 mg QD) was lower than in Western patients (4 mg QD), but the pharmacokinetics and safety profiles were similar. Sapanisertib was well tolerated and showed moderate anti-tumor effects in heavily pretreated patients with nonhematologic malignancies., Nct Number: NCT03370302; Registered December 7, 2017., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To clinically assess the effectiveness of topical chamomile oral gel in the prevention of chemotherapy-induced oral mucositis., Material and Methods: A parallel single-blind randomized clinical trial conducted on 45 patients who were undergoing chemotherapy. Patients were assigned to three equal groups. Group I received conventional symptomatic treatment that included antifungal agents (Miconaz oral gel, Medical Union Pharmaceuticals), topical anesthetics, and anti-inflammatory agent (BBC oral spray, Amoun Pharmaceutical Company) three times per day for three weeks, group II received 3% chamomile topical oral gel, whereas group III patients were given both conventional symptomatic treatment and chamomile topical oral gel. All patients were clinically assessed for pain and oral mucositis severity at three separate time intervals: 1 week, 2 weeks, and 3 weeks., Results: Most patients experienced oral mucositis with more severity reported in the conventional group (grade III = 6.7%) compared to the other two groups, neither of which developed more than grade II. Mean pain scores showed no significant difference between the groups, but intragroup analysis showed that pain score increased in the conventional treatment group more than the other two groups., Conclusion: Topical chamomile 3% gel has demonstrated in this study to lower the severity of the mucositis with lower pain scores compared to the other two groups., (© 2020 Wiley Periodicals LLC.)

Cancer therapy-induced oral mucositis (OM) is one of the most troublesome morbidities after radio-chemotherapy. Age, nutritional status, tumor type, oral hygiene, and treatment method are the determinants for OM incidence. In addition, oxygen-free radicals can act as a trigger for an inflammatory milieu that causes OM. Based on the debilitating nature of OM, finding a safe and inexpensive agent with anti-inflammatory, anti-microbial, and antioxidative properties can be valuable for this situation. Considering the harmful effects of some chemical agents, herbal medicine has been suggested as a potential alternative owing to unique properties such as safety, availability and low cost. Many studies have illustrated several pharmacological properties of herbal medicines in recent years, such as anti-inflammatory, anti-microbial, and antioxidative activities, which are essential factors in the palliation of cancer therapy-induced OM. This review aimed to evaluate herbal medicines' effects on cancer therapy-induced OM. According to this comprehensive review, it is concluded that medicinal plants and phytochemicals can be used as practical agents in the palliation of cancer therapy-induced OM without any serious side effects., (© 2021 John Wiley & Sons Ltd.)

Objectives: This study aimed to investigate the effects of azithromycin suspension on oral mucositis in patients undergoing hematopoietic stem cell transplantation (HSCT)., Methods and Material: The study was designed as a single-blind randomized controlled trial in Taleghani medical center affiliated to Shahid Beheshti University of Medical Sciences Tehran Iran. Patients undergoing HSCT were randomly assigned to intervention or control groups. Azithromycin suspension was administered twice daily by gargling for 30 s and swallowing, on the first day of chemotherapy for patients in the intervention group. Graded oral mucositis (OM) occurrence based on National Cancer Institute Common Toxicity Criteria (NCI-CTC) scale (grade 0 to 5) was considered the main outcome, and the Numerical Rating Scale (NRS:0-10) measured the severity of OM symptoms., Results: In a duration of 15 months, 88 patients were randomly assigned and finally 70 patients were evaluable for study outcomes (randomized 1:1 to azithromycin versus no-azithromycin). The incidence and duration