Correlation between changes of oral bacterial flora and radiation-induced oral mucositis during radiotherapy for head and neck / 中华放射肿瘤学杂志

Objective:To investigate the correlation between the changes of oral bacterial flora during head and neck radiotherapy and radiation-induced oral mucositis (ROM).Methods:The oral bacterial samples of patients with nasopharyngeal carcinoma and accompanying family members were obtained before and at the end of radiotherapy and subjected to high-throughput sequencing. C57BL/6 mice were used to establish the ROM models. On the 9 th day after radiotherapy, oral bacterial samples were collected in the radiotherapy group and the negative control group. On the 3 rd, 5 th, 7 th, and 9 th days post-radiotherapy, the tongue tissues were obtained from another batch of mice in the negative control and radiotherapy groups. Inflammatory factors were detected with PCR and HE staining was performed. Results:The oral bacterial diversity of patients after radiotherapy significantly differed from that of patients before radiotherapy and their accompanying family members before and after radiotherapy in Observed species, Chao1, Simpson index (all P<0.05). There was a significant difference in Shannon index between the severe and mild ROM patients ( P=0.036). LEfSe analysis showed that patients with severe ROM had higher levels of g_ Streptococcus and f_ Streptococcus, and lower levels of f_ Familyxl, g_ Gemini and o_ Bacillus. The Simpson index and PCoA results in the oral bacterial samples significantly differed between the negative control and radiotherapy groups (all P<0.05). Conclusions:Radiotherapy can disrupt the balance of bacterial flora. The dysregulated oral bacterial flora is closely associated with the aggravation of ROM.

A prospective study to assess the predictive factors of radiation-induced oral mucositis in head-and-neck carcinoma and its impact on treatment outcome: Long-term results and lessons learned

Background: Radiation-induced oral mucositis (RIOM) is one of the major dose-limiting toxicities in head-and-neck cancer patients. It is due to normal tissue damage by radiation. It is a potential hazard to treatment delivery as it threatens to alter the therapeutic ratio. The radiation oncologist must find a way to balance between tumor control and sparing of normal mucosa to validate the age-old principle of cancer treatment. The onus lies on them to find the contributory factors to curb them accordingly. Objective: The objective of the study was as follows: (1) To find out the factors associated with RIOM in head-neck squamous cell cancer (HNSCC) and (2) to assess the impact of the RIOM on treatment outcome. Materials and Methods: This was a single-institutional, prospective, non-randomized, and open-label study. All cases were treated after informed consent and tumor board approval. This was an observational study with standard treatment according to the stage of the disease. Results: Tumor site, poor oral hygiene, modality of radiation, addiction, and fractionation appeared to be the significant predictive factors of RIOM in HNSCC. Conclusion: This study helps to identify the contributory factors and gives a comprehensive understanding of the same. More multi-institutional subsite-specific studies are warranted to validate the same.

Recommendation for an oral mucosal contouring method in nasopharyngeal carcinoma patients receiving tomotherapy / 中华放射肿瘤学杂志

Objective@#To evaluate the value of two oral mucosal contouring methods for predicting acute radiation-induced oral mucositis (A-ROM) in nasopharyngeal carcinoma (NPC) patients.@*Methods@#A total of 150 AJCC 7th stage Ⅱ-IVB NPCs receiving radical tomotherapy (TOMO) in Zhejiang Cancer Hospital from 2017 to 2019 were included in this prospective observational study. Oral cavity contour (OCC) and mucosal surface contour (MSC) were applied to delineate the oral mucosal structure. A-ROM grade was prospectively assessed and recorded weekly according to RTOG scoring criteria. The prediction value of two methods for A-ROM was statistically compared.@*Results@#The incidence rate of ≥3 grade A-ROM was 33.3%. In univariate analysis, V5, V10, V15, V45, V50, V55, V60, V65 and V70 of OCC and V5, V10, V50, V55, V60, V65, V70 and Dmean of MSC were significantly correlated with the risk of ≥3 grade A-ROM (all P<0.05). In binary logistic regression analysis, gender and smoking were significantly associated with the incidence of ≥3 grade A-ROM by using OCC (male vs. female: OR=0.141, 95%CI=0.037-0.538, P=0.004; smoking vs.non-smoking: OR=5.109, 95%CI=1.413-18.470, P=0.013). For MSC, gender, smoking, N stage and MSC- V55 were the independent predictors (male vs. female: OR=0.129, 95%CI=0.032-0.519, P=0.004; smoking vs.non-smoking: OR=4.448, 95%CI=1.224-16.164, P=0.023; N stage: OR=2.291, 95%CI=1.268-4.137, P=0.006; MSC-V55: OR=1.432, 95%CI=1.008-2.033, P=0.045). The cutoff value of MSC-V55 was 7.70%, the area under ROC curve was 0.754, the sensitivity and specificity were 0.680 and 0.740, retrospectively (all P<0.001).@*Conclusions@#Compared with OCC, MSC yields a higher prediction accuracy for the severity of A-ROM in nasopharyngeal carcinoma patients receiving TOMO treatment.

