Research progress and comparison of the establishment of animal models of radiotherapy or chemotherapy-induced oral mucositis

The mechanism of radiotherapy or chemotherapy-induced oral mucositis is not yet clear.And model establishment is needed in further study.In order to summarize the methods of model establishment and make a comparison,literature databases including Web of Science、Pubmed and CNKI were searched for related researches from January 2015 to January 2021.Hamsters,mice,rats,guinea pigs and miniature pigs were chosen to be modeling animals and modeling methods could be classified into:chemotherapy,chemotherapy combined with superficial mucosal irritation,radiotherapy,radiotherapy combined with superficial mucosal irritation and chemoradiotherapy.Advantages and disadvantages had been analyzed in this study to provide reference for following studies.

Glycine supplementation reduces the severity of chemotherapy-induced oral mucositis in hamsters

Objective: Oral mucositis (OM) is a devastating toxicity associated with cytotoxic cancer therapy. The OM pathogenesis and the complex interactions occur in response to tissue insult. Application of this evolving model has aided in the development of mechanistically based therapies for the prevention and treatment of mucositis. The present study was to assess the effects of glycine supplementation on chemotherapy-induced oral mucositis. Methods: In a hamster cheek pouch model of chemotherapy-induced oral mucositis, one group of 20 animals received systemic glycine supplementation for 7 days, while another similar control group did not. Clinical mucositis severity and neutrophil infiltrate (on histology) were assessed by blinded examiners. Free radical production was measured as malondialdehyde (MDA) levels. Results: As compared to control animals, glycine-treated animals demonstrated a highly significant reduction in clinical severity of oral mucositis, neutrophil infiltrate, and MDA levels (p < 0.001 for all). Conclusions: Glycine supplementation reduces the severity of chemotherapy-induced oral mucositis in an animal model. This effect is at least partly mediated through inhibition of the inflammatory response and reduced production of damaging free radicals.

A Review of Radiation-Induced Oral Mucositis in Traditional Chinese and Western Medicine Research

Radiation therapy is one of the main treatments for head and neck tumors,and radiationinduced oral mucositis(RIOM)is a common serious adverse effect of radiation therapy.We summarized the pathogenesis,prevention and treatment methods of RIOM related to traditional Chinese and Western medicine in recent years.The treatment of RIOM in traditional Chinese medicine should be based on clearing heat and detoxifying,nourishing Yin and promoting fluid,tonifying spleen and stomach,cooling blood and removing blood stasis.Osteopontin,immunoglobulin A and saliva flow tests may be effective clinical indicators in the future.Through analysis,the author believes that the use of integrated intervention of traditional Chinese and western medicine can better benefit patients,and the prevention and predictive diagnostic tools of RIOM should become the future focus of attention.

Effects of Kangfuxin Solution (康复新液) Combined with Low-level Laser on Cytokines and Immune Function in Patients with Radiation-induced Oral Mucositis

Objective:To investigate the effect of Kangfuxin Solution(康复新液)combined with low-level laser therapy(LLLT)on cytokines and immune function in patients with radiation-induced oral mucositis.Methods:There were 84 nasopharyngeal carcinoma patients with oral mucositis after intensity-modulated radiation therapy(IMRT)were randomly divided into the control group(CG)and the observation group(OG),with 42 cases in each group.The CG was given LLLT,and the OG was treated with Kangfuxin Solution in addition to LLLT for 10 consecutive days.The healing time of oral mucosa,mucositis grading,oral pain scores,cytokines(interleukin-6,interleukin-1βand tumor necrosis factor-α)and T lymphocyte subsets were compared between the 2 groups before and after treatment.Results:The healing time of oral mucosa in the OG was(6.8±1.4)d,which was significantly shorter than(8.6±1.9)d in the CG(t=4.943,P<0.01).After treatment,the grading of oral mucositis in the OG was better than that in the CG,with a statistically significant difference(Z=2.942,P<0.05).The oral pain scores of the OG was lower than that in the CG at different time points after treatment,and the difference was statistically significant(t=8.207,11.017,P<0.01).After treatment,the levels of IL-6,IL-1βand TNF-αin peripheral blood of the OG were significantly lower than those in the CG(t=5.217,2.775,4.053,P<0.01).There were statistically significant differences in CD4+,CD8+and CD4+/CD8+between the OG and the CG after treatment(t=5.692,6.093,3.658,P<0.01).Conclusion:Kangfuxin Solution combined with LLLT can significantly shorten the healing time of oral mucosal,reduce the grading of oral mucositis,relieve oral pain,reduce inflammatory response and improve the immune function of patients.