of the mucositis significantly improved in the intervention group compared to the control. Azithromycin use was consistent with a lower rate of dryness (P < 0.001), dysphagia (P < 0.001), and loss of sense of taste (P < 0.001). Also, in the intervention group, lower intensity of pain due to mucositis (P = 0.01) and lower duration of mucositis were observed (p = 0.045). No significant adverse drug reaction was observed in patients receiving azithromycin., Conclusion: Based on the result from this study, azithromycin suspension is an effective option in the prevention and treatment of chemotherapy-induced OM. Further study is needed to assess the effect of azithromycin and comparison with other therapeutic options., Trial Registration: Iranian Registry of Clinical Trials: IRCT201603093210N13., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Childhood patients have high risks for developing debilitating somatic and mental health side-effects as a consequence of the many different approaches employed in treating their cancer. Early recognition and close monitoring of clinical and psychological problems are essential in planning appropriate interventions and preventing further deterioration., Case: ePROtect was established as an easy-to-use application for daily self-reporting of symptoms during cancer therapy. ePROtect includes six to eight questions pertaining to seven common symptoms: appetite loss, fatigue, nausea, pain, physical functioning, cognitive impairments and sleep quality. The case of a child diagnosed with Burkitt leukemia developing chemotherapy-induced oral mucositis in home care is presented to show the therapeutic impact of early symptom detection with a daily web-based tool., Conclusion: This case highlights how electronic patient-reported outcome measures (PROM) can directly facilitate patient care in real time and might be incorporated in future clinical routine., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

The self-healing of chemotherapy-induced oral mucositis is difficult in practice because of both local bacterial infection and severe inflammation. Herein, in situ mucoadhesive hydrogels (PPP&#95;E) were successfully prepared by using temperature-sensitive PLGA-PEG-PLGA (PPP) as a matrix and epigallocatechin-3-gallate (EGCG) with inherent antibacterial activity as an adhesion enhancer. A series of PPP&#95;E precursor solutions with various EGCG concentrations (1%, 2% and 5%) were prepared by fixing the PPP concentration at 25%. EGCG slightly decreased the sol-gel transition temperature and shortened the sol-gel transition time of the PPP hydrogel. Moreover, the incorporation of EGCG could significantly increase the tissue adhesion properties of the PPP hydrogel at 37 °C. PPP&#95;2%E displayed a suitable gelation temperature (36.2 °C), gelation time (100 s) and storage modulus (48 Pa). Tripeptide KPV as a model drug was easily dissolved in cold PPP&#95;2%E precursor solution to prepare KPV@PPP&#95;2%E hydrogel. The anti-inflammatory activity and promotion of cell migration potential by KPV in PPP-2% E hydrogel were well maintained. Moreover, KPV@PPP&#95;2%E exhibited strong antibacterial efficacy against S. aureus . PPP&#95;2%E precursor solution rapidly transformed to a hydrogel and adhered to the wound surface for 7 hours when administrated to the gingival mucosa of rats. Treatment with KPV@PPP&#95;2%E hydrogel greatly improved the food intake and body weight recovery of rats with chemotherapy-induced oral mucositis. Moreover, the tissue morphology of the ulcerated gingiva after application of KPV@PPP&#95;E hydrogel was also well repaired by promoting CK10 and PCNA expression. In addition, the inflammatory cytokines including IL-1β and TNF-α were significantly inhibited by KPV@PPP&#95;2%E hydrogel while IL-10 was up-regulated. KPV@PPP&#95;2%E hydrogel also had an anti-bacterial effect on MRSA-infected gingival ulcer wounds, which resulted in the obvious inhibition of infiltration by inflammatory cells into submucosal tissues. Conclusively, KPV@PPP&#95;E may be a promising practical application for cancer patients with chemotherapy-induced oral mucositis.