Recommendation for an oral mucosal contouring method in nasopharyngeal carcinoma patients receiving tomotherapy / 中华放射肿瘤学杂志

Objective To evaluate the value of two oral mucosal contouring methods for predicting acute radiation-induced oral mucositis (A-ROM) in nasopharyngeal carcinoma (NPC) patients.Methods A total of 150 AJCC 7th stage Ⅱ-ⅣB NPCs receiving radical tomotherapy (TOMO) in Zhejiang Cancer Hospital from 2017 to 2019 were included in this prospective observational study.Oral cavity contour (OCC) and mucosal surface contour (MSC) were applied to delineate the oral mucosal structure.A-ROM grade was prospectively assessed and recorded weekly according to RTOG scoring criteria.The prediction value of two methods for A-ROM was statistically compared.Results The incidence rate of ≥ 3 grade A-ROM was 33.3％.In univariate analysis,V5,V10,V15,V45,V50,V55,V60,V65 and V70 of OCC and V5,V10,V50,V55,V60,V65,V70 and Dmean of MSC were significantly correlated with the risk of ≥3 grade A-ROM (all P＜0.05).In binary logistic regression analysis,gender and smoking were significantly associated with the incidence of ≥3 grade A-ROM by using OCC (male vs.female:OR=0.141,95％CI=0.037-0.538,P=0.004;smoking vs.non-smoking:OR=5.109,95％CI=1.413-18.470,P=0.013).For MSC,gender,smoking,N stage and MSC-V55 were the independent predictors (male vs.female:OR=0.129,95％CI=0.032-0.519,P=0.004;smoking vs.non-smoking:OR=4.448,95％CI=1.224-16.164,P=0.023;N stage:OR=2.291,95％CI=1.268-4.137,P=0.006;MSC-V55:OR=1.432,95％CI=1.008-2.033,P=0.045).The cutoff value of MSC-V55 was 7.70％,the area under ROC curve was 0.754,the sensitivity and specificity were 0.680 and 0.740,retrospectively (all P＜0.001).Conclusions Compared with OCC,MSC yields a higher prediction accuracy for the severity of A-ROM in nasopharyngeal carcinoma patients receiving TOMO treatment.

Efficacy of Zinc Preparation for Radiation-induced Oral Mucositis in Head and Neck Cancers ：A Meta-analysis / 中国药房

OBJECTIVE： To systematically evaluate therapeutic efficacy of Zinc preparation for radiation-induced oral mucositis （ROM） in head and neck cancers， and to provide evidence-based reference for clinical treatment. METHODS： Retrieved from PubMed， Medline， Embase， the Cochrane library， CJFD，VIP and Wanfang database， RCTs about additional use of Zinc preparation （trial group） in adjunctive treatment of ROM in head and neck cancers base on routine treatment or blank control （control group） were collected during database establishment to Dec. 2018. After data extraction and quality evaluation with Cochrane system evaluator manual 5.1.0， Meta-analysis was carried out for the incidence of ROM within 2 weeks after medication， total incidence of ROM and the incidence of serve ROM by using Rev Man 5.3 statistical software. RESULTS： A total of 8 RCTs were included， involving 550 patients. Results of Meta-analysis showed that there was no statistical significance in the incidence of ROM within 2 weeks [OR＝0.55， 95％CI（0.26，1.17）， P＝0.12]， total incidence of ROM [OR＝0.59， 95％CI（0.08，4.39）， P＝0.60] or the incidence of serve ROM [OR＝0.58， 95％CI（0.23，1.47）， P＝0.25] between 2 group. CONCLUSIONS： Based on routine therapy or blank control， additional use of Zinc preparation can not reduce the incidence and control the development of ROM in head and neck cancers.