Clinical effectiveness of palifermin in prevention and treatment of oral mucositis in children with acute lymphoblastic leukaemia: a case–control study

The aim of this study was to evaluate the efficacy of palifermin, an N-terminal truncated version of endogenous keratinocyte growth factor, in the control of oral mucositis during antiblastic therapy. Twenty patients undergoing allogeneic stem-cell transplantation for acute lymphoblastic leukaemia were treated with palifermin, and compared to a control group with the same number of subjects and similar inclusion criteria. Statistical analysis were performed to compare the outcomes in the treatment vs. control groups. In the treatment group, we found a statistically significant reduction in the duration of parenteral nutrition （P=0.002）, duration of mucositis （P= 0.003） and the average grade of mucositis （P= 0.03）. The statistical analysis showed that the drug was able to decrease the severity of mucositis. These data, although preliminary, suggest that palifermin could be a valid therapeutic adjuvant to improve the quality of life of patients suffering： from leukaemia.

Effects of Yangyin Jiedu Decoction on Acute Oral Mucositis Caused by Radiation

[Objectives] The aim was to observe the clinical effect of Yangyin Jiedu Decoction for acute oral mucositis caused by radiotherapy for nasopharyngeal carcinoma( NPC). [Methods]Total 64 patients with non-keratinizing squamous cell carcinoma of nasopharynx were divided evenly and randomly into two groups,treatment group and control group. In the treatment group,the patients began to take Yangyin Jiedu Decoction one week before radiotherapy; while in the control group,the patients were treated with mixed solution of dexamethasone,lidocaine,recombinant human granulocyte colony stimulating factor and vitamin B12. From the beginning to the end of radiotherapy,the curative effect in the two groups was observed and compared. In addition,the levels of serum CRP,TGF-β1 and IL-6 were measured to detect the inflammatory response. [Results] The incidence of acute oral mucositis in the treatment group was significantly lower than that in the control group( P <0. 05). The effective rate was 96. 88% in the treatment group and 67. 74% in the control group. The levels of serum CRP,TGF-β1 and IL-6 in the treatment group were also lower than those in the control group. [Conclusions]Yangyin Jiedu Decoction has a good effect on prevention and treatment of acute radioactive oral mucositis and it is worthy of clinical application.

A Retrospective Match Controlled Study of Supersaturated Calcium Phosphate Oral Rinse vs. Supportive Care for Radiation Induced Oral Mucositis

Oral mucositis is a common morbidity induced by radiation therapy and chemo-radiotherapy for head and neck malignancies. This often results in treatment delays, premature treatment cessation and increased cost. New treatments of oral mucositis are emerging but effective remedies remain limited. Between February 2007 and May 2008, 21 patients with head and neck malignancies were treated with a supersaturated calcium phosphate oral rinse (Caphosol) that was performed for 4-10 times daily, each consisting of two one-minute rinses. There were 21 matched patients who received supportive care without the oral rinse. All patients in the two groups were treated with intensity modulated radiation therapy (IMRT) for average prescription doses of 66 Gy in 33 fractions. The effects of this rinse vs. supportive care on mucositis, PEG tube requirements, hospitalization, xerostomia, analgesic requirements and weight was respectively evaluated. We have observed statistically significant decreases in the incidence of radiation induced oral mucositis (p=0.0002) with WHO grade 3 (38% vs. 52%) and 4 mucositis (0% vs. 19%), need for PEG tube placement (33% vs. 57%) and hospitalization (0% vs 19%). There was also a favorable impact on the incidence of grade 3 (29% vs. 43%) xerostomia in the treated patients but it was statistically insignificant (p=0.58). Incremental costs related to treatment of oral mucositis were reduced considerably. Our data suggest that use of a supersaturated calcium phosphate oral rinse is an effective treatment for mucositis in patients undergoing IMRT. It may also be helpful in the reduction of hospitalization and PEG tube requirements.