Background: Irritant contact stomatitis (ICS) and contact hypersensitivity stomatitis (CHS) are often caused by alcohol, flavoring agents and additives in dentifrices and foods, and contactants with high or low pH. A well-recognized contactant for ICS is Listerine™ mouthwash, while that for CHS is cinnamic aldehyde. However, many other flavoring agents and even smokeless tobacco are contactants that cause mucosal lesions that are entirely reversible. The objective of this study is to 1) present cases of ICS and CHS with a clear history of a contactant at the site and the histopathologic features of the resulting lesion and 2) define the histopathologic features that characterize such lesions., Methods: 12 cases of ICS and CHS with known contactants that exhibited distinct histopathologic patterns were identified., Results: ICS are characterized by three patterns in increasing order of severity namely: 1) superficial desquamation, 2) superficial keratinocyte edema, and 3) keratinocyte coagulative necrosis with/out spongiosis and microabscesses. CHS is characterized by two patterns namely plasma cell stomatitis with an intense plasma cell infiltrate and a lymphohistiocytic infiltrate with or without non-necrotizing granulomatous inflammation. Three patterns of the latter are recognized: (1) lymphohistiocytic infiltrate at the interface with well-formed or loosely aggregated non-necrotizing granulomas; (2) lymphohistiocytic infiltrate at the interface with peri- and para-vascular lymphohistiocytic nodules; and (3) lymphohistiocytic infiltrate at the interface with peri- and para-vascular lymphohistiocytic nodules containing non-necrotizing granulomas. The same contactant may elicit ICS and CHS, while one histopathologic pattern may be brought on by various contactants., Conclusion: ICS and CHS have distinct histologic patterns. Recognizing that these patterns are caused by contactants would help clinicians manage such mucosal lesions., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Medications used in the treatment of inflammatory bowel disease cause a wide range of dermatologic side effects, and minimal guidance exists on how to manage them. The intention of this review article is to summarize common dermatologic adverse reactions related to inflammatory bowel disease therapy and to provide evidence-based guidance on management. We conducted a scoping review using PubMed and Google Scholar to identify studies reporting clinical information on dermatologic side effects of medications used in the treatment of inflammatory bowel disease. The most commonly reported dermatological adverse effects from inflammatory bowel disease therapy were cutaneous malignancy and cutaneous infections. Thiopurines, methotrexate, tumor necrosis factor (TNF) inhibitors, interleukin (IL)-12/23 inhibitors, and integrin inhibitors can be continued if nonmelanoma skin cancer arises during therapy and the malignancy should be surgically excised. TNF inhibitors and IL-12/23 inhibitors can be continued in the setting of stage I surgically resectable melanoma but should be discontinued in advanced melanoma. For complicated cutaneous bacterial infections, methotrexate and TNF inhibitors should be halted, and IV antibiotics should be administered. Complicated herpes zoster infection warrants discontinuation of TNF inhibitors, whereas IL-12/23 and JAK inhibitors can be continued. Inflammatory bowel disease therapies are associated with several dermatological adverse effects, and management options vary by agent. Certain agents may require discontinuation in the setting of nonmelanoma skin cancer, melanoma, and cutaneous infections. Many other dermatological adverse effects from inflammatory bowel disease therapy require specialized management or referral to dermatology., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Introduction: The aim of this prospective phase II study was to evaluate the efficacy and safety of biweekly docetaxel plus androgen-deprivation therapy (ADT) in patients with metastatic castration-naïve prostate cancer (mCNPC)., Patients and Methods: Patients with histologically-proven, previously-untreated mCNPC received ADT plus docetaxel, 40 mg/m 2 . Docetaxel was repeated every 2 weeks, up to 12 cycles. Endpoints included castration-resistant prostate cancer (CRPC)-free survival, prostate-specific antigen (PSA) response, and safety., Results: A total of 42 patients were registered and analyzed for final outcomes. Of the 42 patients, 36 (86%) completed the 12 planned cycles of docetaxel plus ADT. During a median follow up of 25 months, all but two patients (95%) achieved a PSA response with a nadir PSA level of 0.42 ng/ml (range 0.01-1280.87). The median CRPC-free survival was 26.4 months (95% confidence interval [CI] 20.9-32.0) with a one-year CRPC-free rate of 79% (33 patients, 95% CI 66-91). Multivariable analysis revealed that the performance status of the Eastern Cooperative Oncology Group 0 was independently associated with longer CRPC-free survival (hazard ratio [HR] 0.27, 95% CI 0.07-0.99). The most common adverse events of any grade were anemia (95%), followed by nail changes (33%), fatigue (29%), and oral mucositis (26%). Severe (grade 3 or higher) adverse events were infrequent: pneumonitis (n = 2), diarrhea (n = 1), and neutropenia (n = 1)., Conclusion: Our results suggest that biweekly docetaxel plus ADT is feasible, and clinical efficacy does not seem to be compromised compared to a standard triweekly docetaxel 75 mg/m 2 plus ADT regimen., (© 2021. The Author(s).)