The protection of Xihuang Capsules against acute radiation-induced oral mucositis and its mechanisms / 中成药

AIM To explore the radioprotective function of Xihuang Capsules (Bovis Calculus artijactus,Moschus,Olibanum,Myrrha) in patients with acute radiation-induced oral mucositis and its mechanisms.METHODS Eighty patients with nasopharyngeal carcinoma undergone radiotherapy were randomized into two groups:treatment group (radiation plus Xihuang Capsules) and control group (radiation alone).The comparison of two groups in the onset and the tolerated dose of mucositis was made according to the acute radiation injury classification standard.The levels of TNF-α and IL-6 in saliva were detected by ELISA.RESULTS After the treatment with Xihuang Capsules,the onset of oral mucositis delayed significantly and the tolerated dose elevated markedly comparing with the control group (t =2.180,12.930,P ＜ 0.05).The morbidity rate of Ⅲ-N-degree of oral mucositis in the treatment group was lower than that of the control group at the dosage of 40 Gy and 70 Gy,respectively (Z =3.661,4.270,P ＜0.01).Furthermore,there was no difference in the levels of TNF-α and IL-6 in the pre-treatment in the two groups (t =1.010,1.469,P ＞ 0.05).With the increase in radiant dose,the levels of TNF-α and IL-6 in the two groups both elevated dramatically,and peaked at the dose of 40 Gy,but both levels in the treatment group were lower than those of the control group (t =8.305,6.069,P ＜ 0.05).When DT =70 Gy,the levels of TNF-α and IL-6 were lower than pre-radiation,and the levels of TNF-α and IL-6 in the treatment group were lower than those in the radiation alone group (t =3.835,2.488,P ＜ 0.05).CONCLUSION Xihuang Capsules can delay and reduce acute radiation-induced oral mucositis and improve radiation tolerated dose,so it may involve the release of TNF-oα and IL-6 in saliva.

Effect of concurrent chemoradiotherapy and radiotherapy alone on peripheral myeloid-derived suppressor and T regulatory cells in patients with nasopharyngeal cancer / 中华肿瘤杂志

Objective@#To investigate the percentage of myeloid-derived suppressor cells (MDSC) and T regulatory cells (Treg) in peripheral blood of nasopharyngeal cancer (NPC) patients undergoing concurrent chemoradiotherapy or radiotherapy alone.@*Methods@#Sixty NPC patients who received radiotherapy or concurrent chemoradiotherapy from September 2012 to November 2015 and 20 healthy individuals were included in this study. For the patients, the blood samples were collected at four time points: pre-radiation (Pre-RT), reaching a dose of 40 Gy (RT-40 Gy), finishing radiation (RT-finish) and three months after finishing radiation (3m-post-RT). Flow cytometry was used to evaluate the percentage of Treg (CD4+ CD25+ CD127low/-) and MDSC (HLA-DR-CD11b+ CD33+ ) cells in peripheral blood.@*Results@#Treg and MDSC cells were present in peripheral blood lymphocytes of healthy individuals as a percentage of (7.50±1.62)% and (1.08±0.48)%, respectively. The proportions of peripheral Treg cells in patients at Pre-RT, RT-40 Gy, RT-finish and 3m-post-RT time points were (8.42± 1.52)%, (9.10±1.57)%, (8.87±1.56)% and (7.31±1.43)%, respectively, showing a statistically significant difference between Pre-RT and the other groups (P<0.05). At Pre-RT point, the percentage of Treg cells in Stage Ⅲ-Ⅳ patients [(8.63±1.39)%] was higher than that in Stage Ⅰ-Ⅱ [(7.65±1.94)%, P=0.042]. Moreover, the proportions of peripheral MDSC cells in patients at Pre-RT, RT-40 Gy, RT-finish and 3m-post-RT time points were (2.14±1.21)%, (4.08±1.90)%, (3.76±1.31)% and (1.52±0.88)%, respectively. The percentages of MDSC cells at RT-40 Gy and RT-finish points were significantly higher than those at Pre-RT, while the percentage of MDSC cells at 3m-post-RT was significantly lower than those at Pre-RT (P<0.05). At Pre-RT point, the percentage of MDSC cells in Stage Ⅲ-Ⅳ patients [(2.25±1.26)%] was higher than that in Stage Ⅰ-Ⅱ [(1.35±0.66)%, P=0.007]. At RT-finish point, the proportions of MDSC and Treg cells in patients with Ⅲ-Ⅳ grade of radiation induced oral mucositis [(4.41±1.27)% and (9.91±1.23)%] were significantly higher than those in Ⅰ-Ⅱ grade patients [(3.15±1.04)% and (8.41±1.52)%, both of P<0.05].@*Conclusions@#The proportions of MDSC and Treg cells in initial treated NPC patients are higher than healthy individuals, and they are also associated with the tumor stages. During the concurrent chemoradiotherapy and radiation, the percentage of MDSC and Treg cells is elevated, suggesting a decreased immune activity. The increase of MDSC and Treg cells is related to radiation induced oral mucositis.