Development of Oral Dissolving Gelatin Beads Containing Allopurinol for the Prevention and Treatment of Mucositis

Oral dissolving gelatin beads (GBs) containing allopurinol (AP) were prepared by the seamless capsule method and their rheological properties were examined. The release profiles of both gelatin and AP from GBs were also investigated in limited dissolution medium. GBs containing AP provided an easy-to-handle dosage form, but the physical strength of the beads immediately decreased upon contact with physiological saline at 37℃. Gelatin was released from the outer layer of GBs in physiological saline, with almost all the gelatin dissolved after 5 min, together with approximately 30% of the AP contained in the inner layer of the GB. The oral administration of GBs likely results in immediate softening of the GB upon contact with saliva. The released AP acts directly at inflammation sites, in a manner similar following oral rinsing with an AP suspension. Therefore, GBs are a useful dosage form for preventing or treating localized problems in the oral cavity, such as mucositis.

Clinical relevance of the use of Dentoxol® for oral mucositis induced by radiotherapy: A phase II clinical trial

BACKGROUND Severe oral mucositis associated with cancer therapy is a frequent complication that may affect a patient's systemic condition,resulting in interruption and/or prolongation of cancer therapy.Dentoxol®is a medical solution in the form of a mouthwash that has been shown to result in statistically significant improvement in the prevention of severe oral mucositis.However,knowing the measures of the clinical significance of this therapy is important for accurate decision-making.To describe the clinical impact of Dentoxol®use in severe oral mucositis.METHODS Clinical significance was measured using the results obtained in a randomized controlled clinical trial previously conducted by the same group of researchers.The measures of clinical significance evaluated were the absolute risk or incidence,relative risk,absolute risk reduction,relative risk reduction,number needed to treat,and odds ratio.RESULTS The data obtained show that the impact of Dentoxol®on reducing the severity of oral mucositis has important clinical relevance.CONCLUSION The results of this study justify the incorporation of Dentoxol®mouth rinse into clinical protocols as a complement to cancer therapy to prevent and/or treat oral mucositis secondary to radiotherapy.

Application of the theory of“conducting fire back to its origin”in treating radiotherapy or chemotherapy induced oral mucositis

Oral mucositis is a common adverse reaction of radiotherapy and chemotherapy in cancer patients,which reduces the quality of life of patients and affects the progress of cancer treatment.Most of the patients with malignant tumor belong to the syndrome of deficiency in root case and excess in manifestation.When undergoing radiotherapy or chemotherapy,the patients’ministerial fire becomes hyperactive,which may cause oral mucositis.With the method of“conducting fire back to its origin”,ministerial fire can be led to vital gate,as well as recovering its physiological functions.In the treatment of oral mucositis,instead of attacking ministerial fire with too much heat-clearing herbs,we should,under the guidance of the theory of“conducting fire back to its origin”,differentiate the syndrome,and then we can use the methods of treatment of clearing and lowering heart fire,warmly invigorating spleen and stomach,nourishing liver and kidney,or warmly invigorating vital gate,to conduct ministerial fire back to vital gate.This article aims to provide theoretical reference for Traditional Chinese Medicine treatment of radiotherapy or chemotherapy induced oral mucositis.

Observation on Efficacy of Lanzhou Formula (兰州方) with Bingpeng Powder (冰硼散) Mouthwash in Preventing and Treating Radiation-induced Oral Mucositis