Cancer is a prevalent disease worldwide, and treatments such as radiotherapy and chemotherapy sometimes lead to adverse events. Oral mucositis is one of the most disabling adverse events, and clinical guidelines do not take into account nutritional interventions. The primary endpoint was to gather the evidence about the efficacy of nutritional interventions in the prevention and/or treatment of antineoplastic-induced oral mucositis in oncological patients. A bibliographic review was carried out in the PubMed data base by combining MeSH terms with Boolean operators. Articles were selected based on inclusion and exclusion criteria; 50 final articles were found. Although further evidence is needed, glutamine, honey, and vitamins appear to be good therapeutic options. The rest of the compounds presented controversial or insufficient results, making it difficult to draw conclusions over their utilization as prevention or treatment options. Little evidence is reported about oral mucositis nutritional interventions in spite of them being attainable and affordable compounds. Scarce evidence is shown in paediatric patients compared with adults. Developing higher quality studies and combinations with the compounds researched is necessary for creating a stronger body of evidence.

Purpose: To investigate the incidence and risk factors for oral mucositis (OM) in patients with childhood cancer undergoing chemotherapy., Methods: Eight hundred and twenty-nine cycles of chemotherapy were evaluated in 112 patients with childhood cancer undergoing chemotherapy. Chemotherapy protocol, hematological, hepatic, and renal function parameters were collected and compared to presence and severity of OM, as graded by the World Health Organization (WHO) scale. Patients received counseling on oral hygiene and those who presented with OM (grade ≥1) received photobiomodulation therapy (PBMT)., Results: Age ranged from 0 to 17 years (mean/SD, 8.58 ± 5.05) and fifty-one patients (45.54%) were females. The most common baseline diseases were leukemia (51%) followed by sarcomas (23%) and lymphomas (18%). Eight hundred and twenty-nine cycles of chemotherapy were evaluated, and OM was diagnosed in 527 cycles (63.57%). Higher incidence and severity of OM was observed in protocols using high-dose methotrexate (MTX-HD), MTX-HD cyclophosphamide/doxorubicin combination, and MTX-HD combined with cyclophosphamide (p <0.001). Patients with severe OM had lower levels of leukocytes (p = 0.003), hemoglobin (p = 0.005), platelets (p = 0.034), and higher levels of total bilirubin (p = 0.027), alanine aminotransferase (ALT) (p = 0.001), and creatinine (p = 0.007)., Conclusion: The study contributes to the elucidation of the risk factors for OM in pediatric cancer patients. Chemotherapy protocols using MTX-HD, MTX-HD associated with doxorubicin and cyclophosphamide, and MTX-HD and cyclophosphamide a have higher incidence of severe grades of OM. Other toxicities such as hematological, hepatic, and renal also developed in patients with OM., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The study was conducted to develop a valid and reliable measurement tool for determining the comfort perceptions of patients with oral mucositis., Method: The study was carried out methodologically between April 2017 and October 2019 in outpatient chemotherapy centers and clinics in which malignant patients were treated in a university hospital and educational-research hospital in Erzurum, Turkey of the study sample comprised 380 patients who developed oral mucositis after treatment. A 'Patient Identification Information Form,' draft 'Comfort Perception Scale in Oral Mucositis' and 'General Comfort Scale' were used to collect the study data. Validity and reliability analyses were used when evaluating the data. Percentage, mean, independent groups t-test, Mann-Whitney U test, Kruskal-Wallis test, variance analysis and advanced analyzes were also used., Results: In this study, while the face validity of the scale was obtained, the content validity index was found to be 0.62 Kaiser-Meyer-Olkin value of the scale for