The efficacy of thalidomide on preventing and treating radiation-induced oral mucosi-tis in nasopharyngeal carcinoma / 中国肿瘤临床

Objective:To evaluate the efficacy and safety of thalidomide on preventing and treating radiation-induced oral mucositis (RIOM) in nasopharyngeal carcinoma (NPC). Methods:A total of 60 patients with NPC were randomly divided into treatment group and control group. The treatment group took thalidomide and gargled with mixture of saline+gentamycin+dexamethasone when ra-diotherapy started, and the control group gargled only with mixture of saline+gentamycin+dexamethasone. The time of occurrence and degree of RIOM in both groups were registered at the same time. Results:The incidence of RIOM in treatment group was lower than that in control group (P<0.05). For the incidence of 3 or 4 grade RIOM, the treatment group was also lower than the control group. No statistical difference in terms of objective response rate was found between the two groups (P>0.05). There was no statisti-cally significant difference between the treatment group and the control group in the oral average dose, V30, V35, V40, V45, V50, and V54 (P>0.05). There was no statistically significant difference between the treatment group and the control group in the use of nutri-tion agents, hormones and antibiotics (P>0.05). There was no statistical difference between the groups in the drowsiness, peripheral nerve toxicity, hematologic toxicity and gastrointestinal reaction (P>0.05). Conclusion:Thalidomide can reduce the incidence and se-verity of RIOM for radiotherapy of patients with NPC, which deserves clinic application.

An analysis on risk factors of radiation-induced oral mucositis in patients with nasopharyngeal carcinoma / 实用医学杂志

Objective To investigate the risk factors of radiation-induced oral mucositis (ROM) and to provide evidence for the prevention of ROM. Methods The severity of ROM was observed and recorded in 56 patients with nasopharyngeal carcinoma. The association of the severity of mucositis with age , sex, clinical stage, concurrent chemoradiotherapy, white blood cell count,BMI index, smoking, alcohol intake, and history of diabetes were assessed by using multivariate logistic regression analysis. Results The severity of ROM was significantly associated with a decrease in leucocyte count (P0.05). Conclusions Leukopenia was one of the risk factors for the development of ROM. In clinical pratice,leukopenia should be corrected in patients with bone marrow depression due to radiotherapy in a timely manner.