Objective:To observe clinical efficacy of Lanzhou Formula(兰州方)with Bingpeng Powder(冰硼散)mouthwash in preventing and treating radiation-induced oral mucositis.Methods:A total of 200 patients with malignant tumors in the head and neck who received radiotherapy in our hospital from April 2018 to April 2020 were selected as research objects,and they were randomly divided into the study group and control group.The control group was given radiotherapy combined with mouthwash,which consisted of 500 mL of normal saline,125 mg of vitamin B12,400000 U of gentamicin and 1 g of lidocaine.The study group was given radiotherapy combined with Lanzhou Formula with Bingpeng Powder mouthwash.Incidences of radiation-induced oral mucositis,chewing and swallowing functions,and Karnofsky(KPS)scores were compared between the 2 groups.Results:At the end of the radiotherapy,there was no Grade 4 radiation-induced oral mucositis in the 2 groups.Compared with the control group,the radiation-induced oral mucositis in the study group basically belonged to Grade 1 and Grade 2,with a lower incidence of Grade 3(P<0.05).At the end of the radiotherapy,the chewing and swallowing functions in the 2 groups were decreased,but patients with 2-point chewing and swallowing functions in the study group were more than those in the control group,and patients with the 3-point were less than those in the control group(P<0.05).At the end of the radiotherapy,the KPS scores were decreased,but those in the study group were higher than those in the control group(P<0.05).Conclusion:During radiotherapy for patients with malignant tumors in the head and neck,Lanzhou Formula with Bingpeng Powder mouthwash can decrease the severity of radiation-induced oral mucositis,protect chewing and swallowing functions of patients to a certain extent,and improve the general condition of patients.It is worthy of clinical application and promotion.

Novel oral-targeted therapies for mucosal healing in ulcerative colitis

Ulcerative colitis(UC), a chronic, relapsing, remitting disease of the colon and rectum, is characterized by inflammatory ulceration of the mucosa. Current UC therapy relies on controlling acute episodes and preventing relapse. To predict modifications in the natural course of UC, mucosal healing(MH) has emerged as a major treatment goal. Endoscopic evaluation is considered the gold standard for assessing MH, which can be achieved by conventional drugs and biologics in many, but not all, patients. Consequently, interest is focusing on the development of new substances for UC therapy, and new oral agents are in the pipeline. This review will focus on the ability of newly developed oral drugs to induce and maintain MH in UC patients.

Clinical and impression cytology findings of amniotic membrane and oral mucosal membrane transplantation for the management of socket contracture

AIM:To investigate and compare the cytopathological and clinical effects of amniotic membrane transplantation(AMT)and oral mucosal membrane transplantation(OMMT)in socket contraction.METHODS:Twelve patients who could not be fitted with ocular prosthesis due to socket contracture were included in this study.Seven patients underwent AMT and 5 patients underwent OMMT.Thirteen patients who had healthy sockets were included as control group.Depth of inferior fornix,degree of inflammation,extent of the socket contracture and socket volume were measured in the preoperative period and at sixth and twelfth weeks postoperatively.Impression cytology of conjunctival fornices and tear transforming growth factor beta-1(TGFβ1)levels were determined.RESULTS:In the AMT group,socket volume and lower fornix depth values were significantly higher(P=0.030and P=0.004 respectively)and inflammation levels and impression cytology stages(P=0.037 and P=0.022respectively)were significantly lower in postoperative period compared to preoperative period.In the OMMT group,no statistical differences were found in terms of clinical parameters,inflammation levels and impression cytology stages of preoperative versus postoperative values.Preoperative tear TGFβ1 levels were higher in AMT and OMMT groups compared to the control group(25.5 ng/mL,26.3 ng/mL and 21.7 ng/mL respectively).Decreased tear TGFβ1 levels were observed in both the AMT and OMMT groups postoperatively(median decrease value=2.1 ng/mL and 2.7 ng/mL respectively).CONCLUSION:AMT is associated with postoperative improvement in inferior fornix depth,socket volume,inflammation and impression cytology levels and may bea more proper alternative method than OMMT in the management of socket contracture.

Assessment of Nutritional Status of Clinical Patients by Determining Normal Range of Oral Mucosal Apoptosis and Proliferation Rate

The normal range of oral mucosal cell apoptosis and proliferation rate through a larger sample of non-malnourished crowd was investigated,and the nutritional status of clinical patients was assessed.Of 194 clinical patients selected according to 'NRS2002' guidance,there were 167 non-malnourished patients and 27 malnourished cases,respectively.Twelve patients with toxic reactions of grade III after postoperative chemotherapy (POC) were chosen.The oral mucosal epithelial apoptosis and proliferation rate were measured by using flow cytometry.The statistical significance was processed by using unpaired t-test.The results showed that there was no significant difference in gender,age and body weight between malnourished and non-malnourished groups.The normal range of oral mucosal epithelial apoptosis and the proliferation rate was (27.50±1.50)% and (15.12±1.68)% in non-malnourished patients,and that was (19.90±4.14)% and (6.66±5.83)% in the malnourished patients,respectively.It is concluded that the normal range of oral mucosa cell apoptosis and proliferation rate is achieved,which can not be influenced by gender,age,weight and other factors,and could be used as a sensitive and accurate index to assess the nutritional status of clinical patients.