explanatory factor analysis was 0.94, and Bartlett's test x2 = 9142.156 (P < 0.05). For the confirmatory factor analysis, the corrected chi-square value was 3.54, the root-mean-square error was 0.082, and the scale structure was confirmed according to these results. As a result, the scale consisted of 31 items and 2 sub-scales. Item-total correlation values ranged from 0.83 to 0.33. As a result of similar scale validity, a significant negative correlation was found between the Comfort Perception Scale in Oral Mucositis and General Comfort Scale scores (P < 0.05)., Conclusion: The Comfort Perception Scale in Oral Mucositis is a reliable and valid scale. In this study, it was determined that patient comfort was affected according to some variables., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Purpose: This systematic review aimed to identify effective medicinal plants for the treatment of mucositis induced by oncotherapy., Methods: The clinical question was the following: "Which medicinal plants are effective in the treatment of oral mucositis induced by cancer treatment?" (PubMed, Medline, Web of Science, Scopus, Lilacs, and SciELO). The keywords were the following: phytotherapy OR "herbal drug" OR "plant extract" OR plant OR "medicinal plant" OR pharmacognosy OR ethnobotany OR ethnomedicine OR ethnopharmacology OR "flower essences" OR "natural product" AND mucositis OR mucositides OR stomatitis OR stomatitides OR "oral ulcer" AND chemotherapy OR radiotherapy OR immunotherapy OR cancer OR neoplasm OR neoplasm OR tumor OR tumor. The inclusion criteria for the selection of articles were the type of study design (clinical trials) and the studied population (cancer patients presenting lesions of oral mucositis having undergone treatment with medicinal plants)., Results: After evaluation of the works, 24 of 893 articles were selected. Matricaria chamomilla (chamomilla) presented promising results, such as a reduction in severity and lesion incidence with improved pain symptomatology. The plant extracts Isatis indigótica, Olea europaea, Calendula officinalis, A. digitatae, and M. sylvestris improved the lesions. Mucotrol™ and QRLYD herbal products improved the degree of severity of the lesions, while SAMITAL® and MUCOSYTE allowed for greater pain control., Conclusion: The complementary treatment of oral mucositis in cancer patients, with analgesic and anti-inflammatory actions with lower side effects, is an alternative for healthcare professionals., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Nattokinase (NK) is a promising alternative in the prevention and treatment of cardiovascular diseases due to its potent fibrinolytic activity. In this study, we investigated the effect of crude nattokinase extract on the healing of acetic acid-induced oral mucositis in mice., Methods: Bacillus subtilis culture media (BSCM) was isolated into the supernatant, named nattokinase crude extract (NCE), and the pellet was named Bacillus subtilis mass (BSM). An oral mucositis model was established in mice by applying 50% glacial acetic acid to the buccal mucosa. According to the treatment conditions, the mice were divided into BSCM, NCE, BSM and phosphate buffered saline (PBS) groups. The weight of the mice, oral mucositis healing score and histopathological examination were used to evaluate the treatment., Results: Fibrinolytic activities of BSCM, NCE and BSM were approximately 8069, 10,800 and 80 U/ml, respectively. The weight gain of mice in the NCE group was significantly different from the PBS group after three days' treatment (p < 0.05). The oral mucositis score of NCE group was significantly higher than other groups (p < 0.05). The differences in histopathology scores between the NCE and other groups were statistically significant (p < 0.01)., Conclusions: NCE could possess remarkable potential to reduce pain and promote oral mucositis healing with minimal safety concerns. In this study, we first report that NCE from the supernatant of Bacillus subtilis can promote the healing of oral mucositis, which extends the application scope of NK., (© 2021. The Author(s).)