A Novel Synthetic Compound 3-Amino-3-(4-Fluoro-Phenyl)-1H-Quinoline-2,4-Dione (KR22332) Exerts a Radioprotective Effect via the Inhibition of Mitochondrial Dysfunction and Generation of Reactive Oxygen Species

PURPOSE: Acute side effects of radiation such as oral mucositis are observed in most patients. Although several potential radioprotective agents have been proposed, no effective agent has yet been identified. In this study, we investigated the effectiveness of synthetic compound 3-amino-3-(4-fluoro-phenyl)-1H-quinoline-2,4-dione (KR22332) as a radioprotective agent. MATERIALS AND METHODS: Cell viability, apoptosis, the generation of reactive oxygen species (ROS), mitochondrial membrane potential changes, and changes in apoptosis-related signaling were examined in human keratinocyte (HaCaT). RESULTS: KR22332 inhibited irradiation-induced apoptosis and intracellular ROS generation, and it markedly attenuated the changes in mitochondrial membrane potential in primary human keratinocytes. Moreover, KR22332 significantly reduced the protein expression levels of ataxia telangiectasia mutated protein, p53, and tumor necrosis factor (TNF)-alpha compared to significant increases observed after radiation treatment. CONCLUSION: KR22332 significantly inhibited radiation-induced apoptosis in human keratinocytes in vitro, indicating that it might be a safe and effective treatment for the prevention of radiation-induced mucositis.

A Novel Synthetic Compound 3-Amino-3-(4-Fluoro-Phenyl)-1H-Quinoline-2,4-Dione (KR22332) Exerts a Radioprotective Effect via the Inhibition of Mitochondrial Dysfunction and Generation of Reactive Oxygen Species

PURPOSE: Acute side effects of radiation such as oral mucositis are observed in most patients. Although several potential radioprotective agents have been proposed, no effective agent has yet been identified. In this study, we investigated the effectiveness of synthetic compound 3-amino-3-(4-fluoro-phenyl)-1H-quinoline-2,4-dione (KR22332) as a radioprotective agent. MATERIALS AND METHODS: Cell viability, apoptosis, the generation of reactive oxygen species (ROS), mitochondrial membrane potential changes, and changes in apoptosis-related signaling were examined in human keratinocyte (HaCaT). RESULTS: KR22332 inhibited irradiation-induced apoptosis and intracellular ROS generation, and it markedly attenuated the changes in mitochondrial membrane potential in primary human keratinocytes. Moreover, KR22332 significantly reduced the protein expression levels of ataxia telangiectasia mutated protein, p53, and tumor necrosis factor (TNF)-alpha compared to significant increases observed after radiation treatment. CONCLUSION: KR22332 significantly inhibited radiation-induced apoptosis in human keratinocytes in vitro, indicating that it might be a safe and effective treatment for the prevention of radiation-induced mucositis.

Investigation and Significance of Cytokines in Local Tissues of Radiation-induced Oral Mucositis in a Rat Model / 中山大学学报(医学科学版)

[Objective]This study was designed to explore the dynamic changes of cytokines in the local tissues of radiationinduced oral mucositis in a rat model.[methods]The rat oral mucosal tissues were obtained at 5 d,8 d,and 14 d after irradiation.which were received single X-ray irradiation of 30 Gy locally.RayBio~((R)) Rat Cytokine Array was applied to analyze the 19 cytokines.The mRNA levels of the 8 inflammatory-related cytokines were analyzed by real time-PCR.ELISA was employed to detect IL-1α,IFN-γ,and TIMP-1 protein levels.[Results]Cytokine array detection showed that cytokines such as Frac,IL-4,IL-6,IL-10,and TNF-α were down-regulated after irradiation.IL-1β,LIX,VEGF,and β-NGF were no obviously changed at the same time corse.The elevate range less than 2 fold of the CINC-2,GM-CGF,Leptin,MCP-1,and MIP-3α after irradiation were detected.The increasing range more than 2 fold of CINC-3,INF-γ,IL-1α,and TIMP-1 post irradiation were detected.The mRNA levels of anti-apoptosis,such as Bcl-2,and TNF-α,IL-6,VEGF,and IL-1β were low down,while the levels of promoting apoptosis cytokine such as Bax,and neutrophil recruitment associated cytokines,CINC,and TLR-9 were up-regulated after irradiation.The ELISA results of IL-1α,IFN-γ,and TIMP-1 were identical with the results of the two previom analyses.[Conclusion]The results of the three methods in the study should present evidences to prove each other.Some cytokines in the local lesion of oral mucositis during the initiate,development,and progression stages were blocked,while others were positively up-regulated to involving the control of the pathogensis of oral mucositis.