The mucosal immune system in the oral cavity——an orchestra of T cell diversity

The mucosal immune system defends against a vast array of pathogens, yet it exhibits limited responses to commensal microorganisms under healthy conditions. The oral-pharyngeal cavity, the gateway for both the gastrointestinal and respiratory tracts, is composed of complex anatomical structures and is constantly challenged by antigens from air and food. The mucosal immune system of the oral-pharyngeal cavity must prevent pathogen entry while maintaining immune homeostasis, which is achieved via a range of mechanisms that are similar or different to those utilized by the gastrointestinal immune system. In this review, we summarize the features of the mucosal immune system,focusing on T cell subsets and their functions. We also discuss our current understanding of the oral-pharyngeal mucosal immune system.

Oral mucosal involvement in visceral leishmaniasis

Leishmaniasis affects both the visceral and cutaneous tissues in body.Oral Mucosal involvement in leishmaniasis is rare and is often overlooked.We present a case 17 vear old boy from the north east region of Bihar who has a hislorv of visceral leishmaniasis one year back,came to the department of oral surgery for treatment of persistent oral ulcers.Oral examination did not give any diagnostic information while systemic examination revealed enlarged spleen and low grade fever.Patient was screened for leishmaniasis by rK39 based immunochromatographic strip test which came to be positive.Biopsy of the ulcer as well as splenic and bone marrow aspirate confirmed the presence of leishmaniasis.Patient was administered Amphotericin B for 20 days following which significant clinical and haematological improvement followed.

Cyclodextrin/chitosan nanoparticles for oral ovalbumin delivery: Preparation, characterization and intestinal mucosal immunity in mice

A novel oral protein delivery system with enhanced intestinal penetration and improved antigen stability based on chitosan(CS) nanoparticles and antigen-cyclodextrin(CD) inclusion complex was prepared by a precipitation/coacervation method. Ovalbumin(OVA) as a model antigen was firstly encapsulated by cyclodextrin, either β-cyclodextrin( β-CD) or carboxymethyl-hydroxypropyl-β-cyclodextrin(CM-HP-β-CD) and formed OVA-CD inclusion complexes, which were then loaded to chitosan nanoparticles to form OVA loaded β-CD/CS or CM-HP-β-CD/CS nanoparticles with uniform particle size(836.3 and 779.2 nm, respectively) and improved OVA loading efficiency(27.6% and 20.4%, respectively). In vitro drug release studies mimicking oral delivery condition of OVA loaded CD/CS nanoparticles showed low initial releases at p H 1.2 for 2 h less than 3.0% and a delayed release which was below to 30% at p H 6.8 for further 72 h. More importantly, after oral administration of OVA loaded β-CD/CS nanoparticles to Balb/c mice, OVA-specific sIgA levels in jejunum of OVA loaded β-CD/CS nanoparticles were 3.6-fold and 1.9-fold higher than that of OVA solution and OVA loaded chitosan nanoparticles, respectively. In vivo evaluation results showed that OVA loaded CD/CS nanoparticles could enhance its efficacy for inducing intestinal mucosal immune response. In conclusion, our data suggested that CD/CS nanoparticles could serve as a promising antigen-delivery system for oral vaccination.