Background: In phase I studies, poziotinib has shown meaningful efficacy against various types of cancers. This phase 2 study aimed to investigate the efficacy and safety of poziotinib in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M-HNSCC)., Methods: Overall, 49 patients were enrolled (median age, 62 years; age range, 21-78 years). Patients received a median of two prior treatments including chemotherapy and others and received 12 mg poziotinib orally once daily as part of a 28-day cycle. The primary endpoint was objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Targeted capture sequencing was performed using available tissues to identify translational biomarkers related to clinical response., Results: ORR was 22.4%, median PFS was 4.0 months (95% confidence interval [CI], 1.8-6.2 months), and median OS was 7.6 months (95% CI, 4.4-10.8 months). The most common treatment-related adverse events were acneiform rash (85%) and mucositis (77%). A grade 3 or higher adverse event was acneiform rash (3%). Targeted capture sequencing was performed in 30 tissue samples. TP53 and PIK3CA were the most frequently mutated genes (43%), followed by CCND1 (33%) and EGFR (30%). Mutations in ERBB2, ERBB3, and ERBB4, which are HER family genes, were observed in 17%, 13%, and 10% samples, respectively. There was no difference in the frequency of somatic mutations in the HER family genes between the clinically benefitted and non-benefitted groups., Conclusion: Compared to other pan-HER inhibitors, poziotinib showed clinically meaningful efficacy in heavily treated R/M-HNSCC., Clinical Trial Registration Number: NCT02216916., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Treatment options are sparse for patients with advanced cholangiocarcinoma after progression on first-line gemcitabine-based therapy. FGFR2 fusions or rearrangements occur in 10-16% of patients with intrahepatic cholangiocarcinoma. Infigratinib is a selective, ATP-competitive inhibitor of fibroblast growth factor receptors. We aimed to evaluate the antitumour activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma, FGFR2 alterations, and previous gemcitabine-based treatment., Methods: This multicentre, open-label, single-arm, phase 2 study recruited patients from 18 academic centres and hospitals in the USA, Belgium, Spain, Germany, Singapore, Taiwan, and Thailand. Eligible participants were aged 18 years or older, had histologically or cytologically confirmed, locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements, and were previously treated with at least one gemcitabine-containing regimen. Patients received 125 mg of oral infigratinib once daily for 21 days of 28-day cycles until disease progression, intolerance, withdrawal of consent, or death. Radiological tumour evaluation was done at baseline and every 8 weeks until disease progression via CT or MRI of the chest, abdomen, and pelvis. The primary endpoint was objective response rate, defined as the proportion of patients with a best overall response of a confirmed complete or partial response, as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors, version 1.1. The primary outcome and safety were analysed in the full analysis set, which comprised all patients who received at least one dose of infigratinib. This trial is registered with ClinicalTrials.gov, NCT02150967, and is ongoing., Findings: Between June 23, 2014, and March 31, 2020, 122 patients were enrolled into our study, of whom 108 with FGFR2 fusions or rearrangements received at least one dose of infigratinib and comprised the full analysis set. After a median follow-up of 10·6 months (IQR 6·2-15·6), the BICR-assessed objective response rate was 23·1% (95% CI 15·6-32·2; 25 of 108 patients), with one confirmed complete response in a patient who only had non-target lesions identified at baseline and 24 partial responses. The most common treatment-emergent adverse events of any grade were hyperphosphataemia (n=83), stomatitis (n=59), fatigue (n=43), and alopecia (n=41). The most common ocular toxicity was dry eyes (n=37). Central serous retinopathy-like and retinal pigment epithelial detachment-like events occurred in 18 (17%) patients, of which ten (9%) were grade 1, seven (6%) were grade 2, and one (1%) was grade 3. There were no treatment-related deaths., Interpretation: Infigratinib has promising clinical activity and a manageable adverse event profile in previously treated patients with locally advanced or metastatic cholangiocarcinoma harbouring FGFR2 gene fusions or rearrangements, and so represents a potential new therapeutic option in this setting., Funding: QED Therapeutics and Novartis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Oral mucositis is a painful condition that occurs in patients who undergo chemotherapy. Due to the worsening of oral mucositis, the patient may progress to a worse clinical condition and interrupt antineoplastic treatment. There is little literature on low-power laser therapy in chemotherapy for other solid tumors. The purpose of this study was to investigate whether low-level laser therapy (LLLT) applied before chemotherapy