TLR5 involvement in attenuated IL-8 production in nuclear decorin silenced oral mucosal dysplastic keratinocytes and squamous cell carcinoma

Head and neck cancer is one of the most prevalent cancers in the world. Roughly half of these malignancies originate from oral mucosa and constitute Oral squamous cell carcinomas. Despite many advances in diagnostic and therapeutic regimens, five year survival rate remains at roughly 50 %, indicating the need for in depth understanding of the oral squamous cell carcinoma immunobiology. We have previously shown that in human dysplastic oral keratinocytes (DOK) and malignant squamous cells carcinoma (SCC-25), multifunctional proteoglycan decorin is aberrantly expressed and localized in the nucleus bound to nuclear EGFR. In vitro nuclear decorin knockdown significantly reduced IL-8 and IL8-dependent migration, invasion and angiogenesis in these cells. Since toll-like receptor (TLR) signalling leads to IL-8 production we examined here if these receptors play a role in decorin silencing mediated reduction in IL-8 levels. We have used immunological and molecular techniques to study toll-like receptors involvement in attenuated IL-8 production in nuclear decorin silenced (stable knockdown) oral mucosal dysplastic keratinocytes and squamous carcinoma cells. We show that nuclear decorin silenced DOK and SCC-25 cells show marked diminution of TLR5 mRNA and protein expression compared with respective controls that translated into loss of function in response to appropriate TLR ligand. In these mucosal oral epithelia, decorin stable knockdown significantly down-regulated IL-8 production following activation with TLR5 ligand flagellin. These data suggest that decorin silencing interferes with IL-8 production, in part, by altering TLR5 expression and signaling in dysplastic and malignant oral epithelia. This study highlights the significance of TLR5 expression and signaling in mucosal cancers.

Supersaturated Calcium Phosphate Rinse vs. Standard of Care for Mitigating Mucositis in Head and Neck Chemoradiation

Introduction: Oral mucositis (OM) can have a significant impact on patients’ quality of life, pain and treatment costs. Almost all patients receiving head and neck chemoradiation develop OM. Patients and Methods: Twenty patients were evaluated retrospectively for OM when undergoing head and neck chemoradiation. The control, soda/salt rinse, was compared to a powdered supersaturated calcium phosphate rinse (SSCPR), SalivaMAX. Results: The SSCPR group experienced a delay in the onset of OM, which was not statistically significant, and a marked reduction in peak OM that was statistically significant (p > 0.001). Conclusion: This retrospective study demonstrates that a powdered SSCPR is a safe and effective method of oral mucositis mitigation.

Expression of MMP-1 in the Scar Tissue of Skin and Oral Mucosa

[Objectives] To investigate expression of MMP-1 in the scar tissue of skin and oral mucosa,and to explore if there is the significance of MMP-1 in the scar of skin and oral mucosa.[Methods]All samples were collected from surgical postoperative soft tissue from Department of Oral and Maxillofacial Surgery and Plastic Surgery in the Affiliated Qingdao Hiser Medical Center of Qingdao University Medical College,including 22 samples of dermal scar tissue,20 samples of normal skin tissue,and 13 samples of oral mucosal scar tissue,and 20 samples of normal oral mucosal tissue. HE staining was used to observe the morphology and collagen arrangement of fibroblasts in the scar tissue,the expression of MMP-1 in different tissue was observed by immunohistchemical staining. [Results] The positive expression rates of MMP-1 in skin scar tissue,oral mucousal scar tissue,normal skin tissue and normal mucosal tissue were 27. 27%,69. 23%,5. 00%,10. 00%. Comparison of positive expression of MMP-1 in skin scar tissue and oral mucosal scar tissue: the positive expression rate of MMP-1 in oral mucosal scar tissue was higher than that of MMP-1 in skin scar tissue,and the statistically significant difference was found between them( P < 0. 05).Comparison of positive expression of MMP-1 in skin scar tissue and normal skin tissue: the positive expression in skin scar tissue was higher than that in normal skin,and the statistically significant difference was found between them( P < 0. 05). Comparison of positive expression of MMP-1 in oral mucosal scar tissue and normal oral mucosal tissue: the positive expression rate of MMP-1 in oral mucosal scar tissue was higher than that in normal mucosal tissue,and the statistically significant difference was found between them( P < 0. 05). Comparison of positive expression of MMP-1 in normal oral mucosal tissue and normal skin tissue: the positive expression rate of MMP-1 in oral mucosal scar tissue was higher than that in normal mucosal tissue,and there was no statistically significant difference between them( P > 0. 05). [Conclusions] The positive expression of MMP-1 was different from that in the scar tissue of the oral mucosa,indicating that MMP-1 might be related to the severity of scar formation in different tissues.