could prevent oral mucositis in patients with solid tumors., Methods: Laser therapy was applied at a frequency of 630nm, with a dose of 2J / cm2, for the prevention of oral mucositis induced by chemotherapy specifically for non-hematological tumors. Epidemiological data, total neutrophils, general side effects, development of oral mucositis and degree, and the performance of low-power laser therapy to prevent oral mucositis were collected. The involvement of oxidative stress was evaluated by the enzyme superoxide dismutase (SOD) through blood samples, before and after chemotherapy treatments., Results: LLLT in the proposed protocol is efficient in reducing the development of oral mucositis (only at grade I/II) in patients under chemotherapy and able to reduce the severity of oral mucosal lesions, in patients who developed mucositis after the use of the laser for prevention. All individuals who underwent LLLT protocol did not show a significant reduction of SOD activity after the last chemotherapy cycle., Conclusions: The prophylactic laser therapy protocol proposed by the study, defined at a frequency of 630nm, a dose of 2J / cm2, demonstrated the ability to decrease the occurrence of oral mucositis in patients undergoing chemotherapy protocols to solid tumors. This effect could be related to preserved SOD activity, as it was observed that oral mucositis is related to leukopenia and reduced SOD activity and LLLT protocol prevented the decrease of SOD activity.

Background: Oral mucositis is a common chemotherapy-related adverse event that may result in serious complications. Few studies have evaluated mucositis in pediatric patients., Objective: To evaluate the impact of severe mucositis on resource utilization and on treatment plans of pediatric cancer patients., Setting: Comprehensive cancer center in Amman, Jordan., Method: Retrospective study on pediatric patients undergoing active cancer treatment with a hospital admission diagnosis of severe oral mucositis (January 2015-December 2019). Patients undergoing bone marrow transplant were excluded. Severe oral mucositis was defined as interfering with oral intake and requiring intravenous opioids., Main Outcome Measure: We reviewed the electronic billing system and patient medical charts to determine the resources utilized during hospitalization, cost, and the impact on subsequent treatment protocols., Results: During the study period, 200 patients were eligible; the average age was 8.6±5.6 years (SD) and 45% had acute lymphoblastic leukemia. The median hospital stay was 6 days (range 2-21) with a total median cost of US$ 2,176 (range 635-13,976) per admission. The median medication cost was US$ 1,075 (range 135-9010), and 85% of the patients received antibiotics during hospitalization, at a median cost of US$ 487 (range 23-2,193). Modification of the chemotherapy treatment protocol was required in 110 patients, which included dose reduction (60%), delay (38%), and discontinuation (2%)., Conclusion: Severe oral mucositis is associated with significant resource utilization and modification of the treatment protocols. Further studies are needed to identify strategies to reduce the impact of mucositis in this patient population., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: To discuss the role of benzydamine in the prevention and treatment of radiation-induced oral mucositis (OM) in head and neck (H&N) cancer patients. This document represents an expert opinion paper on indications and key-role aspects in OM pathogenesis, prevention and treatment., Oral Mucositis: OM represents a common side effect of chemotherapy (CHT) and radiotherapy (RT). It consists in a painful erythema involving the oral cavity mucosa, which may progress to ulceration. Five biologically dynamic phases are considered crucial in mucositis: "initiation, signalling, amplification, ulceration and healing". Oral environment and microbiota are fundamental in mucositis development being involved in susceptibility to infections and in ulceration consequences. Different agents against mucositis have been studied and the use of benzydamine is strongly supported in literature. The Multinational Association of Supportive Care in Cancer and International Society for Oral Oncology (MASCC/ISOO) guidelines recommend its use for the prevention of OM in H&N patients undergoing RT and RT/CHT., Benzydamine: Benzydamine is a local anti-inflammatory drug with analgesic properties. It can decrease TNF-α, IL-1β and prostaglandin synthesis, also inhibiting leukocyte-endothelial interactions, neutrophil degranulation, vasodilation and vascular permeability. Literature agrees on the beneficial effects of benzydamine in preventing and reducing oral mucositis severity in H&N cancer patients undergoing RT/CHT., Conclusions: Mucositis represents a major concern in H&N cancer patients and a clinical and economical issue. A multimodal and multidisciplinary approach is needed for its management. International guidelines recommend benzydamine for OM prevention and treatment in H&N cancer patients, but further "real world" trials should be designed., (© 2021. The Author(s).)

Background: Oral mucositis is the most debilitating and troublesome adverse effect of irinotecan (CPT-11) treatment. It adversely affects the patient quality of life. The aim of this work was to study the histological, immunohistochemical, and molecular changes in the oral mucosa by CPT-11 and the possible alleviated role of atorvastatin., Methods: Rats were randomly divided into control, CPT-11-treated group, and CPT-11+ atorvastatin-treated group. At the end of the experiment, the anterior two-thirds of the tongue was dissected out and divided into two parts: one part for light microscopic examination and the second for molecular study., Results: CPT-11-treated group revealed loss of normal mucosal organization, areas of ulceration and inflammation, and loss of architecture of lingual papillae. A significant decrease in immunohistochemical and molecular gene expression of Ki-67 and antiapoptotic Bcl-2 levels was observed. A significant increase in NF- κ B immunohistochemical and mRNA gene expression level and a nonsignificant increase in Nrf2 gene expression were detected. Coadministration of atorvastatin showed remarkable improvement in the histopathological picture with a significant increase in Ki-67 and Bcl-2, a significant decrease in NF- κ B protein and gene expression, and a significant increase in Nrf2 gene expression., Conclusion: Atorvastatin substantially attenuates CPT-11-induced oral mucositis through the initiation of the antiapoptotic gene, modulation of the inflammatory, and antioxidant gene expression., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Eetmad A. Arafat et al.)

Oral mucositis is an inflammation of the oral mucosa mainly resulting from the cytotoxic effect of 5-fluorouracil (5-FU). The literature shows anti-inflammatory action of L-cysteine (L-cys) involving hydrogen sulfide (H 2 S). In view of these properties, we investigate the effect of L-cys in oral mucositis induced by 5-FU in hamsters. The animals were divided into the following groups: saline 0.9%, mechanical trauma, 5-FU 60-40 mg/kg, L-cys 10/40 mg and NaHS 27 µg/kg. 5-FU was administered on days 1st to 2nd; 4th day excoriations were made on the mucosa; 5th-6th received L-cys and NaHS. For data analysis, histological analyses, mast cell count, inflammatory and antioxidants markers, and immunohistochemistry (cyclooxygenase-2(COX-2)/inducible nitric oxide synthase (iNOs)/H 2 S) were performed. Results showed that L-cys decreased levels of inflammatory markers, mast cells, levels of COX-2, iNOS and increased levels of antioxidants markers and H 2 S when compared to the group 5-FU (p < 0.005). It is suggested that L-cys increases the H 2 S production with anti-inflammatory action in the 5-FU lesion., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background/aim: In order to produce an animal model for oral mucositis induced by anticancer drugs, it is necessary to maintain an immunosuppressive state. We determined the optimal dose and frequency of 5-fluorouracil for a model mouse production. In addition, we used this model to investigate the effect of GGsTop ® gelation on the therapeutic effect of oral mucositis., Materials and Methods: Changes in body weight and white blood cell count were measured to determine the optimal dosing schedule. The therapeutic effect of GGsTop ® gel using chitosan was evaluated by observing changes in the ulcer area for three weeks and measuring collagen and glutathione concentrations in oral mucosal tissue., Results: The optimal dose and frequency of 5-fluorouracil were found to be 50 mg/kg every four days. It was revealed that the therapeutic effect of GGsTop ® was enhanced by gelation., Conclusion: GGsTop ® gel is suggested to be a promising formulation for the treatment of oral mucositis., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)